Psoriasis: a fresh look

Clinics in Dermatology (2005) 23, 491 – 502

Psoriasis: a fresh look Ibrahim Galadari, MDa,b,*, Mohamed Omar Sharif, MDa, Hassan Galadari, MDb a

Department of Dermatology, Al Ain Hospital, Al Ain, United Arab Emirates Faculty of Medicine, UAE University, Al Ain, United Arab Emirates

b

Abstract Psoriasis is a disease characterized by scaly skin lesions secondary to keratinocyte hyperplasia. The presence of active T cells in the lesions, experimental observations on disease transfer, and therapeutic efficacy of specific immunosuppressive drugs have led to the identification of the activated T lymphocyte as the primary factor for keratinocyte stimulation. Understanding the pathways of pathogenesis is fundamental in evolving therapies for intervention at different points in the pathogenic model and for curtailing the process. Advances in biotechnological methods have helped to create designer molecules and proteins that specifically recognize target receptors and chemicals that modify their actions. These drugs, termed bbiologic response modifiers,Q are now being studied as specific immunosuppressive agents producing different T-cell and cytokine effects in psoriasis. D 2005 Elsevier Inc. All rights reserved.

Psoriasis is a common skin disease characterized by formation of erythematous and scaly plaques at different sites. Although it was earlier recognized that de novo keratinocyte hyperproliferation associated with abnormal epidermal differentiation was the primary cause of psoriasis, the cause for such multiplication of cells was precisely not determined.1 It is now recognized, however, that the keratinocytes in focal skin regions are stimulated to proliferate with activation of the immune system mediated by primed T lymphocytes, and hence, psoriasis is now considered the most prevalent T cell–mediated inflammatory disease in human beings.

T Corresponding author. Department of Dermatology, UAE University, PO Box 8716, United Arab Emirates. Tel.: +961 4 334822; fax: +971 4 3482220. E-mail address: [email protected] (I. Galadari). 0738-081X/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2005.01.009

Traditional concepts Different theories were proposed to explain the cause of increased cell proliferation. These theories may not be mutually exclusive. (1) Cyclic nucleotides —Cells are blocked in the G1 phase by high levels of cAMP (adenosine 3c,5ccyclic monophosphate). Any increase in cAMP or decrease in cGMP (cyclic guanosine 3c,5c-monophosphate) would increase the number of proliferating cells.2 (2) Arachidonic acid metabolism — Diversion of the arachidonic acid metabolism pathway to the lipooxygenase pathway and release of inflammatory mediators such as 12-hydroxy eicosa tetraenoic acid, leukotriene B4, and prostaglandins stimulate cell multiplication.3 (3) Polyamines — Putrescine, spermidine, and spermine are increased. These polyamines are important in cellular proliferation. Ornithine decarboxylase is the

492 rate-limiting enzyme which increases in the early stages of hyperplasia.4 (4) Protease-antiprotease system —Plasminogen activator (a 1 antitrypsin) and cathepsin 1 have a role in epidermal proliferation and differentiation. Protease activity increases in psoriasis. Cell surface proteases can be activated at the local level. The finding of greatly enhanced keratinocyte proliferation in psoriasis was initially thought to be caused at least in part by a reduced cell-cycle time. Cell cycle turnover time was 37 hours in the psoriatic epidermis compared with 457 hours in the normal epidermis. The normal transit time from the basal layer to the granular layer was 13 days, whereas in psoriasis, it was reduced to 2 days. The basal epidermis contains a mixture of cycling and resting cells and that there is no major difference between normal and hyperproliferative epidermis with respect to cellcycle time. The abnormality in psoriatic epidermis appears to be caused by an increased recruitment of cycling cells from the resting fraction, thus producing an increased growth fraction.

Genetics of psoriasis Psoriasis is a genetically heterogeneous disorder. Multiple genes are involved, and interactions with the environment are also implicated in its development. Based on the genetic framework, the manifestations of disease, such as severity and location (eg, nails, joints, and palmoplantar), may differ between individuals and populations. Population and twin studies in psoriasis suggest a large heritable component. Several large population studies have also suggested a parental sex effect that is more marked if the disease is inherited from the father.5 Three main genetic loci on chromosomes 17q, 4q, and 6p have been reported in genome scans. HLA (human leukocyte antigen) – Cw6 was first shown to be the HLA phenotype most strongly associated with psoriasis, the relative risk of those bearing the HLA-Cw6 phenotype to develop psoriasis being approximately 10-fold. This association is unique, as psoriasis is the only disease known to be primarily linked with the HLA-C locus. Much of the genetic research has concentrated on the approximately 300-kb PSORS1 locus, near HLA-C on 6p21.3.6 It has been estimated that this allele accounts for 30% to 50% of the genetic contribution to psoriasis. A particular allele for the HCR gene (a-helix –coiled –coil rod homologue) may represent a major genetic determinant for psoriasis, probably via a mechanism impacting on keratinocyte proliferation. Other linkages of psoriasis have been made to 17q24-q25 (PSORS2), 4qter (PSORS3), 1q21 (PSORS4), and 3q21 (PSORS5) in different populations, although these linkages are not as reproducible as one with PSORS1.

I. Galadari et al. A study of the genetic pattern in psoriasis, as in other diseases, would lead to the identification of novel biochemical pathways disrupted in this disease and thereby help to identify targets for novel therapeutics. A clearer understanding of the genetic makeup would also allow better prediction of disease presentations and response patterns to drugs (pharmacogenomics). It could guide the creation of suitable therapies, either individualized or designed for specific needs.

The immunology of psoriasis To understand the pathogenesis of psoriasis, it is necessary to have knowledge of the normal immunologic processes occurring in the skin. The skin is the largest organ in the body and is described as a dfirst-levelT lymphoid organ because of the presence of an effective immunologic surveillance conducted within the layers of the skin in conjunction with the peripheral lymph nodes and circulating immunocompetent T lymphocytes. The term bSALT Q (skinassociated lymphoid tissue) has been ascribed to this collection of antigen-presenting cells (APCs), cytokinesynthesizing keratinocytes, the epidermotropic T cells, the dermal capillary endothelial cells, and the draining lymph nodes. Other cells participating in the immune responses at this level include the mast cells, tissue macrophages, granulocytes, fibroblasts, and non-Langerhans APCs (dendritic cells), all of which interact with one another through the synthesis of different cytokines and chemical mediators. Epidermal keratinocytes are activated by a variety of stimuli, such as bacterial products, chemicals, UV radiation, or trauma, to produce cytokines. The synthesis of cytokines is a controlled process, and any imbalance would lead to altered levels and pathological states. Any form of injury or infection on the skin leads to transmission of signals from injured tissue to the immune system. The release of tumor necrosis factor (TNF) a from cells in the skin induces the production of other cytokines and chemokines and modifies cutaneous vessel endothelium leading to extravasation of leukocytes. These leukocytes mediate effector functions, such as the killing of pathogenic bacteria or fungi or repair of the injured tissue. Essentially, this process is a form of natural (innate) immunosurveillance of body surfaces to infections.7 T cells play an important role in immunosurveillance. Each T cell has a different specificity for antigen conferred by its unique T-cell receptor. In lymph nodes, T cells mingle with dendritic cells that have recently migrated through the lymphatics from the peripheral tissue. These APCs are powerful activators of T cells that bear the correct receptor for antigens they have internalized. When activated, naive T cells multiply, express new molecules on their surface, and become effector-memory T cells. They then migrate to the source of the allergen and help eliminate it through the synthesis and release of various cytokines. Although this is a protective phenomenon aimed at removal of antigens, such cell-mediated mechanisms at

Psoriasis: a fresh look times get directed toward autoantigens, cryptic infections, or sometimes other commensals and result in chronic tissuedamaging inflammation. This altered or rather uncontrolled form of a protective phenomenon leads to pathological states such as psoriasis, rheumatoid arthritis, Crohn disease, sarcoidosis, and multiple sclerosis.8

The concept of psoriasis as a T cell–mediated disease There is an increase in the number of T lymphocytes and macrophages in psoriatic plaques.9 Monoclonal antibody probes have shown the T cells as having CD4+ and CD8+ markers, with TH1 cells concentrated in the dermis and type 1 cytotoxic T cells in the psoriatic epidermis. These T cells also carry the CD45RO markers. Both CD4+ and CD8+ T cells in psoriasis produce mainly type 1 cytokines.10,11 The cellular events underlying psoriasis can be divided into two phases: afferent (also known as induction phase/ antigen recognition) and efferent (elicitation phase). In the induction phase, Langerhans cells (LCs) in the epidermis process antigens (either autoantigens or bacterial superantigens) and migrate to draining lymph nodes. In the lymph nodes, the LCs then present this antigenic information to naive CD4 helper T lymphocytes and CD8 T lymphocytes as well. Upon antigen presentation, clonal proliferation of T cells occurs. Both effector and memory T cells are then released from the lymph nodes and recirculate preferentially through the skin. Subsequently, the activated T lymphocytes and other cell populations amplify the inflammatory reaction through the release of a series of cytokines with chemotactic and activating functions toward neutrophils, monocytes, and keratinocytes. Proof for the pathogenic role of T cells in psoriasis comes from various observations: ! The severe combined immune deficiency mouse experiments wherein normal skin taken from a patient susceptible to psoriasis is transplanted onto an immunodeficient mouse. When activated syngeneic T cells are then injected into this transplanted skin, it takes on a psoriasiform expression.12,13 ! Efficacy of cyclosporine in psoriasis because of its inhibitory effects on T-cell activity. Patients with psoriasis who underwent solid organ transplantation and were treated with cyclosporine to prevent graft rejection had improvement in their cutaneous disease.14 ! Use of psoralen – UV-A therapy for psoriasis, which depletes T lymphocytes and LCs in the affected areas. ! Bone marrow transplantation, which can lead to btransfer Q or improvement in psoriasis. ! Treatment of other diseases with proinflammatory interferons causing a flare of psoriasis. ! Clearing of psoriatic plaques by use of a T-cell immunotoxin, Denileukin diftitox.15

493 Psoriasis is therefore now considered an inflammatory disease process, wherein, epidermal proliferation occurs as a result of stimulation of keratinocytes by cytokines secreted by activated T lymphocytes.16 Increased T-cell infiltration is either caused by a dysregulatory response or a continuous activation of the APCs. The antigens causing such constant stimulation could be either bacterial,17 viral (retrovirus), or keratinocyte proteins themselves (autoreactivity). Activated T cells then release various inflammatory cytokines such as interleukin (IL) 1, IL-2, IL-6, IL-8, TNF-a, IFN-c, epidermal growth factor–like, fibroblast growth factor (FGF) – like, and platelet-derived growth factors. These factors cause keratinocyte proliferation, angiogenesis, leukocyte, and lymphocyte migration.

Pathogenesis of disease Afferent arm LC changes The initial changes involve the immature LCs in the epidermis, which capture and internalize the antigen. This is then processed and presented on the cell surface, bound to classes I and II major histocompatibility complex molecules. In addition, the LC also acquires a number of cell surface receptor markers such as CD80, CD86, CD40, CD83, and intercellular adhesion molecule (ICAM) 1. This bmatureQ LC is now primed for stimulating the T cells in the draining lymph nodes.

T-cell events (1) Activation of naive T cells in the lymph nodes into memory-effector (CD45RO) cells. (2) Differentiation and proliferation of these CD45+ cells. (3) Migration of activated T cells to sites of antigen excess in the skin. Endothelial changes, expression of cell markers, and elaboration of various cytokines and adhesion molecules enhance this process. (4) Secretion of proinflammatory T1 cytokines by the effector T cells in the dermis and epidermis, with subsequent effects on keratinocyte proliferation.18-20

T-cell activation This is a multistep process Step 1 (binding) Contact between the APC and the T cell is established by ICAM-1 and lymphocyte function–associated antigen (LFA) 3 on the APC with LFA-1 and CD2 on the T cells, respectively. Step 2 (primary stimulation/signal 1) The primary event is the recognition of the major histocompatibility complex–bound antigen by an appropriate T-cell receptor. Once a match occurs, T cell gets activated, with increase in the synthesis of mRNA for IL-2

494 and IL-2 receptor (CD25). Thus, the primary signal is always antigen-specific. Step 3 (costimulation/signal 2) Additional interactions also take place between the T cell and APC, together described as daccessoryT or dcostimulatoryT signals. These are critical for optimal activation of the T lymphocyte. In the absence of costimulation, the degree of responsiveness of the cell is very limited (anergy), or the cell itself may undergo apoptosis. These costimulatory signals are not antigen-specific. Costimulatory interactions include (i) CD80 and CD86 on the APC with CD28 on T cell, (ii) CD80 and CD86 on the APC with cutaneous T-lymphocyte antigen (CTLA) 4 on the T cell, which is an inhibitory signal, (iii) LFA3 with CD2, and (iv) CD40 and CD40 L. IL-2 from T cells and IL-12 from mature LCs also bind to their receptors on the activated T cells. These reactions regulate transcription of cytokines such as interferon (IFN) c, TNF-a, IL-2, and granulocyte-macrophage colony-stimulating factor. These cytokines are responsible for differentiation, maturation, and proliferation (mitotic activity) of the T cells into memory-effector cells. The naive T cells are thus processed to mature into TH1 and type 1 cytotoxic T cell producing type 1 cytokines. Some of the T cells may also differentiate toward natural killer cell formation, which react with nonprotein antigens.

Efferent arm Migration of effector T cells to the site of antigen excess in the inflamed skin is the next step. T cells acquire a surface protein termed cutaneous lymphocyte–associated antigen. This is an adhesion molecule that mediates attachment of the T cell to the endothelial cells of the dermal vasculature (through E selectin and P selectin), with subsequent entry into the skin. The process also involves triggering of many chemokines and binding of integrins such as vascular cell adhesion molecule, ICAM-1, and LFA-1. Effects of T cells on site Once in the dermis, the TH1 and type 1 cytotoxic T cells release high levels of IFN-c and TNF-a. These induce ICAM-1, CD40, and major histocompatibility complex II proteins on the keratinocytes. Intraepidermal T cells trigger keratinocyte hyperproliferation, which accelerates epidermal growth occurring in the regenerative pathway.21 It is likely that a cascade of cytokines, secreted by different cells in the local environment of the psoriatic plaque, play a role in the phenotypic responses in psoriasis. TNF-a has been found to increase type I vasoactive intestinal peptide receptor mRNA in keratinocytes. Vasoactive intestinal peptide promotes keratinocyte proliferation and stimulates

I. Galadari et al. synthesis of proinflammatory cytokines such as IL-6, IL-8, and RANTES (regulated upon expression, normal T cell expressed and secreted).22 These cytokines from intraepidemal T cells have been shown to be direct keratinocyte mitogens and thus could directly stimulate keratinocyte proliferation. TNF-a also increases plasminogen activator inhibitor type 2, a serine proteinase inhibitor, which is thought to protect cells from apoptosis.23 The prevention of apoptosis by this or other mechanisms could lead to increased longevity of keratinocytes and consequently to a thickened epidermis. IFN-c is also a trigger for epidermal hyperplasia when injected into skin. The other proposed mechanisms for keratinocyte hyperplasia are a wound reparative phenomenon that is triggered by intercellular disruption caused by T-cell entry into the epidermis. Mitogenic cytokines and receptors on keratinocytes such as epidermal growth factor, insulinlike growth factor 1, and keratinocyte growth factor pathways are implicated in regenerative hyperplasia, and these would be stimulated as part of a wound repair response.24 The other features of a psoriatic lesion, such as vascular proliferation and neutrophil infiltration are also caused by the action of the other cytokines such as vascular endothelial growth factor and IL-8 from keratinocytes on endothelium and polymorphonuclear leucocyte recruitment.

Targets for therapeutic intervention With a deeper understanding of the various steps involved in T-cell stimulation leading to psoriasis, therapies can be formulated which act upon specific points in the pathogenic cascade. The different ways in which the chain of events can be interrupted include: (1) Suppressing T-cell activation ICAM-1/LFA-1 interaction blocked by efalizumab (humanized anti-CD11a) (2) Blockage of T-cell receptor stimulation By anti-CD3 and anti-CD4 humanized monoclonal antibodies (3) Blockage of costimulation CD80 and CD86/CD28 by (i) CTLA4Ig and (ii) IDEC-114 CD2/LFA-3 interaction by alefacept (4) Modulation of T-cell proliferation IL-2 receptor a-subunit (CD25) by its antibodies, daclizumab, and basiliximab IL-2 receptor by a fusion protein DAB389–IL-2 (5) T-cell migration and adhesion This can be targeted at three levels —adhesion to endothelial cells, chemokine release, and integrin binding (6) Altering the cytokine balance and neutralizing effects of circulating cytokines Monoclonal antibody against TNF-a–infliximab Circulating TNF-a binding receptor—etanercept

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Treatment aspects

Patients on this treatment should be monitored according to the suggested guidelines.26

Psoriasis is a chronic disease wherein patients have exacerbations, remissions, or recurring lesions. Depending on the extent of disease, severity, safety concerns for systemic agents, economic issues, accessibility to treatment centers (for phototherapy), and patient attitude toward the disease (quality-of-life issues), a decision is taken whether to treat the patient with topical and/or systemic medications. Various treatments are available and are used either alone or in combinations. The therapeutic mechanism of most drugs in psoriasis is being reappraised after recognizing the central role of T cells in the pathogenesis of psoriasis. It is now considered that most therapies for psoriasis including phototherapy, methotrexate, and cyclosporine act through their suppressive actions on T lymphocytes, either by preventing elaboration of inflammatory cytokines or by selective cytotoxic actions. Calcitriol, which has been considered mainly as a modifier of epidermal differentiation, has suppressive effects on IFN-c elaboration from activated T lymphocytes, which may be related to its negative feedback on TH1 cells and a shift to type 2 helper T-cell cytokines, thereby reducing T1 responses. The mechanism of retinoids is somewhat more complicated to explain on immunologic grounds, although it is known that they have an effect on neutrophil migration. They act at the stage of proliferation and differentiation of keratinocytes, a step that follows cytokine stimulation. There has been a rejuvenation of interest into some compounds such as hydroxyurea, which have made a comeback in treatment schedules for specific needs. There have also been many new additions to the armamentarium of drugs for this disease. These include modifications of some conventional treatments, as well as a whole new group of drugs, termed the bbiologics,Q which are drugs (proteins) currently being devised to target various steps in the pathological cascade of the disease. These drugs are also focused upon.

Newer concepts of established topical and systemic treatments: new formulations of known drugs Methotrexate Methotrexate was the first systemic drug to control psoriasis when it was discovered in 1951 and remains the most widely used systemic agent in its treatment. It inhibits replication and function of T and B cells and suppresses the secretion of cytokines such as IL-1, IFN-c, and TNF-a. Methotrexate also suppresses epidermal cell division in psoriasis. Being a competitive inhibitor of the enzyme dihydrofolate reductase, which is responsible for the conversion of folic acid to reduced tetrahydrofolate, it inhibits thymidylate synthesis that results in inhibition of DNA synthesis and arrest of cell division in the S phase.25 The major issues of concern regarding this drug are its acute hematotoxicity and acute and chronic hepatotoxicity.

Cyclosporine Cyclosporine is an immunosuppressive agent derived from the fungus, Tolypocladium inflatum gams that inhibits T–helper cell activation and proliferation. Cyclosporine binds to an immunophilin called cyclophilin, which is an immunosuppressant-binding protein present in all cellular compartments. The cyclosporincyclophilin complex then binds to and inhibits the enzyme, calcineurin. This results in blockage of signal transduction pathways that are dependent on the transcription factor, NF-AT (nuclear factor of activated T cells). Ultimately, the production of cytokines such as IL-2 and IFN-c is inhibited. Cyclosporine is most effective in most forms of severe psoriasis, including pustular and erythrodermic psoriasis.27 Its major side effects are renal dysfunction and hypertension. It is the only systemic drug that can be used in pregnancy (Food and Drug Administration category B). Mycophenolate mofetil (CellCept) Mycophenolate mofetil is the ethyl ester prodrug for mycophenolic acid, which is isolated from Penicillium cultures. It is used primarily as an immunosuppressive agent for the prevention of renal and other allograft rejection. It is also used in the treatment of rheumatoid arthritis and autoimmune bullous diseases. Mycophenolic acid inhibits purine synthesis in lymphocytes by reversibly and noncompetitively inhibiting the enzyme, inosine monophosphate dehyrogenase. Unlike other cells, lymphocytes lack the ability to synthesize guanosine monophosphate sufficiently through the hypoxanthine-guanine phosphoribosyl transferase salvage pathway and thus cannot synthesize purine bases. This prevents synthesis of DNA and RNA in lymphocytes. Consequently, mycophenolic acid inhibits lymphocyte proliferation, antibody production, and the formation of adhesion molecules in response to antigenic or mitogenic stimulation. Mycophenolic acid might also act through its effects on arachidonic acid metabolism, with reduction of leukotriene 4 and hydroxy eicosa tetraenoic acid synthesis. The initial dose is 1 g by mouth twice daily. Doses of up to 3 to 4 g/d may be needed. Neutrophil counts should be followed closely, as severe neutropenia may occur in 2% of patients. Gastrointestinal tract side effects are most common. There is no hepatotoxicity or nephrotoxicity. There is a slightly raised incidence of infections as expected with any immunosuppressive agent. Hydroxyurea Hydroxyurea is a cell cycle–phase antineoplastic such as methotrexate, which inhibits ribonucleotide diphosphate reductase. This enzyme converts ribonucleotides to deoxyribonucleotide triphosphates, the rate-limiting step of DNA synthesis. Hydroxyurea inhibits DNA synthesis during the

496 S phase of mitosis, leading to accumulation of cells at the G1/S phase and eventual apoptosis.28 In psoriasis, hydroxyurea slows down the kinetics of basal cell replication in the epidermis, reverses the abnormal keratin proliferation in psoriatic plaques, inhibits vascular proliferation in the dermis, and lowers the neutrophil count in the skin with decreased formation of pustules and microabscesses in psoriatic plaques. Dose of hydroxyurea ranges from 1 to 1.5 g/d in divided doses. More common adverse reactions have been primarily bone marrow depression and dermatologic adverse effects such as pigmentation of the nails, skin, and mucosae (lichen planus-like) or a dermatomyositis-like rash. Hydroxyurea is safer than methotrexate and can be used as a substitute in cases of hepatotoxicity, but it is not as effective. 6-Thioguanine Thioguanine is a cell cycle–specific antineoplastic similar to azathioprine. It is a chemical analogue of guanine and adenosine and acts as antimetabolite in the S phase of cell division. Thioguanine becomes triphosphorylated and is incorporated into DNA in place of guanine that leads to DNA derangement. It is also metabolized to an intermediate that inhibits the enzyme, hypoxanthine-guanine phosphoribosyl transferase, which is essential for purine biosynthesis.29 Thioguanine is effective in the treatment of psoriasis. Its main side effects are bone marrow suppression and gastrointestinal tract toxicity. Sulfasalazine Sulfasalazine is an anti-inflammatory drug used to treat ulcerative colitis. It is also used in psoriatic and rheumatoid arthritis. Dosage ranges from 500 mg three times per day up to 1000 mg four times per day. Onset of action may take time. An important issue with sulfasalazine is that it causes a reversible oligospermia in more than 80% of users and so is not suitable for treatment of male patients desiring to father children. Liarozole Liarozole, an imidazole derivative, is an inhibitor of the cytochrome P450 pathway. Thereby, it reduces 4hydroxylation of retinoic acid, thus improving plaque psoriasis. There is a decrease in the number of CD11+ cells, ICAM-1 expression, and keratinocyte proliferation. Fumaric acid esters A mixture of different fumaric acid esters is used in Germany for the systemic treatment of severe psoriasis. The mode of action is mainly an inhibition of T-cell activity and a shift from a TH1-type response to a type 2 helper T cell– type pattern. There is a good response to treatment in approximately two thirds of patients in whom clearing of lesions can be achieved in 8 to 12 weeks. Gastrointestinal complaints occur in up to 60% of patients and may lead to

I. Galadari et al. withdrawal of the compounds. Although this therapy has been in use for many years, there are no reports of severe long-term toxicity or development of neoplasias. Phototherapy This is an effective and relatively safe modality of treatment used in moderate to severe psoriasis. It involves suppression of the disease by exposure to UV radiation, either alone as in UV-B, or in combination with a photosensitizing drug, psoralen, as in psoralen–UV-A. The mechanism of action is multifaceted. Formation of photoadducts with DNA inhibits proliferation of epidermal keratinocytes. Immunologic alterations, such as depletion of LCs and cytotoxic T cells, reduced cytokine synthesis; increased pigmentation and metabolism of prostaglandins in the skin also play a role in disease improvement. When UV-B is used, the present recommendation is to use a specific wavelength of 311 nm, termed narrow-band UV-B. It can be combined with retinoids to improve the efficacy of treatment. Tacrolimus (FK506-Prograf/Protopic) Tacrolimus is a macrolide immunosuppressive agent derived from the fungus Streptomyces tsukubaensis. Tacrolimus inhibits T-cell activation in a mechanism similar to cyclosporine by binding to the immunophilin protein, FK binding protein. Topical tacrolimus (0.03%-0.3%) has been found to be effective for atopic dermatitis but less so in psoriasis, which may be because of poor penetration through the psoriatic plaque. The major cause of concern is the systemic absorption from topical applied drug leading to immunosuppression and cutaneous malignancies. Pimecrolimus (SDZ ASM 981-Elidel) Pimecrolimus, a novel ascomycin macrolactam derivative, is a specific inhibitor of the production of proinflammatory cytokines from T cells and mast cells as well as proliferation of T cells after antigen-specific or nonspecific stimulation. It appears to be highly effective in psoriasis therapy when taken systemically.30 It is now used topically for psoriasis, although it is not as effective as tacrolimus. Tazarotene Tazarotene is a retinoid agonist–specific for the retinoic acid receptor bc.31 It up-regulates three genes, TIG-1, TIG-2, and TIG-3 (tazarotene-induced gene), which are related to antiproliferation. It is applied once per day and is in a gel formulation that is cosmetically pleasing and can be used on the face or scalp. Tazorac works less quickly than highpotency topical corticosteroids, with approximately 70% response at 3 months.32 Typical retinoid side effects of burning and itching occur in 20% to 40% of patients. A combination with topical steroids reduces irritancy and improves efficiency in a synergistic manner. The active metabolite of tazarotene has a half-life of 7 to 12 hours, and therefore, contraception may only be necessary for a few days after discontinuation of the drug.

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Targretin Targretin (bexarotene) is specific for the retinoid X receptor.33 Retinoid X receptors are primarily involved in controlling apoptosis, not cell growth and proliferation. Therefore, Targretin is approved for the treatment of cutaneous T-cell lymphoma in pill and gel preparations and not for the treatment of psoriasis. Compared with acitretin, fewer mucocutaneous side effects are seen. As with other retinoids, hyperlipidemia can occur.

What are the biologics? bBiologic response modifiersQ can be defined as a generic term for hormones and neuroactive and immunoreactive compounds that act at the cellular level. They are derived from living material, either human, plant, or microorganism, and used for the treatment, prevention, or cure of disease in human beings. These proteins possess pharmacological activity and can be synthesized in large quantities through recombinant DNA techniques. Biologics include cytokines, lymphokines, and other antiproliferative agents. Biologic molecules can be designed to either mimic the actions of normal human proteins or to interact with circulating proteins or cellular receptors. The biologics in psoriasis have been categorized into 4 groups based upon their modes of action as those that: ! Reduce the number of pathogenic T cells ! Inhibit T-cell activation and migration ! Act as immune modifiers by changing the cytokine profile a T cell may produce from T1 to T2 cytokines, a process called immune deviation ! Block the activity of inflammatory cytokines Strategy 1: decrease the number of the pathogenic T cells Strategy 2: (i) inhibit T-cell activation and (ii) reduce T-cell migration into the skin Strategy 3: alter the cytokine profile Strategy 4: neutralize or inactivate cytokines

Alefacept (Amevive, LFA3TIP), Denileukin diftitox (ONTAK [DAB389–IL-2]) Efaluzimab (Raptiva, anti-CD11a), Daclizumab(Zenapax, anti-CD25), Siplizumab(MEDI-507,anti-CD2), Basiliximab, IDEC 114, CTLA4Ig, OKTcdr4a Recombinant human IL-10 (Tenovil), Recombinant human IL-11 (Oprelvekin) Infliximab (Remicade), Etanercept (Enbrel), ABX–IL-8, SMART anti–INF-c

More than 40 different biologic molecules have been developed and are in various stages of trials in psoriasis and other related inflammatory diseases. Some molecules have shown promising results but significant adverse reactions, whereas in others, the clinical responses are not commensurate with expected outcomes. Financial constraints may have led to development of some drugs to be abandoned in certain indications. It is pertinent to note that animal testing for these chemicals may not be appropriate because the antibodies and proteins are devised specifically against human tissue. Among the many biologics being studied, there has been greater clinical experience with infliximab and etanercept and, to a lesser extent, with alefacept and efalizumab, not only in psoriasis but also in inflammatory bowel disease, rheumatoid arthritis, and other autoimmune conditions. They have been approved for some of those conditions and are discussed in detail herein. A few other biologics are also discussed in short to understand their mode of action.34-37 Drug

Structure

Action

Infliximab

Monoclonal antibody against TNF-a Fusion protein human IgG1 Fc + TNF-a receptor Human IgG + murine variable against CD11a subunit of LFA-1 Fusion protein IgG Fc + LFA-3

Neutralizes serum and membrane bound TNF-a Combines with TNF-a in serum (acts as receptor) Blocks interaction of LFA-1 with ICAM-1

Etanercept

Efalizumab

Alefacept

Denileukin diftitox (ONTAK) IDEC-114

Daclizumab

Three different types of reengineered molecules (biologics) are being used in psoriasis: ! Recombinant human cytokines or growth factors ! Monoclonal antibodies ! Fusion proteins

Siplizumab

IL-2 fusion toxin

Primatized anti-CD80 monoclonal antibody

Human IgG Fc + murine variable region against a-subunit (CD25) of the IL-2 receptor Monoclonal antibody against CD2

Blocks T-cell activation by interfering with CD2/LFA-3 interaction Toxic against activated T cells Blocks T-cell activation by interfering with CD80/CD28 interaction without blocking CD80/ CTLA4 interaction Blocks IL-2 from interacting with IL-2 receptor on T lymphocytes

Blocks T-cell activation

498

Infliximab (Remicade) Structure Infliximab is a mouse/human chimeric antibody comprising a mouse variable region and a human IgG1/a constant region. It has a molecular weight of 149 kDa and a binding specificity for human TNF-a. Mode of action Infliximab interferes with the actions of TNF-a by directly binding to soluble and transmembrane TNF-a molecules in the plasma and the diseased tissue. Infliximab monotherapy decreases epidermal inflammation and normalizes keratinocyte proliferation and differentiation.38 Dosage Three-dose induction regimen of infliximab 5 or 10 mg/ kg at weeks 0, 2, and 6 is used. It is administered via IV infusion over 2 to 3 hours. Patients should be monitored closely for infusion-related reactions for 2 hours after infusion. Serum sickness–like reaction may occur a few days after treatment. It is an approved treatment of Crohn disease and rheumatoid arthritis. Efficacy Infliximab therapy produces a rapid and substantial improvement in disease. Improvements in Psoriasis Area and Severity Index are maintained for as long as 6 months in approximately 50% of patients in the absence of any treatment after the initial three IV infusions of infliximab. Side effects Infliximab is contraindicated in patients with moderate to severe congestive heart failure and in patients with known hypersensitivity to murine proteins or any other component of the product. Infliximab may increase susceptibility to infection or allow reemergence of infection. Patients should also be monitored for infections during and after treatment. Patients should be screened for tuberculosis before treatment. TNF blockade can induce systemic lupus erythematosuslike illness in a small number of previously unaffected patients. Patients might develop transient antinuclear antibody positivity without clinical signs or symptoms. Treatment should be discontinued if lupuslike symptoms occur. Other features No drug interactions have been noted. No renal or liver toxicity is seen. Patients with preexisting or recent onset central nervous system demyelinating or seizure disorders should be carefully monitored.

Etanercept (Enbrel) Structure It is a human dimeric fusion protein consisting of the extracellular ligand-binding domain of the human 75-kDa TNF-a receptor linked to the Fc portion of human IgG1.

I. Galadari et al. Mode of action It competitively binds to circulating TNF-a and prevents interactions with its cell surface receptors. It acts as an external receptor for TNF-a.39 Dosage For adults with psoriatic arthritis and/or rheumatoid arthritis, 25 mg can be administered subcutaneously twice weekly for 12 to 24 weeks. For psoriatic arthritis, it can be used concomitantly with methotrexate. It is an approved drug for psoriatic and rheumatoid arthritis. Side effects Mild to moderate injection site reactions are usually seen. There are reports of serious infections and sepsis, including fatalities with the use of etanercept. Caution should be used when considering etanercept for patients with a history of recurring infections, and etanercept should not be administered to patients with sepsis or active infections, including chronic or localized infections. Disseminated tuberculosis has been seen in patients treated with infliximab, so tuberculin skin testing should be strongly considered before therapy with etanercept too. Caution should be exercised when considering the use of etanercept in patients with preexisting or recent-onset central demyelinating disorders. Cases of drug-induced systemic lupus and subacute cutaneous lupus have been reported. Other features Etanercept has also been studied as monotherapy in moderate to severe psoriasis with statistically significant improvement. It has been noted to prevent joint damage in psoriatic arthritis. Etanercept is well tolerated by both adult and pediatric patient populations. Long-term data have demonstrated an excellent safety profile.

Efalizumab (Raptiva, anti-CD11a) Structure This is a humanized form of a murine antibody directed against CD11a, the a-subunit of LFA-1. Mode of action By binding to CD11a, efalizumab inhibits multiple key pathogenic steps where ICAM-1/LFA-1 interaction occurs such as T-cell activation, cutaneous T-cell trafficking, and T-cell adhesion to keratinocytes. Thus, efalizumab exerts its clinical activity through its action at several points in the pathogenic cycle.40 Dosage The normal dose is 1 mg/kg once weekly or alternate weeks for approximately 12 weeks. Efficacy There is a rapid onset of clinical benefit, but long-term disease suppression is not seen.

Psoriasis: a fresh look Side effects Efalizumab can be effectively and safely administered on a long-term basis.

Alefacept (Amevive) Alefacept was the first Food and Drug Administration– approved biologic for psoriasis affecting the skin. Structure It is a human fusion protein consisting of a fragment of LFA-3 bound to the Fc portion of human IgG1. Mode of action It inhibits T-cell activation and proliferation by binding to CD2 on T cells and blocking the LFA-3/CD2 interaction. It produces a selective reduction in memory T cells, as CD2 expression is higher on activated memory cells than on naive T cells. Alefacept also engages FccRIII IgG receptors (on natural killer cells and macrophages), resulting in apoptosis of those T cells expressing high levels of CD2. Dosage The recommended dose of alefacept is 10 to 15 mg/kg IM/IV once weekly for 12 weeks. Efficacy Alefacept has a slow onset of action. Significant improvement in PASI score is seen in approximately one third of patients.41 Alefacept can produce durable clinical remissions, without rebound after treatment cessation. The safety and incremental effectiveness of a second course of alefacept provide strong support for its use as an intermittent therapy for psoriasis. Side effects There seems to be a relative lesser incidence of infections with this drug.

Reduction in number of T cells Denileukin diftitox (ONTAK [DAB389–IL-2]) DAB389–IL-2 is a fusion toxin composed of the amino acid sequences for diphtheria toxin conjugated to the sequences for IL-2. Because T cells in psoriasis lesions express the high-affinity IL-2 receptor (CD25),12 it binds DAB389–IL-2, which then mediates selective cell death. This drug is only approved for the treatment of cutaneous T-cell lymphoma.

Inhibition of T-cell activation and migration CTLA4Ig CTLA4Ig is a chimeric fusion protein that binds to CD80 and CD86 on APCs and prevents their costimulatory

499 interaction with CD28 on T cells, thus blocking their activation. This drug was the first of the biologic drugs to show efficacy in psoriasis. Clinical improvement with CTLA4Ig is associated with a decrease in keratinocyte proliferation and lesional T cells because of inhibition of T-cell activation, proliferation, and recruitment without associated increase in T-cell apoptosis.42

IDEC-114 IDEC-114 is a primatized monoclonal antibody that binds to the high-affinity CD80 receptor found on APCs and certain activated T cells. On the surface of activated T cells, CTLA4 (CD152 and CD28) is up-regulated and may then interact with CD80, leading to deactivation of the T cell. IDEC-114 blocks the CD28/CD80 interaction (activation) without affecting the CTLA4/CD80 interaction (deactivation).43

Siplizumab Siplizumab, a humanized monoclonal antibody directed against CD2, prevents the CD2–LFA-3 costimulatory signal. Phase I/II studies that involved subcutaneous administration of siplizumab showed significant responses in some patients in a dose-dependent manner.44 In a manner similar to alefacept, peripheral lymphocyte counts may decrease.

Daclizumab (Zenapax, anti-CD25) Daclizumab is a humanized antibody to the a-subunit (CD25) of the IL-2 receptor that blocks normal IL-2 binding to this receptor.45 Variable desaturation of the receptors occurred after 4 weeks and correlated with return of disease. It is approved for acute renal transplant rejection.

Basiliximab (Simulect) Basiliximab is a chimeric human/mouse antibody directed against the IL-2 receptor. It has been used to treat severe recalcitrant psoriasis in combination with cyclosporin.46

OKTcdr4a (IMUCLONE) OKTcdr4a is a humanized anti-CD4 IgG4 monoclonal antibody and has been used in one study in the treatment of moderate to severe psoriasis.47 Sustained CD4 saturation was not necessary for a response. Immunohistochemistry studies showed CD4+ down-modulation without depletion. A decrease in activation via inhibition of CD4+ T cell– mediated activation of APC has been postulated.

Immune modulation Type 2 helper T-cell cytokines decrease TH1-driven processes and vice versa. Therefore, stimulation of keratinocyte proliferation by type 1 cytokines is suppressed by administration of type 2 cytokines.

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Recombinant human IL-10 (Tenovil)

Carcinogenicity

A relative deficiency of IL-10 is seen in psoriasis. IL-10 administration shifts cytokine profiles to a type 2 helper T-cell pattern (increasing IL-4, IL-5, and IL-10).48 IL-10 may decrease the rate of relapse and prolong disease-free intervals in patients with psoriasis. It is given as subcutaneous injections. Side effects are minimal.

The limited studies of the four main biologics do not show any evidence of increase in malignancies. Nevertheless, because this development might take time and longer lengths of therapy, continued follow-up is required before assessing this risk. There have been a number of reports of lymphomas developing in patients on treatment with etanercept and infliximab for Crohn disease. Whether this is caused by the drug or the underlying inflammatory disease, or a combination of both factors, has to be determined.

Recombinant humanized IL-11 (Oprelvekin) Oprelvekin modulates macrophages and type-1 T-lymphocyte function in cell culture and shows anti-inflammatory activity in animal models. Clinical response was associated with a decrease in proinflammatory cytokines.49

Safety concerns and other issues with biologics Immunosuppression Because biologic agents target specific steps in the pathogenesis of psoriasis, they should be less immunosuppressive than agents such as cyclosporine that have broader range of effects on T cells. Nevertheless, emerging data on TNF-a inhibitors suggest that caution must be exercised when combining agents with different immunosuppressive properties. There are few reports of any serious infections with both alefacept and efalizumab, although clinical experience with these drugs is limited. With etanercept, there was no difference in incidence of infections compared with placebo. However, isolated cases of serious infections did occur. Infliximab also caused a rapid reactivation of a latent focus of tuberculosis. It is therefore recommended that tuberculin testing be performed before starting treatment with these cytokines. It is worthwhile to take note of this warning by Kupper— bThe biologic agents interfere with fundamentally important immunologic processes that have evolved over millions of years to protect the host from infection. Their use should not be undertaken lightly, since one would expect immunosurveillance to be altered, at least transiently, in persons who receive them.Q

Teratogenicity These drugs do not appear to have any adverse effect on fetal development and are considered safe for use in pregnancy (Food and Drug Administration category B). Still, it is early days with the biologics, and more clinical experience is required. Because these drugs target immunologic processes, it has to be ascertained whether they can cause any impairment in development of the immune system in the fetus.

Other organ toxicities and autoimmunity There is no evidence of bone marrow suppression, hepatotoxicity, or renal impairment. This supports the very purpose of creation of these drugs to target specific structures. One of the concerns is development of autoimmunity, which may be caused by the presence of IgG in the molecules. It may also occur because of the use of murine antibodies which get recognized as foreign protein, although new technology is rendering this unlikely. Some patients may have a genetic predisposition to autoimmunity which may be unmasked by the biologics. Drug-induced lupus is fortunately reversible upon discontinuation of treatment.

Combination of conventional therapies with the new drugs Combination of some of the conventional treatments with the biologics may have synergistic effects.50 The various biologics may also have complementary effects with one another. Important side effects of some drugs such as methotrexate, cyclosporine, and retinoids can be reduced either by reducing their dose or using them in rotation with the new drugs. As a principle, two drugs having similar side effects should not be used together, and because the biologics lack the usual effects of the wellknown drugs, their combination with the well-known therapies would be relatively safe. Another reason to combine two drugs would be to complement a short-acting drug with a rapid onset of action, and a long-acting one with slower onset to maintain efficacy and disease control over a prolonged period.

The future We are at the dawn of a new era of effective immunemodifying therapeutics for psoriasis. Although the efficacy of some of these agents is unquestionable, the long-term consequences of their immunomodulatory effects are yet to be determined. Responses may also vary between individuals, perhaps because of polymorphisms in genes, a feature that can be better understood by studying pharmacogenomics.

Psoriasis: a fresh look With greater understanding of cutaneous immunology, new biologic immune modifiers with highly specific immune-targeted therapeutics can be constructed that should have a better long-term safety profile than currently available agents. More clinical experience with these drugs would prove whether they satisfy the need for a safe and effective curative treatment of psoriasis in an affordable manner, a hope that may or may not really be fulfilled by these drugs. New advances in these drugs represent the future direction of treatment of psoriasis and many other inflammatory disorders.

Conclusion Psoriasis is a disease with a genetic predisposition in which environmental triggers play a major role. It is now understood to be a disorder of chronic T-cell stimulation. Numerous drugs are available, which most likely act through their immunomodulatory effects. The new biologics are molecules designed to target specific functional areas of the T-cell responses, thereby their immunosuppressive effect is well directed and with lesser side effects.

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