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Psoriasis: A view for the year 2000
Psoriasis: A View For The Year 2 0 0 0 Charles N. Ellis, MD, and Jonathan N. W. N. Barker, MD
We have learned a lot about psoriasis in the last decade, but we must await the future for a full understanding of the disorder. This article focuses on current research directions and where they are likely to lead and includes therapeutic approaches. To capture current thinking on psoriasis by leading researchers, we used electronic mail and requested that our colleagues contribute. A site on the World Wide Web enabled the scientists to submit their thoughts and to see the contributions of others. To our knowledge, this is the first article developed this way.
Immunology In the last two decades of the 20th century, research and therapy for psoriasis took a decidedly immunologic turn (Figure 1). Indeed, many of the therapies discussed in this article may act through immunologic mechanisms, even though this is sometimes unrecognized.
T Cell Activation A major trigger for this exploration into immunology was the dramatic efficacy of cyclosporine in treating psoriasis. A number of derivative drugs and drugs that act through similar mechanisms have been or are in development. These drugs bind to one of several intracellular proteins called immunophyllins; eventually these agents either inhibit the signal transduction that allows receptors on activated T cells to communicate with the nucleus or prevent T-cell response to interleukin-2 (IL-2). This results in reduced cellular production of IL-2 and inhibition of activation of T cells; other immunocytes and nonimmunologic cells may be affected as well. We term drugs that act in this way immunophyllin utilizing substances (IMUSes), which include cyclosporine, rapamycin (sirolimus), a new rapamycin derivative known as RAD, ascomycins, and tacrolimus. These drugs are in development for both topical and systemic use. T-cell activation signals are mediated at the nuclear level by a protein called nuclear factor of activated T cells (NF-AT). Inhibition of the action of this protein by use of small molecule pharmaceuticals could be useful in psoriasis. Curr Probl Dermatol, March~April 2000
Unfortunately cyclosporine and the macrolides tacrolimus and ascomycin are not particularly useful in treating psoriasis topically, although the macrolides are effective topically in atopic dermatitis. Future research will determine if the lack of efficacy is related to penetration or an inability of these drugs to affect psoriasis locally. The next decade will likely see additional macrolides and other drugs that interrupt T-cell signal transduction for the treatment of psoriasis. Topical ascomycins are only effective under occlusive dressings in psoriasis, and tacrolimus is not effective. It might be assumed that we are confronted with the 500-dalton rule for cutaneous penetration. Topical compounds with a molecular weight above 500 d will generally not penetrate the human stratum corneum barrier. Thus compounds such as ascomycin and tacrolimus, with molecular weights above 800 d, are not effective in psoriasis. Exceptions to the 500-d rule are treatment of the mucosa and of atopic dermatitis, which respond to these agents. We anticipate that within the next 5 or 10 years new low molecular weight cyclic immunosuppressive drugs will be introduced for topical treatment. A number of therapies for the treatment of cancer are also being directed toward psoriasis. Methotrexate is probably the best known of these agents, and it is currently in widespread use; analogues are undergoing research. Evidence continues to accumulate that methotrexate works in treating psoriasis by inhibiting the immune system, probably activated T cells; it is unlikely that it works by directly inhibiting keratinocyte proliferation. Activated T cells and other proliferating inflammatory leukocytes are undergoing active metabolism. Therefore agents that interfere with metabolic pathways may preferentially inhibit such cells. An example for potential future development is cladribine, a nucleoside analogue currently used to treat leukemias. Cladribine has already been shown to be effective in the treatment of psoriatic arthritis. Another approach is to inhibit cellular inosine monophosphate dehydrogenase with mycophenolate mofetil and other compounds in development. Administration of nucleoside analogues may inhibit proliferating 45
TARGETS FOR T-CELL IMMUNOTHERAPY 1. inhibit gene transcription:
43Y•
cyclosporine 2. inhibit protein translation: antisense molecule 3. prevent cytokine activity: anti-TNF-c~Ab 4. target cytokine receptors: blockade: anti-CD4 toxin: IL2-DAB T1-T2 switch: IL-10 5. inhibit target cell signaling:
CTLA-4 Ig LFA-3TIP
Fig
1. Schematic representation of targets for immunotherapy. Examples of mechanisms and representative examples of therapy are listed at right. Listed agents may have actions at stages before the end result shown and may have additional effects not shown. APC, antigen-presenting cell; IL, interleukin; TNF, tumor necrosis factor.
immunocytes. Leflunomide (Arava), a pyrimidine synthesis inhibitor, is used in treating rheumatoid arthritis. In a few patients with psoriasis, leflunomide has been effective and may have less lung and liver toxicity than methotrexate. Additionally, intracellular processes in inflammatory cells may be regulated by specific phosphodiesterases (eg, PDE4), by protein kinase C, and by NF-r~B; these molecules can be inhibited by agents in the research pipeline. Apoptosis is the death of cells without necrosis. Inducing apoptosis in certain cells, such as activated T cells or keratinocytes, could be useful in treating psoriasis. However, apoptotic cells may release cytokines that induce undesirable side effects if enough cells undergo apoptosis at once.
T Cell Surface Molecules A principal mechanism of activation of T cellsoccurs when antigen presenting cells and T cells interact. This involves the interaction of proteins on the surface of both T cells and antigen-presenting cells. Another activation signal comes through the IL-2 receptor on T cells. Blocking these cell-surface proteins represents a therapeutic approach using synthetic antibodies (monoclonal antibodies) and other recombinant peptides and fusion proteins. Agents in this class include LFA3-TIP (Amevive), infliximab (Remicade), daclizumab (Zenapax), and basiliximab (Simulect). Antibodies to the Tcell surface proteins CD3 or CD4 have been given to patients with psoriasis with success. Indeed, development proceeds on antibodies to vari46
ous surface molecules that are involved in T-cell activation and function. These antibodies include those to ICAM-3, CD45RB, CBL, CD40, CD-2, CD-3, CD-4, CD-28, B7-1, V~3, and V~13.1. So-called vaccines provide the immune system with fragments of cell surface molecules; the hope is that the patient will make antibodies against his or her own cell surface molecules on activated T cells, thereby inhibiting T cell activity. Recruitment of inflammatory T cells in the skin is mediated by the cutaneous lymphocyte antigen (CLA). Lesional activation of T cells takes place in the presence of dendritic antigen-presenting cells (APC) and as yet unknown antigenic stimuli. Future therapeutic interventions will focus on tolerance induction strategies using newly discovered psoriatic autoantigens (eg, by inducing tolerance in the APC or blocking of APC-T cell costimulation). Furthermore, blockade of T-cell recruitment by inhibiting the cell surface molecule CLA (eg, with fucosyltransferase VII) seems promising. Psoriasis can be treated with CTLA4Ig, a fusion protein that blocks B7-CD28 costimulation. There are humanized antibodies to CD25 (the high-affinity subunit of the IL-2 receptor) used in tissue transplantation settings. In a pilot study in patients with psoriasis, one of these, daclizumab, completely blocked CD25 on circulating T cells within 1 hour after administration, and that blockade was maintained for several weeks with repeated dosing in most patients. Although some patients had remarkable responses to this agent, this pilot study is inadequate to characterize the overall efficacy of CD25 antibodies. Two integrin subunits, C D l l a and CD18, define a functional receptor on T cells termed lymphocyte functional antigen-1 (LFA1). Blockade of CD1 la with an antibody prevents Tcell adhesion to ICAM-1. Although this has multiple effects on T-cell biology, one effect of LFA- 1 blockade is to prevent a costimulatory or accessory activation signal to T cells. Fusion proteins that specifically attack activated T cells by targeting surface protein markers of activation and incapacitate the T cell (eg, DAB-IL-2, which inserts diptheria toxin into activated T cells) appear to be too toxic for the treatment of psoriasis. However, further refinement may enable related drugs to be useful. It is possible that the initiating agent for the increased inflammation in psoriasis is a superantigen. Whether this represents an infection with some unknown bacteria that generates a superantigen or Curr Probl Dermatol, March/April 2000
whether a virus can act as a superantigen remains to be determined. In the next century, we may learn what incites the disease. In the meantime, interfering with T-cell interactions with putative superantigens may yield therapeutic approaches. It may be possible to identify keratinocyte proteins that share immunologically relevant epitopes with streptococcal proteins and that could serve as putative psoriasis antigens in a process of antigen mimicry. Whether the putative superantigen is a bacteria or bacterial product, a virus or viruslike particle (as some tantalizing evidence for human papillomavirns now implies), an autoantigen produced by patients themselves, or some other protein remains to be determined. The future may bring further investigation into oral tolerance therapies. The degree to which antigens stimulate T cells is determined by genetics and by the way the body experiences the antigen. Exposure through eating certain antigens may reduce the body's reaction to them. Alternatively, the antigen may be "infused" through the mucosa to induce tolerance.
Cytokine Effects Activated T cells release a number of cytokines that can stimulate keratinocyte proliferation and generate further inflammation. Activated T cells have been categorized into 2 classes, T1 and T2, depending on the cytokine profile that the cells elaborate. The T1 type of cell predominates in psoriasis, whereas T2 predominates in atopic dermatitis, although there is some overlap of the cell types as well as proportions of T cells that do not neatly fit into one of the two categories. Indeed, psoriasis lesion-derived T lymphocytes may have many TO cells and T2 cells as well. A subtype of T cells responsible for induction of keratinocyte growth expresses Tl-type cytokines IL-2, interferon- 7 (IFN-7) , and tumor necrosis factor-c~ (TNF-a) along with the T2type cytokine IL-5 in the absence of IL-4. Such cells might represent a therapeutic approach for the future. To the extent that T1 lymphocytes (lymphocytes that produce IFN- 7, IL-2, and TNF-cx) are overproduced in patients with psoriasis and that counterregulatory T2 lymphocytes (producing 112-4 and IL-10) are diminished, a viable new approach is to alter T-cell differentiation to decrease the number of T1 cells or to increase the number of T2 cells. A pilot study of recombinant IL- 11 has established anti-inflammatory effects of IL-11 in psoriatic plaques. This agent decreases production of IFN- 7 and TNF-o~ while increasing the production of IL-4. Tcell differentiation is altered by IL-11 in that fewer T1 Curr Probl Dermatol, March/April 2000
CONTROL OF ANGIOGENESIS ~l~ypoxia "~ ~..~flammation~ angiogenic factors:
VEGF
X~-@
other GFs
-- ~ @
angiostatic factors: thrombospondin angiostatin
MMPIs COMPONENTSOFANGIOGENESIS: * endothelial ceil proliferation " endothelial cell migration * basement membrane and
extracellularmatrixremode[ling 2. Angiogenesis is a complex process involving many steps and is controlled by a balance between angiogenic and angiostatic factors. Inflammation, such as found in psoriasis, plays a role in new blood vessel formation in psoriatic lesions. There are potential therapeutic advances in the inhibition of tissue remodeling (eg, with matrix metalloproteinase inhibitors [MMPIs]), that may be applicable to psoriasis. VEGF,Vascular endothelial growth factor; GFs, growth factors Fig
cells and more T2 cells develop during treatment with this cytoldne over a 2-month period. Thus administration of a cytokine can alter T1 vs T2 T-cell differentiation in conjunction with disease improvement. Another cytokine therapy that is quite interesting is IL-10. T2 cells that produce IL-10 are decreased in psoriatic plaques relative to circulating T cells. There are now several reports of improvement of psoriasis through administration of IL-10, a T2 cytokine. IL-10 appears to help to correct the imbalance of T1 to T2 cytokines present in psoriasis. In theory, administering IL-4, another T2 cytokine, might have similar action. Other examples of cytokine manipulation are monoclonal antibodies to IL-8 and amphiregulin, proinflammatory cytokines from keratinocytes found in psoriasis. Because cytokines and antibodies to them can be synthesized and given to patients with psoriasis, using cytokines for their natural effects may prove to be a rich area of drug development. Fumaric acid esters inhibit keratinocyte proliferation, reduce the expression of adhesion molecules on endothelial cells, and may switch T cells from a T1like cytokine secretion pattern to a T2-1ike one. Interestingly, administering a heat-killed preparation of Mycobacterium vaccae (SRL-172) induces a transient T1 response that may cause a compensatory T2 response; the preparation may benefit patients with psoriasis. Cytokines from the family of epidermal growth factors, including epidermal growth factor and transform47
ing growth factor-a, are increased in psoriasis and may be stimulating keratinocyte proliferation. Not only are these cytokines or their receptors targets for inhibition or neutralization, but so is TNF-~, another proinflammatory mediator. TNF-o~ antagonists include soluble TNF-~x receptors that "soak up" excess TNF-a (Enbrel) and monoclonal antibodies to TNF-a (Remicade, CDP571). Enbrel and Remicade have shown positive results in rheumatoid arthritis and could be useful in psoriasis. Thalidomide and its derivatives (IMiDs) and SelCIDs (CDC801) also inhibit TNF-c¢ and other cytokines. Even mast cell products, such as tryptase, have been associated with psoriasis and thus represent potential for therapeutic inhibition. Other locally active inflammatory mediators include the prostaglandins and leukotrienes. Pharmaceutical development includes inhibitors of the phospholipase and 5-1ipoxygenase enzymes that produce prostaglandins and leukotrienes and administration of anti-inflammatory prostaglandins.
Intracellular Nuclear Receptors Drugs that affect the activation and transcription of certain genes are important in psoriasis therapy. Many are related to a family of nuclear receptors that includes the retinoids and vitamin D (deltanoid) receptors. Major advances in psoriasis therapy will likely emerge from the development of new transcription modulating agents that inhibit inflammation and hyperproliferation of keratinocytes without the side effects of retinoids, steroids, or vitamin D analogues. The peroxisome proliferator-activated receptor (PPAR)-gamma may provide a new target for the development of antipsoriatic agents; ligands for this receptor may prove useful in both the topical and systemic treatment of psoriasis. Several topical deltanoids are in clinical trials. New topical retinoids and deltanoids are likely to be developed, and it is possible, but less likely, that the short-term future will bring new oral therapies in these classes.
Angiogenesis and Adhesion Angiogenesis in psoriasis is featured in the proliferation of the capillaries at the dermoepidermal junction. Angiogenesis is a major focus of research in treating cancer that, no doubt, will have a role in psoriasis as well. Vascular endothelial growth factor is increased in psoriatic skin; furthermore, an inhibitor of angiogenesis, thrombospondin-1, is decreased. Examples of therapeutic approaches against vascular proliferation in psoriasis are dexrazoxane, topical paclitaxel, and 48
matrixmetalloproteinase inhibitors. The angiostatins, which are inhibitors of angiogenesis, might also be of therapeutic benefit. (Figure 2). Along with angiogenesis, the adhesion molecules that are expressed by the endothelial cells, such as ICAM-1 and E-selecfin, are a target for research in therapy. These molecules slow down circulating immunocytes and eventually allow them to exit the circulation and move into the skin where inflammation occurs. Inhibiting the expression of these adhesion molecules or blocking their active sites on endothelial cells or immunocytes may reduce the ability for an inflammatory response to be generated in the skin.
Phototherapy Ultraviolet therapy continues to be a major treatment approach and has recently been improved with UVnarrow band (311-312 nm). It is likely that further refinements of ultraviolet approaches to psoriasis will be few and far between. Photodynamic therapy (PDT) involves the sequential administration of a photosensitizing drug followed by exposure of the skin to light; unlike psoralen-UV-A, visible light is used. PDT has immunomodulating effects making it suitable for psoriasis. Pilot clinical studies have demonstrated the potential safety and efficacy of using topical or systemic porphyrins in combination with either local or total body light exposure in psoriasis. Also in development as the photosensitizer is synthetic hypericin originally derived from the Hypericumgenus of plants, which includes St John's wort. One of the advantages of PDT over ultraviolet phototherapy is that PDT does not appear to be intrinsically carcinogenic, provided visible light is used for drug activation.
Nonpharmaceutical Approaches The psychologic aspects of psoriasis continue to be an important factor for individual patients. Stress may increase psoriasis through release of neuropeptides in the skin. The study of stress and its treatment will continue into the next century as an approach to helping psoriasis patients. Certain environmental agents (not known to trigger T cells directly as in the case of superantigens discussed above), such as climate or cigarette smoke, are under study and could represent a useful area of research. Nontraditional approaches for therapy, including meditation and herbal treatments, have government support for legitimate studies. This suggests that there Curr Probl Dermatol, March/April 2000
will likely be progress in these areas. It has been known that affecting the dermoepidermal junction, particularly if moderate to significant damage to the dermis occurs, will inhibit the development of psoriasis at that site. For example, a significant ultraviolet overdose or keratome removal of the epidermis with damage to the dermis often results in a long-lasting absence of psoriasis in that area. The excimer laser has been used successfully to obtain long-term remissions of limited plaques of psoriasis. Cryosurgery has been used as well. Although these therapies have limited value in the average psoriasis patient, if we reach a better understanding of the exact mechanism, perhaps therapies of greater practicability could be developed. It appears that damage of the dennoepidermal junction of sufficient degree to inhibit the "communication" between dermal cells and epidermal cells may prevent psoriasis. Sadly, however, until more effective and safe or curative therapies axe developed, further fraud and deception in the promotion of nonprescription psoriasis therapies will be likely. Research on the impact psoriasis has on patients (eg, quality of life studies) will help ensure that psoriasis treatments are made available in an increasingly managed medical care environment.
Genetics The new millennium will involve a better understanding of the genetics of psoriasis. Finding specific genes involved in the pathogenesis of psoriasis would lead to a basic understanding of the factors causing the disease. Furthermore, we may have a clearer view of why an individual or a family demonstrates a certain expression of psoriasis, including its severity. The epidemiology of psoriasis will be studied more directly by use of genetic analysis. The HLA associations with psoriasis should become even clearer as we understand the genes involved. Certain oncogenes that activate cell proliferation are overexpressed in psoriatic skin; others that stimulate differentiation, such as c-fos, are underexpressed. Eventually these findings may lead to new therapeutic approaches. After a gene is activated, its complementary messenger RNA is translated into specific proteins. Antisense molecules bind to messenger RNA and prevent the protein formation. Such a treatment could be specifically targeted if a crucial gene can be identified and the antisense molecule can reach its site of action. It is possible, given that psoriasis naturally waxes and wanes, that there are endogenous inhibitors that, if overexpressed, would lead to resolution of disease. Curt Probl Dermatol, March/April 2000
Having cells that selectively overexpress these genes in the skin, or perhaps more centrally, would generate "a natural" but specific therapy. These genes and their regulatory elements could be readministered when needed and might respond to the exogenous control of drugs that activate the "extra" genes. The first step will be identifying such genes or their protein products. Important genes within the major histocompatibility complex on chromosome 6p near HLA-C are involved in psoriasis. Delineation of these genes may lead to reclassification of psoriasis based on biologic processes. Identification of such disease-specific biologic pathways should result in better models for drug discovery and rationalization of drug therapy (pharmacogenomics). Diagnostic and prognostic testing may also be achievable. Whole genome scans indicate that genes not linked to the major histocompatibility loci are also critical in psoriasis susceptibility; this implies that nonimmune genes are also important. Elucidation of the function of these genes will represent a major step forward in our understanding of disease pathogenesis and development of model platforms for drug discovery.
Cost-Effectiveness The cost-effectiveness of various therapies will be an area of study in the new millennium. Although dermatologic agents generally fall below the "radar screen" of third-party payers, including the government, it will be important for new drugs to demonstrate that they have value and that scarce resources should be spent in their use. The quality of life of a patient with psoriasis is important to understand because this helps unify the need for these patients to receive adequate treatment. How to assess any individual patient's severity of psoriasis has been the subject of recent Food and Drug Administration meetings. In clinical research studies, investigators use global scoring, the psoriasis area and severity index (PASI), and a new Lattice System global score. For research purposes, computerized methods may be improved to the point of usefulness. In the future, the treating physician may have to use one of the scoring methods for documentation for insurance purposes.
Conclusion New approaches to the therapy of psoriasis will be based on an understanding of the immunologic processes integral to the pathomechanisms of this disease. Such a strategy will include inhibition of T-cell 49
activation via blockade of costimulation; direct inhibition of key transcription factors; prevention of T-cell trafficking to the skin (eg, by blockade of endothelialff-cell adhesion); cytokine-switching (eg, increasing local levels of T2 cytokines); and, more ambitiously, if the autoantigen in psoriasis is known, developing tolerance. Although present evidence points strongly at an immunologic basis, epidermal proliferation and differentiation cannot be forgotten as therapeutic targets. Vitamin D and A analogues may work through these mechanisms, and similar drugs are under research. In the next century, some therapies for psoriasis will come from specialty areas that have already generated antipsoriatic approaches, namely the fields of transplantation, oncology, rheumatology, and inflammatory bowel disease. The converse is also true; many drugs for these indications will be tested first in patients with psoriasis. By improving our basic understanding of all of these disorders, including psoriasis, we will achieve our goal: a safe, easy to administer, effective therapy for psoriasis. We thank the following for their contributions to this article: Kenneth M. Abrams, MD, Novartis Pharmaceuticals Corp, East Hanover, New Jersey Barbara S. Baker, PhD, Dermatology Research, Imperial College School of Medicine at St Mary's, London, United Kingdom Jan D. Bos, MD, PhD, University of Amsterdam, The Netherlands Kevin D. Cooper, MD, Department of Dermatology, Case Western Reserve University, Cleveland, Ohio Robert M. Day, PhD, Pharmaceutical Research Associates, Inc., Charlottesville, Virginia Madeleine Duvic, MD, Department of Dermatology, University of Texas, Houston, Texas Steven R. Feldman, MD, PhD, Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina Lionel Fry, MD, FRCP, Dermatology Research, Imperial College School of Medicine at St Mary's, London, United Kingdom Christopher E. M. Griffiths, MD, FRCP, Department of Dermatology, University of Manchester, Manchester, United Kingdom Tilo Henseler, MD, PhD, Department of Dermatology, University of Kiel, Kiel, Germany James G. Krneger, MD, PhD, Department of Dermatology, The RockefellerUniversity,New York, New York Gerald G. Krueger, MD, Department of Dermatology, University of Utah, Salt Lake City, Utah 50
Theodore W. Kurtz, MD, Department of Laboratory Medicine, University of California, San .Francisco, California Mark Lebwohl, MD, Department of Dermatology, Mt Sinai Medical School, New York, New York Harvey Lui, MD, FRCPC, Division of Dermatology, University of British Columbia, Vancouver, British Columbia, Canada Daniel B. Magilavy, MD, Biogen Corporation, Cambridge, Massachusetts Alan Menter, MD, Baylor Psoriasis Research Center, Dallas, Texas Ulrich Mrowietz, MD, Department of Dermatology, University of Kiel, Kiel, Germany Frank O. Nestle, MD, PD, Department of Dermatology, University of Zurich Hospital, Zurich, Switzerland Joerg C. Prinz, MD, Department of Dermatology, Ludwig-Maximilians-University of Munich, Munich, Germany Menno A. de Rie, MD, Department of Dermatology, University of Amsterdam, The Netherlands David E. Yocum, MD, Arizona Arthritis Center, Tuscon, Arizona Gail Zimmerman, National Psoriasis Foundation, Portland, Oregon
REFERENCES 1. RuhlmannA, NordheimA. Effects of the immunosuppressive drugs CsA and FK506 on intracellular signaling and gene regulation. Immunobiology1997;198:192-206. 2. ZonneveldIM, Rubins A, Jablonska S, Dobozy A, Ruzicka T, KindP, et al. Topical tacrolimusis not effectivein,chronic plaque psoriasis. Arch Dermatol 1998;134:1101-2. 3. MenssenA, TrommlerP, Vollmer S, SchendelD, Albert E, Gttrtler L, et al. Evidence for an antigen-specific cellular immune response in skin lesions of patients with psoriasis vulgaris. J Immunol 1996;155:4078-83. 4. Barna M, Snijdewint FGM, Van der Heijden FL, Bos JD, Kapsenberg ML. Characterizationof lesional psoriatic skin T lymphocyteclones. Acta Derm Venereol (Stockh) 1994; 186 Suppl:9-1t. 5. VollmerS, Menssen A, TrommlerP, SchendelD, Prinz JC. T lymphocytesderived from skin lesions of patients with psoriasis vulgaris express a noveleytokinepattern that is distinct from that of T helper type 1 and T helper type 2 ceils. Eur J Immunol 1994;24:2377-82. 6. MrowietzU, ChristophersE, AltmeyerP. Treatmentof psoriasis with fumaric acid esters. Results of a prospective multicenter study.Br J Dermatol 1997;138:456-60. 7. De Jong P, Bezemer AC, Zomerdijk TPL, Van de PouwKraan T, OttenhoffTHM, Nibbering PH. Selective stimulation of T helper 2 cytokineresponses by the anti-psoriasis agentmonomethylfumarate.Eur J Immunol1996;26:2067-74. 8. Rapp SR, ExumML, ReboussinDM, FeldmanSR, Fleischer A, Clark A. The physical,psychologicaland social impactof psoriasis. J Health Psychology1997;2:525-37. Curt Probl Dermatol, March/ApriL 2000
We have learned a lot about psoriasis in the last decade, but we must await the future for a full understanding of the disorder. This article focuses on current research directions and where they are likely to lead and includes therapeutic approaches. To capture current thinking on psoriasis by leading researchers, we used electronic mail and requested that our colleagues contribute. A site on the World Wide Web enabled the scientists to submit their thoughts and to see the contributions of others. To our knowledge, this is the first article developed this way.
Immunology In the last two decades of the 20th century, research and therapy for psoriasis took a decidedly immunologic turn (Figure 1). Indeed, many of the therapies discussed in this article may act through immunologic mechanisms, even though this is sometimes unrecognized.
T Cell Activation A major trigger for this exploration into immunology was the dramatic efficacy of cyclosporine in treating psoriasis. A number of derivative drugs and drugs that act through similar mechanisms have been or are in development. These drugs bind to one of several intracellular proteins called immunophyllins; eventually these agents either inhibit the signal transduction that allows receptors on activated T cells to communicate with the nucleus or prevent T-cell response to interleukin-2 (IL-2). This results in reduced cellular production of IL-2 and inhibition of activation of T cells; other immunocytes and nonimmunologic cells may be affected as well. We term drugs that act in this way immunophyllin utilizing substances (IMUSes), which include cyclosporine, rapamycin (sirolimus), a new rapamycin derivative known as RAD, ascomycins, and tacrolimus. These drugs are in development for both topical and systemic use. T-cell activation signals are mediated at the nuclear level by a protein called nuclear factor of activated T cells (NF-AT). Inhibition of the action of this protein by use of small molecule pharmaceuticals could be useful in psoriasis. Curr Probl Dermatol, March~April 2000
Unfortunately cyclosporine and the macrolides tacrolimus and ascomycin are not particularly useful in treating psoriasis topically, although the macrolides are effective topically in atopic dermatitis. Future research will determine if the lack of efficacy is related to penetration or an inability of these drugs to affect psoriasis locally. The next decade will likely see additional macrolides and other drugs that interrupt T-cell signal transduction for the treatment of psoriasis. Topical ascomycins are only effective under occlusive dressings in psoriasis, and tacrolimus is not effective. It might be assumed that we are confronted with the 500-dalton rule for cutaneous penetration. Topical compounds with a molecular weight above 500 d will generally not penetrate the human stratum corneum barrier. Thus compounds such as ascomycin and tacrolimus, with molecular weights above 800 d, are not effective in psoriasis. Exceptions to the 500-d rule are treatment of the mucosa and of atopic dermatitis, which respond to these agents. We anticipate that within the next 5 or 10 years new low molecular weight cyclic immunosuppressive drugs will be introduced for topical treatment. A number of therapies for the treatment of cancer are also being directed toward psoriasis. Methotrexate is probably the best known of these agents, and it is currently in widespread use; analogues are undergoing research. Evidence continues to accumulate that methotrexate works in treating psoriasis by inhibiting the immune system, probably activated T cells; it is unlikely that it works by directly inhibiting keratinocyte proliferation. Activated T cells and other proliferating inflammatory leukocytes are undergoing active metabolism. Therefore agents that interfere with metabolic pathways may preferentially inhibit such cells. An example for potential future development is cladribine, a nucleoside analogue currently used to treat leukemias. Cladribine has already been shown to be effective in the treatment of psoriatic arthritis. Another approach is to inhibit cellular inosine monophosphate dehydrogenase with mycophenolate mofetil and other compounds in development. Administration of nucleoside analogues may inhibit proliferating 45
TARGETS FOR T-CELL IMMUNOTHERAPY 1. inhibit gene transcription:
43Y•
cyclosporine 2. inhibit protein translation: antisense molecule 3. prevent cytokine activity: anti-TNF-c~Ab 4. target cytokine receptors: blockade: anti-CD4 toxin: IL2-DAB T1-T2 switch: IL-10 5. inhibit target cell signaling:
CTLA-4 Ig LFA-3TIP
Fig
1. Schematic representation of targets for immunotherapy. Examples of mechanisms and representative examples of therapy are listed at right. Listed agents may have actions at stages before the end result shown and may have additional effects not shown. APC, antigen-presenting cell; IL, interleukin; TNF, tumor necrosis factor.
immunocytes. Leflunomide (Arava), a pyrimidine synthesis inhibitor, is used in treating rheumatoid arthritis. In a few patients with psoriasis, leflunomide has been effective and may have less lung and liver toxicity than methotrexate. Additionally, intracellular processes in inflammatory cells may be regulated by specific phosphodiesterases (eg, PDE4), by protein kinase C, and by NF-r~B; these molecules can be inhibited by agents in the research pipeline. Apoptosis is the death of cells without necrosis. Inducing apoptosis in certain cells, such as activated T cells or keratinocytes, could be useful in treating psoriasis. However, apoptotic cells may release cytokines that induce undesirable side effects if enough cells undergo apoptosis at once.
T Cell Surface Molecules A principal mechanism of activation of T cellsoccurs when antigen presenting cells and T cells interact. This involves the interaction of proteins on the surface of both T cells and antigen-presenting cells. Another activation signal comes through the IL-2 receptor on T cells. Blocking these cell-surface proteins represents a therapeutic approach using synthetic antibodies (monoclonal antibodies) and other recombinant peptides and fusion proteins. Agents in this class include LFA3-TIP (Amevive), infliximab (Remicade), daclizumab (Zenapax), and basiliximab (Simulect). Antibodies to the Tcell surface proteins CD3 or CD4 have been given to patients with psoriasis with success. Indeed, development proceeds on antibodies to vari46
ous surface molecules that are involved in T-cell activation and function. These antibodies include those to ICAM-3, CD45RB, CBL, CD40, CD-2, CD-3, CD-4, CD-28, B7-1, V~3, and V~13.1. So-called vaccines provide the immune system with fragments of cell surface molecules; the hope is that the patient will make antibodies against his or her own cell surface molecules on activated T cells, thereby inhibiting T cell activity. Recruitment of inflammatory T cells in the skin is mediated by the cutaneous lymphocyte antigen (CLA). Lesional activation of T cells takes place in the presence of dendritic antigen-presenting cells (APC) and as yet unknown antigenic stimuli. Future therapeutic interventions will focus on tolerance induction strategies using newly discovered psoriatic autoantigens (eg, by inducing tolerance in the APC or blocking of APC-T cell costimulation). Furthermore, blockade of T-cell recruitment by inhibiting the cell surface molecule CLA (eg, with fucosyltransferase VII) seems promising. Psoriasis can be treated with CTLA4Ig, a fusion protein that blocks B7-CD28 costimulation. There are humanized antibodies to CD25 (the high-affinity subunit of the IL-2 receptor) used in tissue transplantation settings. In a pilot study in patients with psoriasis, one of these, daclizumab, completely blocked CD25 on circulating T cells within 1 hour after administration, and that blockade was maintained for several weeks with repeated dosing in most patients. Although some patients had remarkable responses to this agent, this pilot study is inadequate to characterize the overall efficacy of CD25 antibodies. Two integrin subunits, C D l l a and CD18, define a functional receptor on T cells termed lymphocyte functional antigen-1 (LFA1). Blockade of CD1 la with an antibody prevents Tcell adhesion to ICAM-1. Although this has multiple effects on T-cell biology, one effect of LFA- 1 blockade is to prevent a costimulatory or accessory activation signal to T cells. Fusion proteins that specifically attack activated T cells by targeting surface protein markers of activation and incapacitate the T cell (eg, DAB-IL-2, which inserts diptheria toxin into activated T cells) appear to be too toxic for the treatment of psoriasis. However, further refinement may enable related drugs to be useful. It is possible that the initiating agent for the increased inflammation in psoriasis is a superantigen. Whether this represents an infection with some unknown bacteria that generates a superantigen or Curr Probl Dermatol, March/April 2000
whether a virus can act as a superantigen remains to be determined. In the next century, we may learn what incites the disease. In the meantime, interfering with T-cell interactions with putative superantigens may yield therapeutic approaches. It may be possible to identify keratinocyte proteins that share immunologically relevant epitopes with streptococcal proteins and that could serve as putative psoriasis antigens in a process of antigen mimicry. Whether the putative superantigen is a bacteria or bacterial product, a virus or viruslike particle (as some tantalizing evidence for human papillomavirns now implies), an autoantigen produced by patients themselves, or some other protein remains to be determined. The future may bring further investigation into oral tolerance therapies. The degree to which antigens stimulate T cells is determined by genetics and by the way the body experiences the antigen. Exposure through eating certain antigens may reduce the body's reaction to them. Alternatively, the antigen may be "infused" through the mucosa to induce tolerance.
Cytokine Effects Activated T cells release a number of cytokines that can stimulate keratinocyte proliferation and generate further inflammation. Activated T cells have been categorized into 2 classes, T1 and T2, depending on the cytokine profile that the cells elaborate. The T1 type of cell predominates in psoriasis, whereas T2 predominates in atopic dermatitis, although there is some overlap of the cell types as well as proportions of T cells that do not neatly fit into one of the two categories. Indeed, psoriasis lesion-derived T lymphocytes may have many TO cells and T2 cells as well. A subtype of T cells responsible for induction of keratinocyte growth expresses Tl-type cytokines IL-2, interferon- 7 (IFN-7) , and tumor necrosis factor-c~ (TNF-a) along with the T2type cytokine IL-5 in the absence of IL-4. Such cells might represent a therapeutic approach for the future. To the extent that T1 lymphocytes (lymphocytes that produce IFN- 7, IL-2, and TNF-cx) are overproduced in patients with psoriasis and that counterregulatory T2 lymphocytes (producing 112-4 and IL-10) are diminished, a viable new approach is to alter T-cell differentiation to decrease the number of T1 cells or to increase the number of T2 cells. A pilot study of recombinant IL- 11 has established anti-inflammatory effects of IL-11 in psoriatic plaques. This agent decreases production of IFN- 7 and TNF-o~ while increasing the production of IL-4. Tcell differentiation is altered by IL-11 in that fewer T1 Curr Probl Dermatol, March/April 2000
CONTROL OF ANGIOGENESIS ~l~ypoxia "~ ~..~flammation~ angiogenic factors:
VEGF
X~-@
other GFs
-- ~ @
angiostatic factors: thrombospondin angiostatin
MMPIs COMPONENTSOFANGIOGENESIS: * endothelial ceil proliferation " endothelial cell migration * basement membrane and
extracellularmatrixremode[ling 2. Angiogenesis is a complex process involving many steps and is controlled by a balance between angiogenic and angiostatic factors. Inflammation, such as found in psoriasis, plays a role in new blood vessel formation in psoriatic lesions. There are potential therapeutic advances in the inhibition of tissue remodeling (eg, with matrix metalloproteinase inhibitors [MMPIs]), that may be applicable to psoriasis. VEGF,Vascular endothelial growth factor; GFs, growth factors Fig
cells and more T2 cells develop during treatment with this cytoldne over a 2-month period. Thus administration of a cytokine can alter T1 vs T2 T-cell differentiation in conjunction with disease improvement. Another cytokine therapy that is quite interesting is IL-10. T2 cells that produce IL-10 are decreased in psoriatic plaques relative to circulating T cells. There are now several reports of improvement of psoriasis through administration of IL-10, a T2 cytokine. IL-10 appears to help to correct the imbalance of T1 to T2 cytokines present in psoriasis. In theory, administering IL-4, another T2 cytokine, might have similar action. Other examples of cytokine manipulation are monoclonal antibodies to IL-8 and amphiregulin, proinflammatory cytokines from keratinocytes found in psoriasis. Because cytokines and antibodies to them can be synthesized and given to patients with psoriasis, using cytokines for their natural effects may prove to be a rich area of drug development. Fumaric acid esters inhibit keratinocyte proliferation, reduce the expression of adhesion molecules on endothelial cells, and may switch T cells from a T1like cytokine secretion pattern to a T2-1ike one. Interestingly, administering a heat-killed preparation of Mycobacterium vaccae (SRL-172) induces a transient T1 response that may cause a compensatory T2 response; the preparation may benefit patients with psoriasis. Cytokines from the family of epidermal growth factors, including epidermal growth factor and transform47
ing growth factor-a, are increased in psoriasis and may be stimulating keratinocyte proliferation. Not only are these cytokines or their receptors targets for inhibition or neutralization, but so is TNF-~, another proinflammatory mediator. TNF-o~ antagonists include soluble TNF-~x receptors that "soak up" excess TNF-a (Enbrel) and monoclonal antibodies to TNF-a (Remicade, CDP571). Enbrel and Remicade have shown positive results in rheumatoid arthritis and could be useful in psoriasis. Thalidomide and its derivatives (IMiDs) and SelCIDs (CDC801) also inhibit TNF-c¢ and other cytokines. Even mast cell products, such as tryptase, have been associated with psoriasis and thus represent potential for therapeutic inhibition. Other locally active inflammatory mediators include the prostaglandins and leukotrienes. Pharmaceutical development includes inhibitors of the phospholipase and 5-1ipoxygenase enzymes that produce prostaglandins and leukotrienes and administration of anti-inflammatory prostaglandins.
Intracellular Nuclear Receptors Drugs that affect the activation and transcription of certain genes are important in psoriasis therapy. Many are related to a family of nuclear receptors that includes the retinoids and vitamin D (deltanoid) receptors. Major advances in psoriasis therapy will likely emerge from the development of new transcription modulating agents that inhibit inflammation and hyperproliferation of keratinocytes without the side effects of retinoids, steroids, or vitamin D analogues. The peroxisome proliferator-activated receptor (PPAR)-gamma may provide a new target for the development of antipsoriatic agents; ligands for this receptor may prove useful in both the topical and systemic treatment of psoriasis. Several topical deltanoids are in clinical trials. New topical retinoids and deltanoids are likely to be developed, and it is possible, but less likely, that the short-term future will bring new oral therapies in these classes.
Angiogenesis and Adhesion Angiogenesis in psoriasis is featured in the proliferation of the capillaries at the dermoepidermal junction. Angiogenesis is a major focus of research in treating cancer that, no doubt, will have a role in psoriasis as well. Vascular endothelial growth factor is increased in psoriatic skin; furthermore, an inhibitor of angiogenesis, thrombospondin-1, is decreased. Examples of therapeutic approaches against vascular proliferation in psoriasis are dexrazoxane, topical paclitaxel, and 48
matrixmetalloproteinase inhibitors. The angiostatins, which are inhibitors of angiogenesis, might also be of therapeutic benefit. (Figure 2). Along with angiogenesis, the adhesion molecules that are expressed by the endothelial cells, such as ICAM-1 and E-selecfin, are a target for research in therapy. These molecules slow down circulating immunocytes and eventually allow them to exit the circulation and move into the skin where inflammation occurs. Inhibiting the expression of these adhesion molecules or blocking their active sites on endothelial cells or immunocytes may reduce the ability for an inflammatory response to be generated in the skin.
Phototherapy Ultraviolet therapy continues to be a major treatment approach and has recently been improved with UVnarrow band (311-312 nm). It is likely that further refinements of ultraviolet approaches to psoriasis will be few and far between. Photodynamic therapy (PDT) involves the sequential administration of a photosensitizing drug followed by exposure of the skin to light; unlike psoralen-UV-A, visible light is used. PDT has immunomodulating effects making it suitable for psoriasis. Pilot clinical studies have demonstrated the potential safety and efficacy of using topical or systemic porphyrins in combination with either local or total body light exposure in psoriasis. Also in development as the photosensitizer is synthetic hypericin originally derived from the Hypericumgenus of plants, which includes St John's wort. One of the advantages of PDT over ultraviolet phototherapy is that PDT does not appear to be intrinsically carcinogenic, provided visible light is used for drug activation.
Nonpharmaceutical Approaches The psychologic aspects of psoriasis continue to be an important factor for individual patients. Stress may increase psoriasis through release of neuropeptides in the skin. The study of stress and its treatment will continue into the next century as an approach to helping psoriasis patients. Certain environmental agents (not known to trigger T cells directly as in the case of superantigens discussed above), such as climate or cigarette smoke, are under study and could represent a useful area of research. Nontraditional approaches for therapy, including meditation and herbal treatments, have government support for legitimate studies. This suggests that there Curr Probl Dermatol, March/April 2000
will likely be progress in these areas. It has been known that affecting the dermoepidermal junction, particularly if moderate to significant damage to the dermis occurs, will inhibit the development of psoriasis at that site. For example, a significant ultraviolet overdose or keratome removal of the epidermis with damage to the dermis often results in a long-lasting absence of psoriasis in that area. The excimer laser has been used successfully to obtain long-term remissions of limited plaques of psoriasis. Cryosurgery has been used as well. Although these therapies have limited value in the average psoriasis patient, if we reach a better understanding of the exact mechanism, perhaps therapies of greater practicability could be developed. It appears that damage of the dennoepidermal junction of sufficient degree to inhibit the "communication" between dermal cells and epidermal cells may prevent psoriasis. Sadly, however, until more effective and safe or curative therapies axe developed, further fraud and deception in the promotion of nonprescription psoriasis therapies will be likely. Research on the impact psoriasis has on patients (eg, quality of life studies) will help ensure that psoriasis treatments are made available in an increasingly managed medical care environment.
Genetics The new millennium will involve a better understanding of the genetics of psoriasis. Finding specific genes involved in the pathogenesis of psoriasis would lead to a basic understanding of the factors causing the disease. Furthermore, we may have a clearer view of why an individual or a family demonstrates a certain expression of psoriasis, including its severity. The epidemiology of psoriasis will be studied more directly by use of genetic analysis. The HLA associations with psoriasis should become even clearer as we understand the genes involved. Certain oncogenes that activate cell proliferation are overexpressed in psoriatic skin; others that stimulate differentiation, such as c-fos, are underexpressed. Eventually these findings may lead to new therapeutic approaches. After a gene is activated, its complementary messenger RNA is translated into specific proteins. Antisense molecules bind to messenger RNA and prevent the protein formation. Such a treatment could be specifically targeted if a crucial gene can be identified and the antisense molecule can reach its site of action. It is possible, given that psoriasis naturally waxes and wanes, that there are endogenous inhibitors that, if overexpressed, would lead to resolution of disease. Curt Probl Dermatol, March/April 2000
Having cells that selectively overexpress these genes in the skin, or perhaps more centrally, would generate "a natural" but specific therapy. These genes and their regulatory elements could be readministered when needed and might respond to the exogenous control of drugs that activate the "extra" genes. The first step will be identifying such genes or their protein products. Important genes within the major histocompatibility complex on chromosome 6p near HLA-C are involved in psoriasis. Delineation of these genes may lead to reclassification of psoriasis based on biologic processes. Identification of such disease-specific biologic pathways should result in better models for drug discovery and rationalization of drug therapy (pharmacogenomics). Diagnostic and prognostic testing may also be achievable. Whole genome scans indicate that genes not linked to the major histocompatibility loci are also critical in psoriasis susceptibility; this implies that nonimmune genes are also important. Elucidation of the function of these genes will represent a major step forward in our understanding of disease pathogenesis and development of model platforms for drug discovery.
Cost-Effectiveness The cost-effectiveness of various therapies will be an area of study in the new millennium. Although dermatologic agents generally fall below the "radar screen" of third-party payers, including the government, it will be important for new drugs to demonstrate that they have value and that scarce resources should be spent in their use. The quality of life of a patient with psoriasis is important to understand because this helps unify the need for these patients to receive adequate treatment. How to assess any individual patient's severity of psoriasis has been the subject of recent Food and Drug Administration meetings. In clinical research studies, investigators use global scoring, the psoriasis area and severity index (PASI), and a new Lattice System global score. For research purposes, computerized methods may be improved to the point of usefulness. In the future, the treating physician may have to use one of the scoring methods for documentation for insurance purposes.
Conclusion New approaches to the therapy of psoriasis will be based on an understanding of the immunologic processes integral to the pathomechanisms of this disease. Such a strategy will include inhibition of T-cell 49
activation via blockade of costimulation; direct inhibition of key transcription factors; prevention of T-cell trafficking to the skin (eg, by blockade of endothelialff-cell adhesion); cytokine-switching (eg, increasing local levels of T2 cytokines); and, more ambitiously, if the autoantigen in psoriasis is known, developing tolerance. Although present evidence points strongly at an immunologic basis, epidermal proliferation and differentiation cannot be forgotten as therapeutic targets. Vitamin D and A analogues may work through these mechanisms, and similar drugs are under research. In the next century, some therapies for psoriasis will come from specialty areas that have already generated antipsoriatic approaches, namely the fields of transplantation, oncology, rheumatology, and inflammatory bowel disease. The converse is also true; many drugs for these indications will be tested first in patients with psoriasis. By improving our basic understanding of all of these disorders, including psoriasis, we will achieve our goal: a safe, easy to administer, effective therapy for psoriasis. We thank the following for their contributions to this article: Kenneth M. Abrams, MD, Novartis Pharmaceuticals Corp, East Hanover, New Jersey Barbara S. Baker, PhD, Dermatology Research, Imperial College School of Medicine at St Mary's, London, United Kingdom Jan D. Bos, MD, PhD, University of Amsterdam, The Netherlands Kevin D. Cooper, MD, Department of Dermatology, Case Western Reserve University, Cleveland, Ohio Robert M. Day, PhD, Pharmaceutical Research Associates, Inc., Charlottesville, Virginia Madeleine Duvic, MD, Department of Dermatology, University of Texas, Houston, Texas Steven R. Feldman, MD, PhD, Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina Lionel Fry, MD, FRCP, Dermatology Research, Imperial College School of Medicine at St Mary's, London, United Kingdom Christopher E. M. Griffiths, MD, FRCP, Department of Dermatology, University of Manchester, Manchester, United Kingdom Tilo Henseler, MD, PhD, Department of Dermatology, University of Kiel, Kiel, Germany James G. Krneger, MD, PhD, Department of Dermatology, The RockefellerUniversity,New York, New York Gerald G. Krueger, MD, Department of Dermatology, University of Utah, Salt Lake City, Utah 50
Theodore W. Kurtz, MD, Department of Laboratory Medicine, University of California, San .Francisco, California Mark Lebwohl, MD, Department of Dermatology, Mt Sinai Medical School, New York, New York Harvey Lui, MD, FRCPC, Division of Dermatology, University of British Columbia, Vancouver, British Columbia, Canada Daniel B. Magilavy, MD, Biogen Corporation, Cambridge, Massachusetts Alan Menter, MD, Baylor Psoriasis Research Center, Dallas, Texas Ulrich Mrowietz, MD, Department of Dermatology, University of Kiel, Kiel, Germany Frank O. Nestle, MD, PD, Department of Dermatology, University of Zurich Hospital, Zurich, Switzerland Joerg C. Prinz, MD, Department of Dermatology, Ludwig-Maximilians-University of Munich, Munich, Germany Menno A. de Rie, MD, Department of Dermatology, University of Amsterdam, The Netherlands David E. Yocum, MD, Arizona Arthritis Center, Tuscon, Arizona Gail Zimmerman, National Psoriasis Foundation, Portland, Oregon
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