New approaches to psoriasis treatment. A review
A. Godic
S U M M A R Y -
Psoriasis is one of the most frequent inflammatory skin disorders in Caucasians. It is genetically determined and often reveals autosomal dominant features. The inheritance seems to be polygenic, but the exact mechanisms are still not clear. Eight gene loci are reported in the literature as contributing to expression of psoriasis. They are designated as PSORS 1 to PSORS 8, the first one being the most important. During the last 10 years or so a number of immunologic mechanisms provoking psoriatic lesions have been reported, some authors even stress the autoimmune traits. Activated T lymphocytes seem to play the crucial role, but other immunologically competent cells and molecules are also relevant. Clinical studies have revealed that a substantial reduction of CD4 T lymphocytes in the dermis and of the CD8 in the epidermis essentially ameliorated the psoriatic lesions.
The new biologic preparations inhibit the T-cell activation and migration, interfere with the immune deviation or block the activity of inflammatory cytokines. Alefacept, efalizumab, etanerscept, infliximab and oprelevkin are discussed in detail.
Introduction
Psoriasis is one of the most frequent inflammatory skin disorders in Caucasians. It is a genetically determined disease that affects the skin, scalp and nails. It is characterized by sharply demarcated erythematous plaques with silvery scales, which appear typically on the knees, elbows, sacral region and scalp, but the entire skin may be involved. Nail changes include distal onycholysis, pitting and "oil spots". Clinically a spectrum of different subtypes may be observed: psoriasis vulgaris, guttate psoriasis, erythrodermic psoriasis, pustular pso-
riasis, inverse psoriasis, and sebopsoriasis. The prevalence of psoriasis is estimated to be 2% of Cocasian the Caucasian population and it may develop at any age (1).
Psoriatic arthritis occurs in 5-30% of patients with cutaneous psoriasis (1,2) and can appear in 10-15% of patients before involvement of the skin. It can be manifested as mono- and asymmetrical oligoarthritis, arthritis of the distal interphalangeal joints, rheumatoid arthritis-like changes, arthritis mutilans, and/or spondylitis and sacroileitis.
KEY
WORDS
psoriasis,
genetics,
immunologic
aspects,
treatment,
alefacept,
efalizumab,
oprelevkin,
etanercept,
infliximab
Figure 1. Signals for specific and nonspecific activation of T-lymphocytes. A simplified presentation.
nonspecific activation
SAg
APC MHC
TCR
f T cell ) CLA ^ E-selectin
C
Ende J E-selectirr
homing T cells into skin
specific activation
APC T cell B7-1 (CD80) |-
B7-2 (CD86)
LFA
ICAM-1
CD28
CD28
CD2
CTL 4
Legend:	
LFA	lymphocyte function antigen
ICAM	intracellular adhesion molecule
SAg	superantigen
APC	antigen presenting cell
MHC	major histocompatibility complex
TCR	T-cell receptor
CLA	cutaneous lymphocyte antigen
End c	endothelial cell
Histological characteristics of psoriasis are hyperkeratosis, parakeratosis, acanthosis of the epidermis, tortuous and dilated capillary vessels and an inflammatory infiltrate composed mainly of lymphocytes and is located in the upper dermis. Such pathology reflects the abnormal epidermal proliferation and differentiation as well as the deviated activation of the immune system.
Genetics
Based upon analyses of family pedigrees, a polygenic inheritance provides the best model for the complex genetics of psoriasis. Linkage studies have demonstrated several genetic loci potentially responsible for development of psoriasis (3). PSORS1 has been mapped to chromosome 6p21.3, and is considered to be the major gene locus involving psoriasis. The critical region appears to be a 300 kb interval around the centromere of class I major histocompatibility complex (MHC). Other gene loci linked to psoriasis are PSORS2 on chromosome 17q, PSORS3 on chromosome 4q, PSORS4 on chromosome 1q, PSORS5 on chromosome
3p, PSORS6 on chromosome 19p, and PSORS7 on chromosome 1p. The locus on chromosome 16q12-13, known also as PSORS8 has been shown to have linkage with both psoriasis and Chron's disease (4).
Immunology
As it has been mentioned ample data indicates the importance of genetics, but the immunologic mechanisms, however, seem to be responsible for the immediate development of skin lesions. Psoriasis is now recognized as the most prevalent T-cell mediated inflammatory disease in humans (5).
The Kobner phenomenon has inspired researchers to investigate the stratum corneum as a possible source of antigens responsible for a specific immune response in psoriasis (6). Although the presence of circulating anti-stratum corneum antibodies and deposits of im-munoglobulins and C3 in lesional epidermis were demonstrated some decades ago, the identity of stratum corneum antigens remains to be disclosed. Observations on the investigated subpopulations of T-lympho-
LFA 3
LFA 3
APC
LFA 3
LFA 3
LFA 3 binding site
Fc portion of IgG
Legend:
APC antigen presenting cell LFA lymphocyte function antigen
Figure 2. Sites of action of alefacept.
cytes and antigen presenting cells (APC) in psoriatic plaques suggest that a specific immunologic response and/or super antigen-induced activation of T-lympho-cytes are the major pathogenetic factors. Streptococcal
Figure 3. Sites of action of efalizumab.
antigens have also been suggested to activate T-lym-phocytes in psoriasis (7), but such an activation is less convincing in plaque psoriasis.
Several observations suggest that psoriasis is a T-lymphocyte-mediated autoimmune disease. T-lympho-cyte already predominate in the cell infiltrate in psori-atic plaques in early lesions (7). T-lymphocytes, both CD4+ and CD8+ cells, are activated (HLA DR+ and CD 25+). In the dermis the CD4+ cells predominate, while CD8+ cells prevail in the epidermis. One of the earliest events in the psoriatic plaques is the influx of activated CD4+ cells. In resolving plaques an influx of CD8+ cells predominates, while there is a decrease of CD4+ cells. CD4+ cells interact with APCs, expressing MHC class II antigens, while CD8+ cells interact with APCs, expressing MHC class I antigens. The induction of T-cell activation by psoriatic epidermal cells is highly dependent on the population of CD1a-DR+ dendritic cells (8), while CD1a+ Langerhans cells, HLA-DR+ keratinocytes and dermal dendrocytes might also be relevant APCs in psoriasis.
Activated T-lymphocytes produce two different patterns of cytokines: Th1 cells produce IL-2 and IF-y whereas Th2 cells produce IL-4, IL-5, and IL-10. Psoriasis can be considered as a Th1 dominant disease. Activated T-cells in the psoriatic plaques and other blood derived cells have been shown to secrete a series of cytokines which may account for many characteristics of the psoriatic lesion. TNF-a, IL-3, IL-6, GM-CSF and IF-y are responsible for epidermal proliferation, TNF-a has been linked to the production of skin-associated antileukoproteinase and P defensins by epidermal cells, and to IL-8 for neutrophil accumulation (9). On the other hand, IL-10 which is secreted by Th2 lymphocytes, has been shown to inhibit the production of Th1 cytokines. The interaction between integrins of blood derived cells and ICAM-1/VCAM-1 on endothelial cells of vessels in psoriatic plaques promotes cell migration to psoriatic plaques and is crucial in the pathogenesis of psoriasis (10).
Interactions between T-lymphocytes and antigen presenting cells
For a better understanding of the mechanisms involved in the biologic treatment a short outline of the interactions between T lymphocytes, antigen presenting cells and active molecules has to be given. For more detailed information see the article by JM Kruger (5).
APCs present antigens to T-lymphocytes causing their activation. Activation of T-lymphocytes is followed by clonal expansion of T cells' population in psoriatic plaques. It is believed that T-lymphocyte receptor rearrangements suggest that specific antigen stimulation is relevant in the pathogenesis of psoriasis (9,10). Antigens activate lymphocytes in two ways: specific and nonspecific. Streptococcal super antigens may bind in
ICAM-1
APC
CD11a subunit
resting T-cell
LFA-1
efalizumab
Legend:
APC	antigen presenting cell
LFA	lymphocyte function antigen
ICAM	intracellular adhesion molecule
infliximab (nonclonal antibody)
TNF-a
chimeric anti-TNF-a antibody
TNF-a receptor
etanercept (fusion protein)
__^ TNF-a
_TNF-a receptor (extracellular domain)
Fc-IgG
extracellular part
intracellular part
Figure 4. Mechanisms of action of etanercept and infliximab.
a nonspecific way to the MHC complex on one hand and with a variable region of the P-chain of the T-lym-phocyte on the other hand (9). Super antigens activate T-lymphocytes in a nonspecific way and induce the expression of cutaneous lymphocyte-antigen (CLA) on T-lymphocytes (11). CLA binds to E-selectin proteins on the endothelial cells resulting in a preferential homing of T-lymphocytes into the skin. In the process of activation three sets of signals between Langerhans cells and T cells take place: primary signals (e.g. TCR to MHC I or to MHC II), accessory signals (co stimulation) and proliferation and differentiation signals. Co stimulatory pathways between APC and the T-lympho-cyte are required for full T-lymphocyte activation. One of these pathways is LFA-3 on the APC and CD2 on the surface of the T cell resulting in T-lymphocyte activation. Another co stimulatory pathway is between CD80 and CD86 (B7 molecule) on the APC and CD28 or CTLA4 on the T-cell. CD28 transmits activation and CTLA4 inhibits T-lymphocyte activity (Fig. 1).
Established treatments for psoriasis
Topical and/or systemic treatments, UV irradiation as well as balneologic procedures are widely used. The therapeutist has to take into consideration the patho-genesis, the subtype of the disease, triggering factors and the patient's personality. The rather long-term management requires individualization of the therapy, reconciling the extent of the disease and the patient's per-
ception of the disease as well as the potential side effects of the specific medications.
Topical treatment
Emollients and baths are helpful in restoration of the stratum corneum barrier function, since it is disturbed in psoriasis and is characterized by an increased transepi-dermal water loss (12). At the beginning keratolytic agents should be administered for shedding the scales and for a better penetration of antipsoriatics are given (13). Other substances like urea, tar, selen disulfide, pyrithion zinc, tioxolon and sodium bituminosulfonate are used. Retinoids (14), vitamin D analogues (15), and corticosteroids (16,17) are also prescribed. New preparations are tacrolimus and pimecrolimus.
Systemic medications and photo(chemo)-therapy
Cyclosporine (18), retinoids (19,20), methotrexate (21,22,23), mycophenolate mofetil (24), fumaric acid derivatives (25), oral calcitriol (26), hydroxyurea (27), and 6-thioguanin (28), which suppress the T cells are still used. Psoriasis patients also tolerate well UV treatment, which can be administered as selective ultraviolet phototerapy (SUP), narrow band UVB (311-313 nm) phototherapy, balneophototherapy, and systemic, bath or topical photo chemotherapy (PUVA) (29,30,31). Photodynamic therapy (PDT) (32), 308-excimer laser therapy (33), bexarotene (34) and 4-hydroxilase inhibitors (35) are some of the newer therapeutic possibilities.
Biological approach
Knowledge of the immunopathogenetic processes inducing psoriasis has contributed to the development of new biologic therapeutic agents. These biologic agents are proteins that possess pharmacologic activity and can be extracted from animal tissue or synthesized through recombinant DNA techniques. Biologic molecules either mimic the actions of normal human proteins or they interact with circulating proteins or cellular receptors. There are three distinct types of molecules that have been developed for use in psoriasis and some other disorders: recombinant human proteins, monoclonal antibodies, and fusion proteins.
Recombinant human proteins are exact replicas of normal human proteins that have been developed through DNA combinations, and in physiological doses they exert specific effects (36). Monoclonal antibodies are chemically and immunologically homogeneous proteins that specifically bind to proteins on cell surface. Initially murine monoclonal antibodies were used, but patients frequently developed allergic responses to the foreign protein. Since recently the so called humanized antibodies are available (37): the specific binding site from a murine antibody is attached to the Fc portion of human immunoglobulin (38). Fusion proteins are molecules that combine sections of different proteins. The receptor domain of a human protein is fused to the constant region sequences of human IgG, thus the fusion protein has binding specificity for a particular ligand and is soluble in plasma. Two distinct types of fusion proteins are recognized: it may be combined with a toxin (39) or it may be similar to humanized monoclonal antibodies. In the last mentioned combination, fusion proteins use human receptors for proteins to confer specificity instead of using a mouse antibody binding site (38). Receptors are then bound to the Fc portion of human immunoglobulin in a similar manner to humanized monoclonal antibodies.
The mechanisms of action of biologic agents include four strategies: reduction of pathogenic T cells, inhibition of T-cell activation, immune deviation and blocking the activity of inflammatory cytokines.
Reduction of pathogenic T cells
The ideal strategy would be to reduce activated T cells responsible for induction of psoriasis, which produce Th1 cytokines (CD45RO+), without altering other immunologic processes (40). The advantage of such a strategy is a prolonged remission because it may be assumed that the involved T cells need time to repopulate the skin. A representative drug in this group is alefacept (LFA-3TIP, Amevive®). It is a fusion protein combining the binding site of lymphocyte function-associated antigen-3 (LFA-3) with the Fc portion of human IgG. This medication binds specifically to T cells expressing CD2, the natural
ligand of LFA-3. The CD2 is expressed maximally in T cells that have been activated and express CD45RO, the sign of a memory T-cell phenotype (Figure 2). These cells are most important for the spreading and persistence of psoriasis. Certain results show that psoriatic lesions as measured by Psoriasis Activity and Severity Index (PASI) (41), considering the baseline values, improve in 50-60% of patients by 50% and in 20-30% of patients by 75% (42). It was also proven that the mean duration of remission lasted eight months, which reflects the slow repopulation of the skin with native T cells (40).
Inhibition of T-cell activation and migration
Pathogenic cells in psoriasis are activated T-lympho-cytes. T-cell activation requires interactions between an APC (e.g. Langerhans cell) and a T cell (43) (referred to as signal 1 and 2.). APC presents a specific antigen to the T cell mediated through the MHC which associates with CD4 or CD8 on the T cell and ICAM-1 with LFA-1 (signal
I).	The T lymphocyte recognizes this antigen through the T-cell receptor (and signals through CD3). The cos-timulatory signal, referred as signal 2, is accomplished through the APC-T-cell interactions (CD80/CD86 with CD28 and LFA-3 with CD2) (44,45). Biologic agents interact with either signal 1 or 2 and may block the T-cell activation. One of the representative drugs in this group is efalizumab (Raptiva®, anti-CD11a). It is a humanized antibody which binds to CD11a on T cells, which is a part of LFA-1, thus blocking the binding to intracellular adhesion molecule-1 (ICAM-1) (Figure 3). The LFA-1 to ICAM-1 interaction is also important for T-cell adhesion to en-dothelial cells and prevents T-cell migration into the inflamed skin. Clinical studies demonstrated improvement of the PASI index in 62% of patients by 50%, while 30% of patients had a 75% improvement (5,42,46).
Deviation of a Th1 immune response
As mentioned before, the activated T cells in psori-atic plaques produce cytokines of the Th1 phenotype, which include IL-2 and IFN-y. On the other hand, cytokines produced by Th2 T cells (IL-4, IL-10 and IL-
II)	tend to reduce the activity of Th1 cells, which are most important in pathogenesis of psoriasis. Th2-type cytokines are important in the down-regulation of outgoing Th1 immune response. Such deviation of an immune response results in improvement of psoriasis (47). Oprelevkin, a recombinant form of human IL-11, induce immune deviation in psoriasis. The same effect is noticed when IL-10, an important Th2-type cytokine, is administered subcutaneously in psoriasis patients. There was a mean reduction of 55% in the PASI index in patients receiving recombinant human IL-10, the effect persisted several months after the last dose (48, 49).
Blocking the activity of cytokines
Biologic agents from this group of medications bind to secreted cytokines and thus interfere with the development of psoriasis. Tumor necrosis factor a (TNF-a) is a central cytokine for both the persistence of the immune response that maintains psoriasis and for the aberrant keratinocyte response (50). The anti-TNF-a agents etanercept and infliximab bind to TNF-a and inhibit its activity through two different mechanisms (Figure 4). Etanercept (Enbrel®) is a fusion protein using the extracellular domain of the TNF-a receptor to block the circulating TNFa. It is administered subcuta-neously and is approved for rheumatic and psoriatic arthritis. Infliximab (Remicade®) is a monoclonal antibody directed against human TNF-a and is given intravenously. In psoriatic arthritis trials with etanercept, there was a noticeable response in several patients with cutaneous lesions. Mean improvement in the PASI index was at least 46-50% (42). Likewise, a number of case reports and studies demonstrated an excellent response of psoriatic lesions to infliximab, with a more than 75% improvement in the PASI index (51,52).
It should be mentioned that additionally to the four mentioned substances, other similar substances are already available, while more are being developed.
Adverse effects of biological medications
Biologic agents are metabolized similarly to endogenous proteins, therefore severe drug reactions are unlikely. There are two major concerns with biologic therapy that should be addressed. Cytokine release syndrome (CRS) has been observed in solid organ transplant patients who were treated with OKT3, which is a humanized monoclonal antibody that binds to CD3, the
R E F E R E N C E S -
initial signaling step in the T-cell receptor. CRS evolves due to a rapid release of TNF-a and IFN-y (53,54). It is potentially life threatening, and is characterized by fever, hypotension, headache, skin rash, and abdominal symptoms (55). Immunosuppression is an additional concern. Current evidence indicates that the risk of im-munosuppression from biologic agents used in psoriasis exists. One has to consider its use carefully in patients at high risk for malignancy or with diabetes in whom the risk of an infection is increased.
The most common adverse reactions, usually associated with the first dose, are headache, fever, chills, nausea or myalgia. Before starting the treatment it is recommended that baseline laboratory tests are performed, including hepatitis and HIV serology and also the tuberculin skin test (56).
Conclusions
Knowledge of the pathogenesis and new treatment modalities of psoriasis have been substantially expanding during the last two decades. Psoriasis is now considered by many authors to be an autoimmune disease. New therapeutic modalities, especially biological immunomodulators, promise extremely good results, are relatively safe, easy to produce, and will come to take an important place in the future of psoriasis treatment. A certain restraint is probably justified concerning their possible long range effects on the immune system.
alefacept: (Amevive®, Biogen, Cambridge, MA, USA) efalizumab:(Raptiva®, Genentech, South San Francisco, CA, USA)
etanercept: (Enbrel®, Amgen, Seattle Washington, USA) infliximab: (Remicade®, Centocor, Malvern, PA, USA)
1.	Christophers E. Psoriasis - epidemiology and clinical spectrum. Clin Exp Dermatol 2001; 26: 314-20.
2.	Espinoza LR, Cuellor ML, Silveira LH. Psoriatic arthritis. Curr Opin Rheumatol 1992; 4: 470-8.
3.	Barker JNWN. Genetic aspects of psoriasis. Clin Exp Dermatol 2001; 26: 321-5.
4.	Nair RP, Hensler T, Jenisch S et al.vidence for two psoriasis susceptibility loci (HLA and 17q) and two no el candidate regions (16q and 20p) by genome wide scan. Hum Mol Genet 1997; 6: 1349-56.
5.	Krueger JG. The immunologic basis for treatment of psoriasis with new biologic agents. J Am Acad Dermatol 2002;46(1):1-23.
6.	Beutner EH, Jablonska S, Jarzabek CM, et al. Studies in immunodermatology. VI IF studies of autoantibodies to the stratum corneum and of in vivo fixed IgG in stratum corneum of psoriatic lesions. Int Arch Allergy Appl Immunol 1975; 48: 301-23.
7.	Kang S, Voorhees JJ. Immunopathogenesis. In: Van de Kerkhof PCM, ed. Textbook of psoriasis. Oxford, Blackwell Science, 1999: 106-18.
8.	Baadsgaard O, Gupta AK, Taylor RS, et al. Psoriatic epidermal cells demonstrate increased numbers and function of non-Langerhans antigen presenting cells. J Invest Dermatol 1989; 92: 190-5.
9.	Prinz JC. Psoriasis vulgaris, a sterile antibacterial skin reaction, mediated by cross-reactive T-cells? An immunological view on the pathophysiology of psoriasis. Clin Exp Dermatol 2001; 26: 326-32.
10.	Smith CH, Barker JNWN. Cell trafficking and role of adhesion molecules in psoriasis. In: van de Kerkhof, Bos JD, eds. Pathogenic aspects of psoriasis. New York, Elsevier 1995; 13: 151-60.
11.	Leung DYM, Gately M, Trumble A, et al. Bacterial superantigens induce T cell expression of the skin-selective homing receptor, the cutaneous lymphocyte-associated antigen (CLA). J Exp Med 1995; 191: 747.
12.	Baker CG. Moisturization: new methods to support time proven ingredients. Cosmet Toilet 1987; 102: 99-102.
13.	Huber C, Christopher E. Keratolytic effect of salicylic acid. Arch Dermatol Res 1977; 257: 293-7.
14.	Lewkaya DA, Sefton J, Krueger FF, et al. Safety and efficacy of a new retinoid gel in the treatment of psoriasis. J Invest Dermatol 1992; 98: 600.
15.	Van de Kerkhof PCM. Biological activity of vitamin D analogues in the skin, with special reference to antipsoriatic mechanisms. Br J Dermatol 1995; 132: 675-82.
16.	Hradil E, Lindström C, Müller H. Intermittent treatment of psoriasis with clobetasol propionate. Acta Derm Venereol 1978; 58: 373-3.
17.	Katz HI, Hien NT, Prower SE, et al. Betamethasone in optimized vehicle. Intermittent pulse dosing for extended maintenance treatment of psoriasis. Arch Dermatol 1987; 123: 1308-11.
18.	Timonen P, Friend O, Abeywickrama K, et al. Efficacy of low dose cyclosporin A in psoriasis: results of dose finding studies. Br J Dermatol 1990; 122: 33-40.
19.	Gollnick H, Bauer R, Brindley C, et al. Acitretin versus etretinate in psoriasis. Clinical and pharmacokinetic results of a German multicenter study. J Am Acad Dermatol 1988; 19: 458-69.
20.	Gollnick H, Zuan H, Ruzicka T, et al. Relapse rate of severe generalized psoriasis after treatment with acitretin or etretinate. Results of the first randomized double blind multicenter half-year follow-up study. Eur J Dermatol 1993; 3: 442-6.
21.	Van de Kerkhof PCM, Mali JWH. Methotrexate maintenance following ingram therapy in difficult psoriasis. Br J Dermatol 1982; 106: 623-7.
22.	Nyfors A. Benefits and adverse drug experiences during long-term methotrexate treatment of 248 patients. Danish Med Bull 1978; 25: 208-11.
23.	Zachariae E, Zachariae H. Methotrexate treatment of psoriatic arthritis. Acta Derm Venereol 1987; 67: 270-3.
24.	Grundmann-Kollman M, Korting HC, Behrens S, et al. Treatment of chronic plaque-stage psoriasis and psoriatic arthritis with mycophenolate mofetil. J Am Acad Dermatol 2000; 42: 835-7.
25.	Altmeyer PY, Mattheus U, Pawlak F, et al. Antipsoriatic effect of fumaric acid derivatives: results of a multicenter double-blind study in 100 patients. J Am Acad Dermatol 1994; 30: 977-81.
26.	Perez A, Raab R, Chen TC, et al. Safety and efficacy of oral calcitriol (1,25-dihydroxyvitamni D3) for the treatment of psoriasis. Br J Dermatol 1996; 134: 1070-8.
27.	Layton AM, Sheehan-Dove RA, Goodfild MJD, et al. Hydroxyurea in the management of therapy resistant psoriasis. Br J Dermatol 1989; 121: 647-53.
28.	Zackheim HS, Glogau RG, Fisher DA, et al. 6-thioguanine treatment of psoriasis. J Am Acad Dermatol 1994; 30: 452-8.
29.	Hönigsmann H. Phototherapy for psoriasis. Clin Exp Dermatol 2001; 6: 343-50.
30.	Parrish JA, Jaenicke KF. Action spectrum for phototherapy of psoriasis. J Invest Dermatol 1981; 76: 35962.
31.	Tanew A, Radakovic-Fijan S, Schemper M, et al. Narrow band UV-B phototherapy vs photochemotherapy in the treatment of chronic plaque-type psoriasis: a paired comparison study. Arch Dermatol 1999; 135: 51924.
32.	Boehncke WH, Elshorst-Schmidt T, Kaufmann R. Systemic photodynamic therapy is a safe and effective treatment for psoriasis. Arch Dermatol 2000; 136: 271-2.
33.	Bonis B, Kememy L, Dobozy A, et al. 308-nm UVB excimer lasers for psoriasis. Lancet 1997; 350: 1522.
34.	Smit J, de Jong E, van Hooijdonk C, et al. A multicenter phase II clinical and immunohistochemical trial of systemic bexarotene (Targetin) in psoriasis. J Invest Dermatol 2000; 114: 776.
35.	Dockx P, Decree J, Degreef H. Inhibition of the metabolism of endogenous retinoic acid as treatment for severe psoriasis: an open study with oral liarozole. Br J Dermatol 1995; 133: 426-32.
36.	Ryffel B. Safety of human recombinant proteins. Biomed Environ Sci 1997; 10: 65-72.
37.	Choy EH. Clinical pharmacology and therapeutic potential of monoclonal antibody treatment in rheumatoid arthritis. Drugs Aging 1998; 12: 139-48.
38.	Parren PW. Preparation of genetically engineered monoclonal antibodies for human immunotherapy. Hum Antibodies Hybridomas 1992; 3: 137-45.
39.	Gottlieb SL, Gilleaudeau P, Johnson R, et al. Response of a psoriasis to a lymphocyte-selective toxin (DAB389-IL2) suggests a primary immune, but not keratinocyte, pathogenic basis. Nat Med 1995; 1: 442-7.
40.	Magilavy D, Kruger GG. The response of chronic plaque psoriasis to Amevive (LFA3TIP) and the selective suppresion of peripheral memory/effector T cells (CD45RO+) versus naive T cells (CD45RA+) is linked to serum levels of LFA3TIP. J Invest Dermatol 2000; 114: 776.
41.	Ellis CN, Krueger GG. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Eng J Med 2001; 345: 248-55.
42.	Singri P, West DP, Gordon KB. Biologic therapy for psoriasis. Arch Dermatol 2002; 138: 657-63.
43.	Nickoloff BJ. The immunologic and genetic basis of psoriasis. Arch Dermatol 1999; 135: 110410.
44.	Damle NK, Klussman K, Linsley PS, et al. Differential costimulatory effects of adhesion molecules B7, ICAM-1, LFA-3, and VCAM-1 on resting and antigen-primed CD4+ T lymphocytes. J Immunol 1992; 148: 1985-92.
45.	Wingren AG, Parra E, Varga M, et al. T cell activation pathways: B7, LFA-3, and ICAM-1 shape unique T cell profiles. Crit Rev Immunol 1995; 15: 235-53.
46.	Gottlieb A, Miller B, Chaundhari U, et al. Clinical and histologic effects of subcutaneously administered anti-CD11a (hu1124) in patients with psoriasis. J Invest Dermatol 2000; 114: 840.
47.	Finkelman FD. Relationships among antigen presentation, cytokines, immune deviation, and autoimmune disease. J Exp Med 1995; 182: 279-82.
48.	Asadullah K, Docke WD, Ebeling M, et al. Interleukin 10 treatmenet of psoriasis: clinical results of a phase II trial. Arch Dermatol 1999; 135: 187-92.
49.	Asadullah K, Sterry W, Ebeling M, et al. Clinical and immunological effects of IL-10 therapy in psoriasis. Br J Dermatol 1999; 141: 989.
50.	Ettehadi P, Greaves MW, Wallach D, et al. Elevated tumor necrosis factor-alpha (TNF-alpha) biological activity in psoriatic skin lesions. Clin Exp Immunol 1994; 96: 146-51.
51.	Oh CJ, Das KM, Gottlieb AB. Treatment with anti-tumor necrosis factor alpha (TNF-alpha) monoclonal antibody dramatically decreases the clinical activity of psoriasis lesions. J Am Acad Dermatol 2000; 42: 829-830.
52.	Chaudhari U, Romano P, Mulcahy LD, et al. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 2001; 357: 1842-7.
53.	Chatenoud L, Ferran C, Legendre C, et al. In vivo cell activation following OKT3 administration: systemic cytokine release and modulation by corticosteroids. Transplantation 1990; 49: 697-702.
54.	Gaston RS, Deierhoi MH, Patterson T, et al. OKT3 first-dose reaction: association with T cell subsets and cytokine release. Kidney Int 1991; 39: 141-8.
55.	Norman DJ, Chatenoud L, Cohen D, et al. Consensus statement regarding OKT-3 induced cytokine-release syndrome and human antimouse antibodies. Transplant Proc 1993; 25: 89-92.
56.	Abramovits W. Raptiva (efalizumab). Skin Med 2004; 3: 37-8.
AUTHOR'S Aleksandar Godi}, MD, PhD, University Clinical Centre, ADDRESS Department of Dermatovenereology, Zalo{ka 2,1525 Ljubljana, Slovenia