Immunopathogenesis of Psoriasis and Mechanism of Biologics
A review of the current understanding of the immunologic basis of psoriasis pathogenesis and the mechanisms by which biologic medications target disease.
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Psoriasis is a chronic, relapsing inflammatory disease affecting approximately 2% of the population worldwide.1,2 Plaque-type psoriasis vulgaris is the most common clinical subtype of disease and is observed in more than 80% of patients.3 Cutaneous lesions are characterized by well-demarcated erythematous plaques with adherent overlying silvery scales (see Figure 1). Treatment is personalized based on the extent and character of lesions, the sites affected, patient preferences and the patient’s perceived burden of treatment. Approach to management is guided by disease severity, which is classified into one of two categories: mild-to-moderate or moderate-to-severe.4 Approximately 80% of patients suffer from mild-to-moderate disease, which covers 5% to 10% of the body surface area (BSA) and is generally well-managed with topical therapies.4 The remaining 20% of patients suffer from moderate-to-severe disease, which covers >10% BSA, and receive the most benefit from systemic therapy in conjunction with topical medications.4
Systemic treatment options have evolved through advances in deciphering the underlying pathogenesis of disease. Specifically, better understanding of the intricate immunologic mechanisms occurring at the core of the psoriatic plaque has led to the development of immunomodulating therapies, such as the biologic drugs, also commonly known as “biologics.” Their introduction almost a decade ago broadened the therapeutic armamentarium for psoriasis and marks a new era in the way psoriasis is treated. Here, we review the current understanding of the immunologic basis of psoriasis pathogenesis and the mechanisms by which biologic medications target disease.
Etiology of Disease
Until the early 1990s, psoriasis was solely perceived as a disease of disordered keratinocyte proliferation associated with disordered epidermal differentiation.5 Over the past two decades, subsequent studies have revealed an immunologic etiology of disease, specifically involving a T cell-mediated pathogenesis.6,7
Moreover, the etiology of psoriasis involves a complex interplay of genetic and environmental factors (see Figure 2). Environmental triggers such as trauma, infection (eg, β-hemolytic streptococcal infection, HIV), drugs (eg, lithium, beta-blockers, NSAIDS) and stress (eg, psychogenic) can promote an exaggerated immune-mediated response in the skin of genetically-susceptible individuals.8 These poorly regulated immunologic processes ultimately lead to excessive epidermal proliferation and vascular changes in focal skin regions. These changes are some of the hallmark histological features present in psoriasis (see Figure 3).
Immunopathogenesis of Psoriasis
The skin is the body’s primary defense against external invasion. Epidermal keratinocytes exhibit an intimate relationship with the immune system and are capable of recruiting and activating T cells. Activated T cells present in the skin express cutaneous lymphocyte-associated antigen (CLA), an adhesion molecule that guides T-cell skin homing.9 In psoriatic skin, both the innate and adaptive immune responses are implicated in mediating the inflammatory cascade.8 Specifically, T cells, and the cytokines they produce, play a central role in initiating and perpetuating the immune response evident in psoriasis.
Dentritic cells (DCs) are a sentinel component of the innate immune system. They are found in the epidermis as Langerhan cells (LCs) and in the dermis as myeloid and plasmacytoid cells.10 Activation of these antigen-presenting cells (APCs) results in production of inflammatory mediators that promote activation and differentiation of naïve T cell in the epidermis and dermis. Currently, the exact nature of the antigens that activate APCs in psoriasis is unknown. The onset of the psoriatic immune response involves activation of the T cell by the APC.6 This requires the presence of a primary signal and presentation of antigen via the major histocompatibility complex on the APC to the T cell receptor (TCR), as well as a variety of co-stimulatory interactions (see Figure 4). These include linkage of intracellular adhesion molecule-1 (ICAM-1), LFA-3, CD40 and B7 on the surface of the antigen-presenting cell with LFA-1, CD3, CD4/CD8, CD2, CD40L and CD28 on the surface of the T lymphocyte.10 Signaling between the CD28 glycoprotein (located on the T cell) and CD80/CD86 (located on the APC) promotes transcription of a variety of cytokines.10 This results in production of IL-2, IFN-γ, TNF-α and granulocyte-macrophage colony-stimulating factor (GM-CSF), which are all crucial mediators of T cell activation in psoriasis.10
There are differences in the cellular composition, specifically the type and number of inflammatory mediators, present in lesional skin compared to unaffected skin. In psoriasis patients, the predominant T cell subtypes found in lesional skin are: T helper 1 cells (Th1; CD4+), cytotoxic T cells (Tc1; CD8+), Th17 cells (a subtype of CD4+ T helper cells) and regulatory T cells (Treg).11 CD4+ T cells are present within the dermis, whereas the epidermis is mainly infiltrated with CD8+ T cells.3 Pro-inflammatory cytokines produced by Th1 cells and Th17 cells are a predominate component of the cytokine profile present in psoriasis.8 Moreover, there is an unbalanced elevation of the type 1 cytokines (IFN-γ, TNF-α and IL-12) compared to the anti-inflammatory cytokines produced by T helper 2 cells (Th2).3,8 Presence of Th1 cytokines in the dermis and epidermis induces proliferation and disordered maturation of keratinocytes, as well as the vascular changes observed in psoriasis.
Evidence of high concentrations of TNF-α, IL-12 and IL-23 have been found in psoriatic skin compared to non-lesional skin.9,12 TNF-α plays a crucial role in both the initial and perpetuating inflammatory processes by promoting the release of a variety of cytokines and chemokines. Furthermore, it promotes expression of ICAM-1 and vascular adhesion protein-1 (VCAM-1) in keratinocytes and endothelial cells, respectively.10 These processes cause increased proliferation of keratinocytes and endothelial cells, resulting in epidermal hyperplasia and the formation of neocapillaries. This perpetuates the inflammatory process by further increasing local lymphocytic vascular circulation.6,10 IL-12 induces Th1 differentiation and further promotes TNF-α production. Th17 cells have more recently come into the spotlight. In psoriasis, keratinocytes and dentritic cells overproduce IL-23, which stimulates Th17 cell production of IL-6, IL-17A, IL-17F, IL-21 and IL-22 in the dermis.13 These pro-inflammatory cytokines, specifically IL-22, stimulates keratinocyte hyperproliferation and epidermal acanthosis and hyperparakeratosis.8
Activated keratinocytes also produce pro-inflammatory cytokines, including IL-6, IL-8, TNF-α and growth transforming factor.10 In addition to promoting keratinocyte proliferation, these mediators promote neutrophil chemotaxis and formation of Munro’s microabcesses by causing rupture of keratinocyte desmosomes.10
Novel Therapeutic Approaches
Systemic agents such as methotrexate and cyclosporine have traditionally been used for the treatment of moderate-to-severe psoriasis. The chronic nature of the disease typically requires long-term therapy, resulting in high cumulative doses and associated concerns of organ toxicities, such as hepatotoxicity, nephrotoxicity and bone marrow suppression. These side effects primarily result from their non-specific mechanisms of immune suppression and limit their use after a certain dose or time period.14,15
The past decade has seen a revolutionary advancement in the treatment of psoriasis. The development of new therapeutic strategies has largely been driven by two complementary forces. First, a better understanding of disease pathophysiology led to a paradigm shift from a keratinocyte-based etiology to an immune-mediated disease.16 This, coupled with the advent of novel techniques in the field of molecular biology, enabled the development of therapeutic agents that specifically target the implicated immunologic processes in psoriasis.15
Biological agents fulfill the unmet need for treatment options that are both safe and efficacious for managing psoriasis. Biologics are custom-engineered, protein-like molecules that target specific cytokines and immune cells responsible for psoriasis pathogenesis.14,15 Their therapeutic exclusiveness results in higher efficacy and a limited side effect profile.17 The biologic agents used in psoriasis can be broadly divided into three categories: a) monoclonal antibodies (mAbs), b) fusion proteins and c) recombinant cytokines and interleukins.18 Monoclonal antibodies (ending in –mab) are further classified based on their composition as either chimeric (ending in –ximab), humanized (ending in –zumab) or human (ending in –umab) mAbs.18 Chimeric mAbs are composed of foreign-derived, murine amino acids linked to heavy and light constant regions of human origin (see Figure 5). Humanized mAbs contain segments of murine amino acids distributed within a human-derived backbone. Human mAbs do not contain any foreign-derived amino acids and are entirely composed of human sequences.18,19 Fusion proteins consist of a receptor domain that has binding affinity for a specific human protein or ligand. This portion is fused to the constant region (Fc) of a human IgG, enabling it to be soluble in plasma.7,18 Currently, the two classes of biologics FDA-approved to treat psoriasis (and psoriatic arthritis) are tumor necrosis factor (TNF)-α inhibitors and anti-interleukin (IL)-12/IL-23 therapies (see Figure 6 and Table 1).
Tumor necrosis factors are a distinct group of naturally-occurring cytokines that possess important anti-tumor and immune-regulating properties. These inflammatory cytokines occur in two distinct classes, TNF-α and TNF-β, which are now known as TNF and lymphotoxin-alpha (LTα), respectively.10 TNF-α is a pleotropic, pro-inflammatory cytokine present in two biologically active forms, soluble TNF (sTNF) and transmembrane TNF (tmTNF).18 These cytokines are released from T cells, keratinocytes, macrophages, mast cells and dermal dendrocytes.18 Both forms have the capability to bind to membrane receptors, TNFR1 or TNFR2, which are expressed on the surfaces of many cells in the immune cascade. Once these cytokines are internalized into the cell cytoplasm, they exert their pro-inflammatory effects via synthesis of a family of transcription factors, such as nuclear factor kappa B1 (Nf-κB1), which regulates a variety of inflammatory genes.10 The predominant presence and disordered production of TNF-α results in recruitment, migration and activation of T cells. This promotes increased secretion of cytokines and further perpetuates the inflammatory cascade involved in the pathogenesis of psoriasis. TNF-α causes hyperproliferation of keratinocytes, vascular changes, inflammation and subsequent tissue damage in psoriasis.14 The important role of this cytokine in psoriasis pathogenesis confers it an ideal therapeutic target. The three TNF-α inhibitors currently FDA-approved for the treatment of psoriasis and psoriatic arthritis are infliximab, adalimumab and etanercept. Golimumab is the most recently added drug to this class and is currently approved for psoriatic arthritis.
Infliximab (Remicade) was approved by the FDA for the treatment of moderate-to-severe plaque psoriasis in 2006 and for psoriatic arthritis in 2005. It is administered intravenously at a recommended starting dose of 5mg/kg at weeks 0, 2 and 6, and then continued once every 8 weeks at an infusion center.20
Infliximab is a chimeric IgG1 monoclonal antibody composed of a murine-derived variable region and a human-derived constant region.21 It binds avidly to the trimeric, dimeric and monomeric forms of TNF-α with high specificity and affinity.18,21 In addition to its ability to neutralize soluble TNF, the clinical efficacy of infliximab is also attributed to its ability to bind membrane-bound TNF. This causes additional effects to TNF-α-producing cells, including apoptosis, complement-dependent lysis and antibody dependent cellular cytotoxicity, and thus expands the mechanisms by which it may modulate the immune processes seen in psoriasis. Particularly, by binding the tsTNF on dentritic cells, infliximab impairs their ability to activate T cells and perpetuate the inflammatory cascade.22
Adalimumab (Humira) was FDA approved for treatment of moderate-to-severe plaque psoriasis in 2008 and for psoriatic arthritis in 2005. It is administered via subcutaneous injection at a recommended dose of 80 mg at week 0 and then continued every other week at a dose of 40 mg starting at week 2.20
Adalimumab is an entirely human-derived IgG1 monoclonal antibody that targets both sTNF and tmTNF.18,21 It has similar binding properties to infliximab and prevents TNF interaction with the p55 and p75 cell surface TNF receptors.14,18 The cell-depleting effects of adalimumab are not as well characterized as infliximab, and it may also induce apoptosis, complement-dependent lysis and andibody-dependent cellular cytotoxicty in TNF-α producing cells.21
Etanercept (Enbrel) was FDA approved for treatment of moderate-to-severe plaque psoriasis in 2004 and for psoriatic arthritis in 2002. It is administered via subcutaneous injection at a recommended dose of 50 mg twice weekly for the first 12 weeks, then followed by a dose frequency reduction to once every week.20
Etanercept is a soluble dimeric recombinant fusion protein composed of the p75 cell surface TNF receptor fused to the Fc portion of IgG1.18,21 This complex forms an exogenous receptor for both the soluble and transmembrane forms of TNF and reduces their binding to cell-bound receptors, thus interrupting TNF-mediated inflammatory responses.22 Unlike infliximab and adalimumab, etanercept is univalent for TNF-α and also has the ability to bind lymphotoxin α (TNF-β).21,23 Etanercept does not appear to fix complement even though it contains the Fc portion of IgG1 and thus is unlikely to promote complement-dependent lysis and antibody-dependent cell-mediated cytotoxicty of TNF-producing cells.21
Golimumab (Simponi) (also referred to as CNTO148) is the most recently approved TNF-α inhibitor for the treatment of psoriatic arthritis and received FDA approval in 2009. It is administered by subcutaneous injection once a month and is supplied as prefilled, single-dose syringes that contain 50 mg of medication.23
Golimumab has a similar structure to adalimumab and is a human IgG1κ monoclonal antibody with a variable region that binds to both soluble and transmembrane forms of TNF-α.23 It neutralizes human TNF-α with high affinity and capacity, resulting in decreased circulation and binding of the cytokine to endogenous receptors. Moreover, studies have reported that golimumab also decreases tissue levels of C-reactive protein, vascular adhesion growth factors, matrix metalloproteinase-3, intercellular adhesion molecule-1 and interleukin 6.23
The recent discovery of the important role Th17 cells play in psoriasis pathogenesis has led to the development of therapeutic agents that specifically target this pathway.12 Specifically, IL-23 promotes the differentiation of Th17 cells and sustains their proliferation. In turn, activated Th17 cells produce important pro-inflammatory cytokines, such as IL-20 and IL-22, which induce keratinocyte hyperproliferation and epidermal remodeling implicated in psoriasis.24 Psoriatic lesions improve after blocking the IL-23/Th17 axis.24 This has paved the way for the development for a novel class of drugs, which selectively target this branch of psoriasis immunopathogenesis.
Ustekinumab (Stelara) received FDA approval in 2009 for the treatment of moderate-to-severe plaque psoriasis. It is administered via subcutaneous injection at weeks 0 and 4 and then continued once every 12 weeks thereafter.20 The recommended starting dose is 45 mg for patients weighing less than 100 kg and 90 mg for patients weighing more than 100 kg.20
Ustekinumab is a fully human IgG1 monoclonal antibody that binds with high affinity and specificity to the p40 subunit.25 This subunit is a shared component of IL-23 and IL- 12, both of which are key immune regulators in psoriasis. While IL-23 promotes the Th17 pathway, IL-12 is a heterodimeric cytokine that perpetuates the Th1 pathway.25 Therefore, ustekinumab neutralizes the bioactivity of these cytokines by preventing their interaction with the common receptor subunit IL-12Rβ1, ultimately affecting the differentiation of naïve T cells into Th17 and Th1 cells.26
Anti-T cell Agents/T-cell Blockers
T cells play a pivotal role in the pathogenesis of psoriasis. This led to the development of therapeutic approaches that directly target the T cell and inhibit their activation. Two drugs have showed promise, but one was discontinued as more data on its long-term safety became available and the other was voluntarily discontinued by the manufacturer. Here we will discuss the mechanisms of action of alefacept and efalizumab.
In 2003, alefacept (Amevive) was the first biologic drug to receive FDA approval for treatment of moderate-to-severe plaque psoriasis. However, in November 2011, it was voluntarily discontinued by the manufacturer. Alefacept was engineered as a recombinant human fusion protein containing the CD2 binding region of the leukocyte function associated antigen-3 (LFA-3) fused to the constant domain of human IgG1.20 It interfered with T cell activation by binding CD2+ and CD8+ memory T cells.20 In addition to inhibiting T cell activation, its anti-T cell effects were attributed to its ability to induce memory T cell apoptosis.27
Efalizumab (Raptiva) received FDA approval for treatment of moderate-to-severe plaque psoriasis in 2003, but was withdrawn from the market in 2009 after causing four reported cases of progressive multifocal leukoencephalopathy (PML).20 Efalizumab is a humanized recombinant IgG1 monoclonal antibody that targets the CD11a subunit of LFA-1. LFA-1 is an important cell surface antigen that facilitates T cell activation via communication with other cells.20 Efalizumab binding prevented T cell mediated processes central in psoriasis pathogenesis. In addition to its anti-T cell effects, Efalizumab also caused a decrease in the NK cell population and lesional CD11c+ dendritic cells.14,22
Ongoing clinical trials are testing the safety and efficacy of a variety of biologics for treatment of moderate-to-severe psoriasis and psoriatic arthritis (see Table 2).
Certolizumab pegol (Cimzia) is a Fab-9 fragment of a humanized anti-TNF-α monoclonal antibody that is bound to a polyethylene glycol moiety.20 It is FDA approved for the treatment of rheumatoid arthritis and severe Crohn’s disease.28 Recently, Phase II trials have been performed to investigate its use for the treatment of moderate-to-severe plaque psoriasis. Currently, ongoing Phase III studies are underway to evaluate their safety and efficacy in patients with psoriatic arthritis (www.clinicaltrials.gov). Certolizumab pegol has shown similar efficacy to that of other TNF-inhibiting agents.29 Furthermore, unlike the other TNF inhibitors, certolizumab lacks the Fc fragment of a mAb and thus does not have the capacity to induce antibody- or complement-dependent cell cytotoxicty.30
Anti-IL-17 agents are another therapeutic approach against psoriasis pathogenesis. IL-17 is produced by neutrophils, mast cells and CD4+ and CD8+ T cells.31 The two isoforms of IL-17 (IL-17A and IL-17F) are expressed as homodimers and IL-17A/17F heterodimeric proteins by T cells. However, all three cytokines have similar functions and transduce their signal via the same IL-17 receptor complex.31 Three therapeutic targets against IL-17A are being developed. A Phase III clinical trial is currently investigating the safety and efficacy of LY2439821, a humanized IgG4 anti-IL-17A monoclonal antibody. AIN-457 is a fully human IgG2 monoclonal antibody that also targets IL-17A.32 AMG-827 is a fully human IgG2 monoclonal antibody that inhibits all three forms of IL-17 by binding directly to the IL-17 receptor.25,31
Anti-IL-23 agents, such as SCH900222, are currently undergoing clinical trials to investigate their safety and efficacy for clinical use. SCH900222 is a humanized monoclonal antibody that specifically binds to the p19 subunit unique to IL-23.31 Unlike other anti-IL-23 biologics that target the p40 subunit unique to both IL-23 and IL-12, SCH900222 does not affect IL-12 and, consequently, the Th1 pathway.31
Biologics have revolutionized the treatment of psoriasis by offering therapeutic selectivity and restricting immune suppression to specific targeted pathways. While TNF-α inhibitors, anti-IL12/23 therapies and anti-T cell agents have been the main therapeutic approaches for psoriasis, current drugs will need to be modified as long-term safety data becomes available. Moreover, newer classes of drugs will need to be developed as the underlying immunologic circuits implicated in psoriasis are further deciphered.
Ms. Narahari, Dr. West and Dr. Bashiyan are with the Center for Dermatology Research and the Department of Dermatology at Wake Forest University School of Medicine in Winston-Salem, NC.
Dr. Feldman is with the Center for Dermatology Research and the Departments of Dermatology, Pathology and Public Health Sciences at Wake Forest University School of Medicine in Winston-Salem, NC.
Disclosure: The Center for Dermatology Research is supported by an unrestricted educational grant from Galderma Laboratories, L.P.