Psoriasis, a common inflammatory skin disorder, has receivedattention as a target for new pathogenesis-oriented biologictherapies. In this article, we review the genetic, clinical,and pathogenic aspects of psoriasis and discuss their implicationsfor new therapies.
Epidemiologic and Genetic Features
Though psoriasis is a common skin disease, its definition byFerdinand von Hebra as a distinct entity dates back only tothe year 1841, and estimates of its prevalence — around2 percent, according to standard textbooks — stem fromonly a few population-based studies. Perhaps the most comprehensivefield study was performed in the Faroe Islands, where 2.8 percentof the inhabitants were reported to be affected.1 This prevalencerate is higher than that in central Europe, where prevalenceis approximately 1.5 percent, according to a more recent analysis.2Ethnic factors also appear to influence the prevalence of psoriasis,which ranges from no cases in the Samoan population to 12 percentin Arctic Kasach'ye.2 The influence of ethnic factors is particularlyevident when one compares prevalence rates within the UnitedStates. The prevalence among blacks (0.45 to 0.7 percent)3 isfar lower than that in the remainder of the U.S. population(1.4 to 4.6 percent).4
Numerous family studies have provided compelling evidence ofa genetic predisposition to psoriasis, although the inheritancepattern is still unclear.5 The illness develops in as many ashalf of the siblings of persons with psoriasis when both parentsare affected, but prevalence falls to 16 percent when only oneparent has psoriasis and to 8 percent when neither parent isaffected.6 The concordance rate for monozygotic twins is around70 percent, as compared with some 20 percent for dizygotic twins,a finding that further supports the concept of genetic predisposition.7,8As many as 71 percent of patients with childhood psoriasis havea positive family history.9
Within the past decade, several putative loci for genetic susceptibilityto the disease have been reported on the basis of genome-widelinkage studies, but there has not been widespread replicationof the results — a problem that has also been encounteredin the investigation of other complex diseases.10,11 However,one locus in the major-histocompatibility-complex (MHC) regionon chromosome 6 has been replicated in several populations12,13(see Glossary for definitions of terms). This locus, termedpsoriasis susceptibility 1 (PSORS1), is considered the mostimportant susceptibility locus. On the basis of associationstudies of three tightly linked susceptibility alleles (HLA-Cw6,14HCR*WWCC,15 and the HLA-associated S gene16), PSORS1 appearsto be associated with up to 50 percent of cases of psoriasis.Other susceptibility loci are located on chromosomes 17q25 (PSORS2),174q34 (PSORS3),18 1q (PSORS4),19 3q21 (PSORS5),20 19p13 (PSORS6),21and 1p (PSORS7).22 Most recently, an additional gene locus forpsoriasis susceptibility has been discovered on chromosome 17q25.23This locus, a runt-related transcription factor 1 (RUNX1) binding-sitevariant, encodes for a gene involved in the development of bloodcells, including those of the immune system.
Clinical and Histopathological Features
People with psoriasis typically have sharply demarcated chronicerythematous plaques covered by silvery white scales, whichmost commonly appear on the elbows, knees, scalp, umbilicus,and lumbar area (Figure 1A to Figure 1D). An inverse type ofpsoriasis spares these sites and instead appears in intertriginousareas, where scaling is minimal (Figure 1E). Eruptive guttatepsoriasis, which may be the initial manifestation of the diseaseand is often preceded by streptococcal infection by two to threeweeks,24 exhibits small, disseminated erythematosquamous papulesand plaques (Figure 1B). Psoriatic diaper rash appears to bethe most common type of psoriasis in children under the ageof two years.9
The typical psoriatic lesion is a sharply demarcated erythematous plaque covered by silvery white scales, often appearing on the elbow (Panel A). Initial eruptions of psoriasis may exhibit a guttate distribution pattern and are often triggered by streptococcal infections (Panel B). In a dark-skinned patient, erythrodermic psoriasis (Panel C), a clinical subtype of the disease, affects the entire body surface. Psoriatic erythroderma may arise from any type of psoriasis. Scalp involvement is seen in approximately 50 percent of patients with psoriasis, and the lesions typically extend a short distance beyond the region covered by terminal hair (Panel D). Inverse psoriasis (Panel E) is located at intertriginous areas and usually shows only scant scaling. In patients with psoriasis vulgaris, small sterile pustules may develop (Panel F, which is a magnification of the periumbilical region from Panel B). Generalized pustular psoriasis may start from coalescing disseminated pustules on deeply erythematous skin (Panel G). Localized forms of psoriasis include acrodermatitis continua suppurativa, or Hallopeau's disease (Panel H, which shows the fingers of a patient with severe onychodystrophy). Approximately 5 to 20 percent of patients with psoriasis have psoriatic arthritis (Panel I). Nail involvement is frequent in patients with psoriasis, and mild cases are characterized by small pits and yellowish discoloration of the nail plate (Panel J). Psoriatic nail pits were recreated in a wax-model moulage manufactured approximately 100 years ago (Panel K, which is item 1766 from the collection of the Johann Wolfgang Goethe University, Frankfurt, Germany).
In addition to small pustules that may occur in lesions of psoriasisvulgaris, various forms of pustular psoriasis have been described(Figure 1F). Generalized pustular psoriasis (Figure 1G) is characterizedby disseminated deep-red erythematous areas and pustules, whichmay merge to extensive lakes of pus. In contrast, there aretwo localized variants termed palmoplantar pustulosis and acrodermatitiscontinua suppurativa (Figure 1H, depicting onychodystrophy inthe latter condition). Despite its wider clinical spectrum,pustular psoriasis is quite rare as compared with nonpustularforms. Both pustular and the more common vulgar forms may progressto psoriatic erythroderma affecting the entire body surface(Figure 1C).
Psoriatic arthritis is an extracutaneous manifestation thataffects at least 5 percent and perhaps as many as 20 percentof patients with psoriasis (Figure 1I).25,26 The nails are affectedin the majority of patients with psoriatic arthritis, but nailinvolvement can be seen in all types of psoriasis. The fingernailsare more frequently affected than are toenails (on average,in 50 percent of patients as compared with 35 percent), andlesions range from pits and yellowish discoloration (Figure 1Jand Figure 1K) to severe onychodystrophy, a typical complicationof acrodermatitis continua suppurativa (Figure 1H).25,26
For many patients, the symptoms of psoriasis improve in thesummer and worsen in the winter, reflecting the well-establishednotion that the course of the disease is influenced by variousenvironmental factors. Physical trauma may trigger psoriaticlesions at sites of injury (Koebner's phenomenon), possiblythrough the release of proinflammatory cytokines, the unmaskingof autoantigens, or both.27 In fact, some treatments for psoriasisthat have proinflammatory potential (e.g., anthralin and phototherapy)appear to trigger psoriasis if applied too aggressively —for example, in high initial doses.
Molecular mechanisms underlying drug-induced flares of psoriasisare incompletely understood. Mechanisms for certain medicationsare partially delineated. For example, beta-adrenergic blockersmay induce epidermal hyperproliferation associated with a decreaseof intraepidermal cyclic AMP; lithium may elevate proinflammatorycytokines, thereby stimulating cutaneous leukocyte recruitment;and chloroquine blocks epidermal transglutaminase, an enzymethat is pivotally involved in the terminal differentiation ofkeratinocytes.28
Infections, particularly streptococcal infections of the upperrespiratory tract, have long been recognized as triggers ofpsoriasis.24 In addition, exacerbation or even initial manifestationof psoriasis has been observed in patients infected with thehuman immunodeficiency virus (HIV). However, because of clinicalsimilarities, psoriasis in patients with HIV infection may bemisinterpreted as seborrheic eczema.29
Psoriatic skin exhibits pathological changes in most, if notall, cutaneous cell types. The typical erythematosquamous plaquecontains histopathological hallmark features that include hyperproliferationof epidermal keratinocytes and hyperkeratosis, as well as infiltrationof immunocytes along with angiogenesis, with resultant typicalthickening and scaling of the erythematous skin. Mitotic activityof basal keratinocytes is increased by as much as a factor of50 in psoriatic skin, so keratinocytes need only 3 to 5 daysin order to move from the basal layer to the cornified layer(instead of the normal 28 to 30 days). This dramatically shortenedmaturation time is accompanied by altered differentiation, reflectedby the focal absence of the granular layer of the epidermisand parakeratosis, or nuclei still present in the thickenedcornified layer (Figure 2A through 2D).
Figure 2. Complex Pathological Tissue Alterations in Psoriatic Skin.
As compared with normal skin (Panel A), the epidermis in psoriatic skin (Panel B) is characterized by dramatic histopathological alterations, including profound acanthosis (thickening of the viable cell layers) with elongation of epidermal rete ridges (arrowheads), marked hyperkeratosis (thickening of the cornified layer), loss of the granular layer, and parakeratosis (nuclei in the stratum corneum). In addition, dermal blood vessels are increased in number and size (by both angiogenesis and dilatation); they are contorted and reach up to locations directly underneath the epidermis (arrows). Finally, a mixed leukocytic infiltrate is seen in both dermis and epidermis. As a histopathological hallmark of psoriatic lesions, neutrophilic granulocytes transmigrate through the epidermis (Panel C, arrow) and form the telltale Munro microabscesses underneath the stratum corneum (Panel C, arrowhead). As the lesions progress, these microabscesses are transported to the upper layers of the stratum corneum, where they slough off (Panel D, arrow). (Panels A through D show staining with hematoxylin and eosin.) Focal expression of intercellular adhesion molecule 1 (ICAM-1) in psoriatic epidermis (Panel E) indicates the activation of keratinocytes. Immunostaining of CD3, a T-cell receptor–associated antigen, shows that abundant T lymphocytes are present in psoriatic skin within both the dermis and the epidermis (Panel F). The integrin E(CD103)7, an adhesion receptor that binds to epidermal E-cadherin, is expressed almost exclusively by intraepidermal T cells (Panel G). (Panels E through G are highlighted with an immunoperoxidase stain.) It is thought that ICAM-1, the E(CD103)7 integrin, and other adhesion receptors contribute to the recruitment of pathogenic lymphocytes to psoriatic skin.
Psoriatic epidermis demonstrates aberrant expression of antigensassociated with hyperproliferation, such as the heterodimerkeratin 6–keratin 16 and heat-shock proteins. In addition,induced expression of MHC class II antigens and intercellularadhesion molecule 1 (ICAM-1) is observed.4,30 These moleculesare involved in interactions with lymphocytes such as adhesionor antigen recognition (Figure 2E). Moreover, vascular endothelialcells are primed to take part in angiogenesis in psoriasis,and blood vessels that are associated with psoriatic lesionsbecome dilated and contorted, reaching directly beneath theepidermis in the dermal papillar regions (Figure 2B). The involvedvascular endothelial cells express increased levels of ICAM-1(CD54), E-selectin (CD62E), vascular-cell adhesion molecule1 (CD106), and MHC class II antigens, indicating activation.31Then a mixed inflammatory infiltrate that contains activatedCD3+ T lymphocytes within both the dermis and epidermis is evident(Figure 2F),32 within which CD4+ T cells are distributed randomly.In contrast, the majority of CD8+ T cells, some of which expressepithelial-specific adhesion receptors (Figure 2G),33 residepreferentially within the epidermis.34
Many T cells within psoriatic skin exhibit an activated phenotypecharacterized by increased expression of costimulatory moleculessuch as CD2, adhesion molecules including leukocyte-function–associatedantigen 1 (LFA-1) and cutaneous lymphocyte-associated antigen(CLA), or the high-affinity interleukin-2 receptor. Neutrophilslocalize to the dermis, migrate focally into the epidermis,and form Munro microabscesses, which become translocated upwardwithin the epidermal stratum corneum (Figure 2C and Figure 2D).35In addition, psoriatic skin contains an increased number ofdermal mast cells and dendritic cells.36
Immunopathogenesis
Psoriasis is an instructive model for studying interactionsof immigrating immunocytes with resident epithelial and mesenchymalcells. This disease vividly highlights the pathogenic importanceof T cells and simultaneously illustrates how advances in ourunderstanding of molecular immune mechanisms can be translatedinto innovative therapies.
Although many factors that contribute to the generation of psoriaticlesions remain obscure, compelling circumstantial and experimentalevidence suggests a primary T-lymphocyte–based immunopathogenesis(Figure 3).30 The response of psoriasis to treatment with compoundsthat act on lymphocytes, such as cyclosporine, first describedfor use in psoriasis in 1979, is an early example.38 More recently,other compounds specifically targeting T-cell functions werefound to alleviate psoriasis. These include interleukin-2 fusedto truncated diphtheria toxin (DAB389IL-2)39 and antibodiesdirected against CD2,40 CD11a,41,42 or, in some cases, CD4.43,44In addition, there is a possible linkage of the psoriasis-susceptibilitygene PSORS2 with a gene involved in the regulation of interleukin-2.17Furthermore, psoriasis may not recur after bone marrow transplantation(performed in order to treat disorders unrelated to psoriasis)from healthy donors45 or may develop for the first time afterbone marrow transplantation from a donor with psoriasis.46 Theaforementioned association of psoriasis with certain MHC alleles— such as HLA-B13, HLA-B17, HLA-Bw57, and HLA-Cw6 —also suggests a pathogenic role of T cells.4 Indeed, some investigatorshave reported that there is a restricted use of T-cell receptorvariable genes within psoriatic lesions, a finding that impliesantigen-specific T-cell responses.47 Although the pathogenicrelevance of this oligoclonal T-cell expansion is not entirelyclear,48 it is possible that the failure to demonstrate oligoclonalityin some cases of psoriasis is due, at least in part, to thecolonization of psoriatic lesions by bacteria that produce superantigen,triggering the T-cell receptor without using the variable antigen-recognitionsites.49 The permissive role of bacterial superantigens in thepathogenesis of psoriasis is well established.49 In addition,sequence similarities between streptococcal M peptides and humankeratins, such as keratin 17, led to the hypothesis that keratinocyteproteins function as autoantigens in psoriasis.50
Figure 3. Putative T-Cell Responses in the Pathogenesis of a Psoriatic Lesion.
To generate a cutaneous T-cell response, antigen-presenting cells (Langerhans' cells in the epidermis) take up and process autoantigens and migrate to the regional lymph nodes. There, they come in contact with naive T lymphocytes (CD45RA+). Within an immunologic synapse (inset), molecular interactions result in T-cell activation.37 According to the putative theory, antigen-presenting cells present processed antigen bound to major-histocompatibility-complex (MHC) molecules to the T-cell receptor (TCR). MHC class II molecules present antigen to CD4+ T cells, whereas MHC class I molecules present antigen to CD8+ T cells. Additional signals are transmitted through interactions of costimulatory molecules with their ligands such as CD2 with CD58, CD28 with either CD80 or CD86, or both. In addition, adhesive interactions (e.g., by integrins and their immunoglobulin superfamily ligands) also stabilize the immunologic synapse and transmit additional signals. Following the activating signals, T cells differentiate into CD45RO+ memory T cells and express skin-homing receptor cutaneous lymphocyte-associated antigen (CLA). Once activated, T cells (CD45RO+ and CLA+) reenter the circulation and preferentially extravasate at sites of cutaneous inflammation. In the skin, on encountering the respective antigen, T cells exert their effector functions, which include the secretion of proinflammatory cytokines. Psoriasis is characterized by a chronically persisting response in effector T cells. ICAM-1 denotes intercellular adhesion molecule 1.
The generation of psoriasis-like skin lesions has been describedin animal models, by a process based on T-cell dysregulationwithout prior epithelial abnormalities.51,52 In addition, therole of T lymphocytes as key effector cells is strongly supportedby work from various groups in xenotransplantation models. Injectionof activated T lymphocytes from patients with psoriasis intounaffected skin transplanted from the same patients onto SCID(severe combined immunodeficiency) mice resulted in the generationof psoriatic lesions in the animals.53,54,55 Although additionalrodent models support the prominent role of T lymphocytes, itis also clear that these T lymphocytes can trigger the diseaseonly in a susceptible environment, since these results are obtainedwith skin from psoriatic, but not from healthy, donors.56
Cytokines, Chemokines, and Adhesion Molecules
Psoriasis may serve as a model of a disease that clearly showsthe central role of cytokines and chemokines and the functionalinteraction of these proteins with adhesion molecules in therecruitment of tissue-specific lymphocytes.57,58 Cytokine dysregulationmay explain, at least in part, the complex tissue alterationsin psoriasis (Figure 4). Proinflammatory cytokines59,60,61,62induce the expression of adhesion molecules on endothelial cellsand keratinocytes, allowing them to interact with leukocytes.This results in leukocyte extravasation at the site of inflammation,along with migration through the cutaneous matrix toward theepidermis.63,64 Numerous studies have identified tumor necrosisfactor (TNF-) as a particularly relevant cytokine regulatingthis complex inflammatory cascade. Its key role is underlinedby the therapeutic efficacy of compounds that interfere withTNF- functions.41,65,66 Psoriatic skin is further characterizedby increased angioneogenesis in a milieu rich in proangiogenicfactors.31,67 Complementary to the up-regulation of proinflammatorycytokines, reduced levels of the antiinflammatory cytokine interleukin-10,along with the relative dominance of type 1 helper T (Th1) cytokines,such as interferon- and interleukin-2, add to a milieu withmediator imbalance.68,69,70 The exact mechanisms by which thesecytokines regulate the microenvironment that influences psoriasisneed further clarification.
The transition from normal skin to the full-fledged psoriatic lesion is orchestrated by complex interactions of various cytokines and chemokines. Proinflammatory cytokines are thought to account for many of the histopathological changes seen in psoriatic skin. For example, interferon- and tumor necrosis factor (TNF-) can stimulate the expression of major-histocompatibility-complex (MHC) class II molecules and intercellular adhesion molecule 1 (ICAM-1). Vascular endothelial growth factor (VEGF) and TNF- stimulate angiogenesis. At the same time, interleukin-1 activates mast cells, granulocyte–macrophage colony-stimulating factor (GM-CSF) activates neutrophils, nerve growth factor (NGF) stimulates the growth of cutaneous nerves, and interleukin-6 and transforming growth factor (TGF-) promote keratinocyte proliferation. TNF-, in particular, appears to affect the functions of many different cell types in psoriatic skin. Thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) are expressed by the cutaneous vasculature and contribute to the recruitment of CCR4+ T cells. Cutaneous T-cell–attracting chemokine (CTACK) contributes to epidermal recruitment of T cells expressing its receptor, CCR10. In addition, macrophage inflammatory protein 3 (MIP-3) colocalizes in psoriatic epidermis with epidermal T cells expressing its receptor, CCR6, and can be induced on keratinocytes by proinflammatory cytokines, such as TNF-. Another T-cell–attracting chemokine, monokine induced by interferon- (MIG), is expressed by endothelial cells and macrophages directly underneath the hyperplastic psoriatic epidermis. Since MIG can be induced by T-cell–derived interferon-, there is a microenvironmental T-cell–associated inflammation-boosting loop. This process may be augmented by RANTES (regulated on activation, normal T-cell expressed and secreted) and monocyte chemotactic protein 1 (MCP-1), both of which also attract mast cells to psoriatic skin. Within psoriatic scales, there is a high content of interleukin-8 and growth-related cytokine (GRO-), both of which are neutrophil-attracting chemokines that contribute to the formation of Munro microabscesses, a hallmark of psoriatic epidermis. Keratinocyte hyperproliferation in psoriatic skin also appears to be induced, at least in part, by interleukin-8 and GRO-.
Recent evidence strongly suggests that chemokines are pivotalfor the trafficking and compartmentalization of leukocytes inthe psoriatic disease process (Figure 4).58,71 The effector-T-cellpopulation that is putatively the most relevant in psoriasisis characterized by the expression of skin-homing receptor CLAand the CC chemokine receptor 4 (CCR4).72 Other chemokines thatare implicated in the recruitment of T cells into psoriaticplaques include CCL20 (macrophage inflammatory protein 3, orMIP-3),58 CCL27 (cutaneous T-cell–attracting chemokine,or CTACK),71 monokine induced by interferon- (MIG),73 or RANTES(regulated on activation, normal T-cell expressed and secreted),and monocyte chemotactic protein 1 (MCP-1).
It is thought that neutrophils, another leukocyte populationabundantly present in psoriatic infiltrates, are recruited bythe neutrophil-attracting chemokine interleukin-8 (CXCL8). However,this pathway is probably not the exclusive means of neutrophilrecruitment, since an interleukin-8–blocking monoclonalantibody had only modest efficacy in a clinical study.74
In addition to the mediators involved in leukocyte recruitmentand activation, substances such as neuropeptides appear to beinvolved in the pathogenesis of psoriasis. These include substanceP and nerve growth factor, along with its receptor, the p75neurotrophin receptor, and tyrosine kinase A.75,76 That neuropathogenicmechanisms contribute to the development of psoriasis is furthersuggested by the increase in terminal cutaneous nerves withinpsoriatic lesions. Finally, clinical observations, such as thesymmetric distribution pattern of psoriatic lesions and theresolution of psoriasis at sites of administration of localanesthesia, are currently interpreted as evidence of the intimateinvolvement of the nervous system in the pathogenesis of psoriasis.
As in other inflammatory disorders, leukocyte recruitment topsoriatic skin occurs in consecutive steps mediated by complexinteractions of cytokines, chemokines, and adhesion receptors.77,78Although psoriasis-specific steps have not been identified,this disease has served as a model for in-depth investigationsof several adhesion-molecule interactions that are of generalimportance in the generation of inflammatory reactions.41,42
The first step of leukocyte recruitment is the transition fromfree flow in the vascular lumen to a rolling motion along theendothelium of the vessel wall, mediated primarily by a familyof adhesion molecules called selectins.77,78,79,80 Activatedendothelial cells express P-selectin (CD62P) and E-selectin(CD62E).81 The pivotal role of selectins in leukocyte rollinghas been confirmed in many experimental approaches that interferewith their adhesive interactions.81 Selectin functions overlapto a considerable extent, as can be concluded from the efficacyof selectin-blocking strategies. A monoclonal antibody thatwas specifically directed against E-selectin failed to alleviatepsoriasis in a recent clinical trial, whereas less selectivecompounds, such as efomycine M, which inhibits both E-selectinand P-selectin, showed significant anti-psoriatic efficacy inanimal models.82,83
Endothelial cells express E-selectin, which can interact withspecific ligands expressed by T cells. These ligands are transmembraneglycoproteins bearing a special carbohydrate moiety, calledsialyl-LewisX, displayed on cell-surface proteins.81 T lymphocyteslocalizing to the skin express the sialyl-LewisX–bearingCLA,84 which is thought to confer the tissue selectivity ofthese cells, at least in part.85
Once rolling leukocytes are subject to activation by chemokines,they attach firmly to the endothelium through the interactionsbetween 2 integrins (e.g., LFA-1, or L2 integrin) and adhesionmolecules of the immunoglobulin superfamily, such as ICAM-1(CD54). Additional interactions occur between 1 integrins andtheir ligands, such as 41 integrin and vascular-cell adhesionmolecule 1. The importance of LFA-1 in T-cell recruitment intothe skin is highlighted by the antipsoriatic efficacy of efalizumab,a new monoclonal antibody directed against LFA-1.41,42
In contrast to the relatively well understood process of lymphocyteextravasation, little is known about the subsequent migrationthrough the cutaneous extracellular matrix and the processesdetermining the ultimate localization and arrest of lymphocyteswithin the epidermal compartment. The epidermis of psoriaticskin is characterized by induced expression of ICAM-1 (Figure 2E).63,86ICAM-1, induced by proinflammatory cytokines, enables activatedlymphocytes to attach through their surface molecules, suchas LFA-1.42 In addition, other adhesion molecules may contributeto epidermal T-cell localization.78 For example, the E(CD103)7integrin (Figure 2G), which binds to epidermal E-cadherin,87has been implicated in epidermal recruitment of CD8+ T cellsin psoriatic lesions.33,88 However, it is also possible thatlymphocytes are transported passively to the upper epidermallayers owing to the accelerated upward migration of keratinocytesin psoriasis. Overall, given the central role of T lymphocytesin the pathogenesis of psoriasis, agents that would influencethe function or recruitment of leukocytes are appealing therapeuticcompounds.89,90
Therapy
Most accepted treatments for psoriasis have been developed empiricallyor were found by chance. However, recent insights into the immunopathogenesisof psoriasis have further elucidated the mode of action of someaccepted compounds91,92 and have provided new treatment strategies.93,94The severity of the disease usually determines the therapeuticapproach. Approximately 70 to 80 percent of all patients withpsoriasis can be treated adequately with use of topical therapy.Mainly for practical reasons, the vitamin D3 analogues (calcipotrioland tacalcitol) and the topical retinoid tazarotene —all of which affect keratinocyte functions and the immune response— are in wider use than is either anthralin or coal tar.Since most of the compounds that have been mentioned may irritatedelicate areas of skin, topical corticosteroids are used incombination with those compounds, particularly in intertriginousareas.
In cases of moderate-to-severe psoriasis (e.g., affecting largesurface areas), the use of phototherapy, systemic drugs, orboth must be considered. Among the established regimens, varioustherapeutic methods may have distinct modes of action. For example,fumarates and cyclosporine are primarily immunosuppressive agents,whereas retinoids and methotrexate also target keratinocytefunctions. Rational combination treatments target inflammationas well as epidermal alterations and may provide improved efficacyand safety. Thus, combinations of topical vitamin D3 analogueswith phototherapy or systemic retinoids plus psoralen and ultravioletA phototherapy (RePUVA) are well-established treatment regimensfor psoriasis.
Psoriasis in children, in pregnant women, or in patients withthe acquired immunodeficiency syndrome may provide considerabletherapeutic challenges, arguably best handled by consultationwith a specialist. Likewise, severe nail involvement or pustularpsoriasis should be the province of the specialist.
Although most established treatment regimens are reasonablyeffective as short-term therapy for psoriasis, extended diseasecontrol is difficult to achieve because the safety profile ofmost therapeutic agents limits their long-term use.95 Anotherunmet medical need is for agents that can be applied easily,since application of various currently available agents is difficultand thus compliance may be problematic. More convenient preparationsimprove adherence to recommended regimens.96 Patients with severepsoriasis often become frustrated with the management of theirdisease and the perceived ineffectiveness of the therapies prescribed.97Studies have indicated that the impairment of the quality oflife caused by psoriasis equals or even exceeds that due toother major illnesses such as diabetes, rheumatoid arthritis,and cancer.4,98
As already noted, recent advances in psoriasis research haveprovided a sound platform for the rational design of new biologicagents and biologic-immune-response modifiers that specificallytarget key mechanisms of the pathogenesis of psoriasis.41 Threeof these agents — alefacept, efalizumab, and etanercept— are currently approved by the Food and Drug Administration(FDA) for the treatment of psoriasis; several others (e.g.,infliximab) are in the final phase of clinical development.The most promising compounds are monoclonal antibodies, cytokines,and fusion proteins. Three fundamental modes of action are beingexplored: decreasing the number of pathogenic T cells, blockingT-cell migration and adhesion, and antagonizing effector cytokines(Figure 5).
Figure 5. New Pathogenesis-Oriented Therapeutic Principles.
Five general therapeutic principles target the key pathogenic mechanisms of psoriasis. The first involves inhibition of T-cell activation through inhibition of molecules involved in the formation of the immunologic synapse (Panel A). The second principle is depletion of pathogenic T cells (Panel B). This has been achieved by targeting molecules expressed specifically by activated T cells, such as the high-affinity interleukin-2 receptor or CD4. The third approach involves inhibition of leukocyte recruitment to the inflamed skin — for example, by inhibiting key adhesion molecules such as selectins or certain integrins (Panel C). A prominent example is the use of efalizumab, a monoclonal antibody that interferes with adhesion mediated by leukocyte-function–associated antigen 1 (LFA-1). The fourth principle is functional inhibition of key inflammatory cytokines (Panel D). Perhaps the most important example is tumor necrosis factor (TNF-), the functions of which are targeted by several biologic agents, the monoclonal antibodies infliximab and adalimumab, and the fusion proteins etanercept and onercept. Finally, it is possible to induce an immune deviation to shift the cytokine milieu dominated by type 1 helper T (Th1) cells to a milieu weighted with type 2 helper T (Th2) cells, thus alleviating psoriasis. This has been demonstrated in principle for interleukin-10 and interleukin-4 (Panel E).
As demonstrated by antibody-mediated targeting of CD4 on helperT cells43,44,99 or by targeting of the T-cell–expressedinterleukin-2 receptor with an interleukin-2–diphtheriatoxin,39 psoriasis can be alleviated by decreasing the numberof pathogenic T cells. The first biologic agent approved bythe FDA for treating psoriasis was alefacept, a fusion proteinin which the binding site of leukocyte-function–associatedantigen 3 (LFA-3) and the human IgG Fc portion are combined.Alefacept binds to CD2 on activated T cells, thus impairingcostimulatory signals delivered by LFA-3 and (possibly the bestexplanation for the long-lasting effect in the subgroup of patientswho respond to the drug) inducing apoptosis in circulating memoryT cells.40
Interruption of the molecular cascade resulting in cutaneousrecruitment of pathogenic leukocytes has been achieved by efalizumab,a humanized monoclonal antibody that is directed against anextracellular epitope of the LFA-1 chain, which was approvedby the FDA for the treatment of psoriasis in October 2003.42Other substances, which include small-molecule compounds, arecurrently under development.78
A key cytokine in psoriasis (and in other inflammatory diseases)is TNF-, which can be functionally inhibited by the chimericantibody infliximab or by the recombinant human TNF-receptorfusion protein etanercept. Both agents competitively inhibitinteractions of TNF- with cell-surface receptors and show convincingefficacy in treating psoriasis.65,66 Shifting the immunologicmicroenvironment in psoriatic skin, dominated by Th1-type cytokinesthrough substitution of type 2 helper T-cell–type cytokines,such as interleukin-1069 and interleukin-4,70 has been reportedas effective in some cases of psoriasis.
Numerous other biologic agents and immune-response modifiersare under development; all of them use at least one of the mechanismsmentioned above.100 As a class, these compounds have the potentialto handle some of the unmet medical needs in the treatment ofpsoriasis.
Supported by a Rudolf Virchow Award and a research grant (Scho565/5-1) from the Deutsche Forschungsgemeinschaft (to Dr. Schön).
Dr. Schön reports having received lecture fees from Seronoand grant support from 3M Pharmaceuticals. Dr. Boehncke reportshaving received consulting and lecture fees from Serono, Biogen,and Wyeth and lecture fees from Schering AG.
We are indebted to Professor U. Mrowietz (University of Kiel,Kiel, Germany) for helpful discussions and critical proofreadingof the manuscript and to Professor C.E.M. Griffiths (Universityof Manchester, Manchester, United Kingdom) for a helpful suggestion.
Source Information
From the Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, and the Department of Dermatology, University of Würzburg, Würzburg (M.P.S.); and the Department of Dermatology, University of Frankfurt, Frankfurt (W.-H.B.) — both in Germany.
Address reprint requests to Dr. Schön at the Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine and Department of Dermatology, Julius Maximilians University, Versbacher Str. 9, 97078 Würzburg, Germany, or at michael.schoen{at}virchow.uni-wuerzburg.de.
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CC chemokines: A subfamily of small chemoattractant peptidesthat have two N-terminal cysteine residues adjacent to eachother.
Cutaneous lymphocyte-associated antigen (CLA): A selectin ligandbearing the sialyl-LewisX carbohydrate moiety; expressed preferentiallyby skin-homing lymphocytes.
CXC chemokines: A subgroup of leukocyte-attracting chemokineswith a different amino acid between the two N-terminal cysteineresidues.
Intercellular adhesion molecule 1 (ICAM-1): Also known as CD54,an adhesion molecule of the immunoglobulin superfamily functioningas a counterreceptor for adhesion molecules of the integrinfamily; expressed on endothelial cells and some activated epithelialcells.
Interferon-: A cytokine produced primarily by T lymphocytes,characteristic for immune responses dominated by type 1 helperT (Th1) cells, including psoriasis.
Leukocyte-function–associated antigen (LFA): CD11a–CD18,a heterodimeric adhesion molecule of the integrin family expressedby lymphocytes; binds to ICAM-1, ICAM-2, and ICAM-3.
Major-histocompatibility-complex (MHC) molecules: Surface moleculesimportant for antigen presentation to T lymphocytes.
PSORS: Psoriasis-susceptibility locus, one of several genomicsequences associated with psoriasis.
SCID mice: Mice with severe combined immunodeficiency due toa spontaneous mutation and lacking functional B and T lymphocytes;used for transplantation and immunologic transfer studies.
Transforming growth factor (TGF-): A cytokine involved in sometissue alterations in psoriatic skin.
Vascular cell adhesion molecule 1: Also known as CD106; a vascularadhesion molecule of the immunoglobulin superfamily, a counterreceptorfor the 41 integrin.
Vascular endothelial growth factor (VEGF): A key regulator ofangiogenesis, overexpressed in psoriatic skin.
Psoriasis
Madariaga M. G., Naldi L., Chatenoud L., Khan S., Schön M. P., Boehncke W.-H.
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(TNF-
and interleukin-2, add to a milieu with mediator imbalance.68,69,70 The exact mechanisms by which these cytokines regulate the microenvironment that influences psoriasis need further clarification. 
2 integrins (e.g., LFA-1, or 
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