Potential of Tumor Necrosis Factor Inhibitors in Psoriasis and Psoriatic Arthritis FREE

CYTOKINES ARE SOLUBLE PROteins that help orchestrate cell-to-cell communication by regulating processes in nearby cells. Affected processes may include gene expression and cell proliferation, survival, differentiation, and migration.^{1 - 3} The role of cytokines is particularly clear during an immunologic response; they are responsible for initiating, maintaining, and resolving inflammation. Indeed, the evolution of an inflammatory event is dependent on a coordinated and balanced production of cytokines (Table 1).

One of the key cytokines central to many biological processes is tumor necrosis factor (TNF). Low levels of TNF produced by tissue macrophages under physiologic conditions may be involved in maintaining cellular and tissue homeostasis.¹² The production of TNF increases in response to microbial infection and tissue injury. Macrophages, T cells, mast cells, neutrophils, dendritic cells, keratinocytes, and endothelial cells are capable of producing TNF when exposed to inflammatory stimuli.^{13 - 19} As a primary mediator of inflammation,^{12 ,20 - 21} TNF promotes the recruitment of leukocytes from the circulation into tissue by stimulating an increase in the expression of adhesion molecules on endothelial cells (E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1) and keratinocytes.^{22 - 26} Leukocyte recruitment is accompanied by an increase in vascular permeability, which allows macromolecules in the plasma, such as fibrinogen, immunoglobulin, and complement, to enter the site of inflammation.²⁷ Tumor necrosis factor also modulates the communication between T cells and the vascular endothelium by altering the cell surface expression of class I major histocompatibility complex molecules on endothelial cells.^{28 - 29} Experiments using mixed lymphocyte reactions and TNF knockout mice have shown that TNF also regulates the recruitment of leukocytes by stimulating the production of chemokines, a subset of cytokines that are mainly involved in promoting leukocyte migration. These chemokines include monocyte chemoattractant protein-1, interleukin (IL) 8, RANTES, and interferon-γ–induced monokine.^{21 ,30 - 31} Tumor necrosis factor also stimulates the production of other proinflammatory cytokines, including IL-1, IL-5, IL-6, and transforming growth factor.^{32 - 34}

The synthesis of TNF, as well as other cytokines, is stringently regulated to prevent immunologic responses from becoming persistent. Chronic inflammation is problematic because the continuous production of proteases and reactive oxygen species can cause tissue damage,^{35 - 36} and the overproduction of cytokines themselves may cause injury.^{37 - 38} Therefore, mechanisms have evolved to counteract high cytokine levels, such as the production of soluble cytokine receptors. Soluble receptors for TNF, IL-1, and IL-6 are present in healthy individuals, but levels are elevated during certain inflammatory diseases, presumably to neutralize excess cytokines.^{39 - 40} Perturbations in cytokine production and/or release can result in pathologic conditions. For example, the continuous synthesis of TNF in localized areas is associated with the development of chronic inflammatory diseases, including psoriasis, psoriatic arthritis (PsA), and rheumatoid arthritis.^{41 - 43}

Substantial evidence suggests that TNF plays a fundamental role in the pathogenesis of psoriasis and PsA. In patients with psoriasis, higher levels of TNF immunoreactivity and biological activity have been found in lesions than in clinically normal skin.⁴⁴ Intense TNF immunoreactivity has been localized to epidermal keratinocytes, intraepidermal Langerhans cells, and dermal cells, including endothelial cells, fibroblasts, and macrophages.^{45 - 46} Elevated levels of TNF have also been detected in the synovial fluids of patients with PsA.⁴² Importantly, Mizutani and colleagues⁴⁷ observed that the production of TNF by peripheral blood mononuclear cells from patients with active psoriasis was positively linked with clinical severity. Levels of TNF in psoriatic skin blister fluids are also significantly correlated with Psoriasis Area and Severity Index (PASI) scores, linking TNF and the symptoms of psoriasis.⁴⁸ However, the most convincing evidence implicating TNF in the pathogenesis of both psoriasis and PsA is the ability of TNF antagonists to reduce the symptoms of disease. Patients with psoriasis or PsA experience clinical benefit when treated with therapies that directly inhibit TNF function, such as etanercept and infliximab.^{49 - 55} Furthermore, inhibitors of inflammation that improve clinical symptoms of disease also reduce serum and lesional levels of TNF.^{56 - 58}

The synthesis and release of TNF and other proinflammatory factors by mast cells and epidermal keratinocytes are early events during inflammatory processes.^{18 ,59 - 60} In psoriasis and PsA, TNF may induce myriad cellular responses because of the structural and functional heterogeneity of the TNF receptors and the diversity of postreceptor signal transduction pathways.⁶¹ The 2 major TNF receptors, p55 and p75, are expressed on a variety of cell types, including neutrophils, monocytes, lymphocytes, vascular endothelial cells, and fibroblasts,^{62 - 64} and can have distinctive as well as overlapping functions. Studies using p55- and p75-deficient mice have found that the p55 receptor, but not the p75 receptor, is involved in mediating several host defense and inflammatory responses.^{65 - 67} In contrast, the p75 receptor has a dominant role in suppressing TNF-mediated inflammatory responses,⁶⁶ although both receptors are involved in certain processes, such as TNF-induced vascular permeability.⁶⁸

Signals initiated by TNF via the p55 and p75 receptors lead to the induction and perpetuation of inflammatory responses in the skin and/or synovium during flares of psoriasis and PsA. Studies examining the effects of recombinant or purified TNF in vivo and in short-term tissue cultures of skin have shown that this cytokine initiates inflammation by stimulating the expression of adhesion receptors on endothelial cells and keratinocytes, thereby promoting the infiltration of inflammatory cells.^{25 - 26} Tumor necrosis factor is also thought to stimulate these effects in psoriasis and PsA, since TNF levels, adhesion receptor expression, and inflammatory cell numbers are elevated in psoriatic skin lesions and in the synovial membrane of patients with PsA.^{42 ,46 ,69 - 72} This induction of adhesion receptor expression on vascular endothelial cells and keratinocytes is a crucial step during inflammation because these receptors facilitate rolling, adhesion, and migration of inflammatory cells from the peripheral blood into tissue. Indeed, the number of T lymphocytes in new and active psoriatic skin lesions has been shown to significantly correlate with the degree of E-selectin and vascular cell adhesion molecule-1 expression on microvessels in the lesions.⁷³

The inflammatory infiltrate that occurs in lesional psoriatic skin and in the synovial membrane in PsA consists mainly of activated leukocytes (CD4⁺ and CD8⁺ T lymphocytes, macrophages, and neutrophils), which can mediate tissue damage by producing proteases and reactive oxygen species.^{72 - 75} In psoriasis, the accumulation of leukocytes in the skin may also play a role in stimulating keratinocyte proliferation. Basal keratinocyte stem cells hyperproliferate in lesional skin during psoriasis, but proliferation rates are near normal in the asymptomatic normal-appearing skin.⁷⁶ The exact cause of this abnormal growth response is not fully understood, although the local production of growth factors, including epidermal growth factor, heparin-binding epidermal growth factor–like growth factor, insulinlike growth factor 1, and fibroblast growth factor, could, directly or indirectly, drive the hyperproliferative response in the epidermis.^{77 - 79} Indirect evidence suggests that these growth factors may be produced by leukocytes that have infiltrated the lesion; T lymphocytes derived from lesional psoriatic skin can promote keratinocyte proliferation in vitro, and cultured T lymphocytes can synthesize heparin-binding epidermal growth factor–like growth factor and fibroblast growth factor.^{80 - 81} Thus, TNF supports key elements in the development of psoriasis and PsA, namely, the recruitment of leukocytes that produce factors mediating tissue damage and cell proliferation.

In addition to initiating inflammation, TNF may also act synergistically with other cytokines to maintain an immune response that perpetuates psoriasis and PsA. These other cytokines may include interferon-γ, IL-1, and IL-6, which have been localized to psoriatic skin lesions and PsA synovial fluid.^{42 ,48 ,82 - 83} Studies conducted in vitro indicate that TNF, in combination with other cytokines, augment cytokine-driven processes. The combination of TNF plus IL-1 was more effective at stimulating chemokine production from synoviocytes than either of these cytokines alone.¹⁰ Tumor necrosis factor has also been shown to synergize with interferon to enhance intercellular adhesion molecule-1 expression on keratinocytes and with IL-6 to stimulate extracellular matrix production from monocytes.^{84 - 85} This provides additional support for the concept that TNF further stimulates inflammatory phenomena in the skin and synovium by acting synergistically with other cytokines produced at these sites.

In addition to TNF, activated T cells also play an integral role in the development of psoriasis⁸⁶ and PsA. Evidence for this includes the observation that these cells accumulate in psoriatic skin lesions and in the synovium of patients with PsA.^{72 ,75 ,87} Furthermore, T cells from patients with psoriasis triggered the development of psoriatic plaques when injected into autologous uninvolved skin that was transplanted to immunodeficient mice.^{88 - 89} This suggests that activated T cells are a major driving force in the pathogenesis of psoriasis.

The molecular mechanisms by which T cells promote the development of psoriasis and PsA are not fully understood but likely involve an interrelationship between these cells and TNF. This notion is strengthened by experiments that show that the repeated intradermal injection of TNF leads to the formation of an inflammatory infiltrate consisting primarily of CD4⁺ T cells.²⁵ The accumulation of T cells, as well as the infiltration of T cells in the synovium of patients with PsA, is largely due to the TNF-mediated production of soluble factors that are known to attract T cells, such as monocyte chemoattractant protein-1 and macrophage inflammatory protein-3α.^{11 ,90} The T-cell population that accumulates in psoriatic lesions has a type 1 cytokine profile; that is, they produce TNF, IL-2, and interferon.⁶⁹ These T-cell–derived cytokines can facilitate the recruitment of more leukocytes by stimulating the expression of cell adhesion molecules, chemokines, and proteinases. Thus, it is proposed that there is a cyclic interaction between TNF and T cells, which results in the maintenance of chronic inflammation in patients with active psoriasis and PsA. The key components of this cyclic interaction are increased production of proinflammatory cytokines, increased expression of adhesion molecules, and increased trafficking of immune cells.

The fundamental role of T cells in the development of psoriasis and PsA makes this cell type a logical therapeutic target. In fact, new drugs that inhibit T-cell activation or specifically kill activated T cells are currently under development for the treatment of these diseases.^{91 - 92} Since TNF plays a central role in psoriatic diseases, therapies that target this cytokine have also been developed. Certain biologic agents that specifically inhibit TNF are efficacious in rheumatoid arthritis and have also been shown to be effective in the treatment of psoriasis and PsA.

The best-characterized TNF inhibitors that have been developed for therapeutic purposes are etanercept and infliximab. Etanercept is a soluble, dimeric fusion protein consisting of 2 molecules of the ligand-binding portion of the human TNF receptor (p75) fused to the Fc portion of human IgG1.⁹³ Since etanercept is dimeric, it has the capacity to bind to 2 molecules of TNF. Etanercept binds to soluble and transmembrane-bound TNF and lymphotoxin-α, thereby inhibiting their interaction with cell surface TNF receptors.⁹⁴

Infliximab is a mouse-human chimeric monoclonal antibody that binds specifically to soluble and membrane-bound TNF.⁹⁵ This biologic agent blocks TNF function by inhibiting the interaction between the cytokine and its receptor. Because infliximab is a complement-fixing antibody, it can trigger complement-dependent and cell-mediated cell lysis when bound to TNF on the cell surface. This was confirmed by Scallon and colleagues,⁹⁵ who used in vitro cytotoxicity assays to examine the lytic potential of infliximab. In this study, infliximab promoted complement-dependent and cell-mediated lysis of cells expressing membrane-bound TNF.⁹⁵ These observations may have negative implications in vivo, since several cell types, such as monocytes and activated T cells, express membrane-bound TNF.^{96 - 98} Alternatively, the destruction of these cells may help dampen the immune response and thus improve clinical symptoms.

Etanercept is effective at reducing the signs and symptoms of arthritis and has been approved by the Food and Drug Administration (FDA) for use in PsA. In a double-blind, placebo-controlled trial of 60 patients with PsA and psoriasis, etanercept, 25 mg, given twice weekly for 12 weeks, was found to improve both joint and skin symptoms.⁴⁹ At 12 weeks, 87% of the patients in the etanercept group met the PsA response criteria compared with 23% of the patients in the placebo group. The American College of Rheumatology criteria for improvement (ACR20) was achieved by 73% of the patients given etanercept compared with 13% of the patients given placebo.⁴⁹ Efficacy with etanercept was also observed in a large randomized, double-blind, placebo-controlled, phase 3 trial by Mease and colleagues.⁵⁴ In this study, 101 patients received etanercept and 104 received placebo. At 12 weeks, the ACR20, ACR50, and ACR70 responses were met by 59%, 38%, and 11%, respectively, of the patients in the etanercept group compared with 15%, 4%, and 0%, respectively, of the patients in the placebo group.⁵⁴ Efficacy with etanercept was maintained after 24 weeks; 50%, 37%, and 9% of the patients given etanercept met the ACR20, ACR50, and ACR70, respectively, compared with 13%, 4%, and 1% of the patients receiving placebo. Lesions from psoriasis patients were evaluated by PASI and by improvement in target lesion score. At 24 weeks, patients treated with etanercept had a median improvement in PASI score of 47%, while no improvement was seen in patients taking placebo. Similarly, patients treated with etanercept had a median 33% improvement in target lesion score compared with 0% in patients treated with placebo.⁵⁴

In a 1-year open-label extension from the original baseline, radiographic progression was compared in patients receiving etanercept vs placebo. Scoring of all 205 patients' x-ray films revealed significantly reduced radiographic progression among the etanercept-treated patients, with a negative mean rate of change in Sharp score of −0.02 units. In contrast, patients receiving placebo showed a mean rate of progression of +1.03 units. Additionally, etanercept-treated patients showed a mean rate of change in erosion score of −0.08 units per year vs a change of +0.69 units per year in the placebo group. Joint space narrowing mean rates of change also favored etanercept-treated patients (+0.06 units per year compared with +0.35 units per year for placebo).⁵³

Patients with chronic plaque psoriasis are also highly responsive to etanercept. This was recently shown in a phase 2 study that examined the efficacy of etanercept in patients who had plaque psoriasis affecting at least 10% of their total body surface area. The investigators found that 56% of the patients achieved a 75% improvement in PASI score after 24 weeks of therapy with etanercept, 25 mg twice weekly.⁵⁵ In contrast, only 5% of the placebo-treated patients reached this end point. Therapy with etanercept also resulted in substantial target lesion clearing: a 75% response in lesion clearing was observed in 56% of patients treated with etanercept compared with only 4% of patients treated with placebo.⁵⁵ This early study indicates that etanercept will be useful in the management of chronic plaque psoriasis.

Etanercept has also been studied in patients with refractory PsA.^{50 ,99 - 100} Cuellar and colleagues⁹⁹ examined etanercept therapy in 12 patients with PsA who were unresponsive to methotrexate alone or in combination with other disease-modifying antirheumatic drugs. The mean PASI score was 8 ± 6 at baseline, but improved to 1 ± 1 after treatment with etanercept (average duration of follow-up was 10 months). Most patients (10 of 12) experienced complete resolution of skin lesions, nail lesions, and joint involvement.⁹⁹ In a similar study, etanercept, 25 mg, was administered twice weekly to 10 patients with refractory PsA.⁵⁰ Before receiving etanercept, patients had a mean of 6.1 actively inflamed joints, which decreased to 1.1 at 3 months after treatment.⁵⁰ At 12 months after treatment with etanercept, 3 of the 4 patients with active skin disease had complete skin clearing.

Disease-modifying antirheumatic drug–refractory patients with PsA experienced an improvement in health-related quality of life after treatment with etanercept, as shown by data from a randomized, double-blind, placebo-controlled study. Patients in this trial completed the Health Assessment Questionnaire, the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and the EuroQoL Feeling Thermometer at baseline and at 24 weeks after treatment with either etanercept, 25 mg twice weekly (n = 101), or placebo (n = 104).¹⁰¹ The mean Health Assessment Questionnaire score at 24 weeks improved by 53.6% in the etanercept group and 6.4% in the placebo group. In the Physical Component Summary (PCS) of the SF-36, the mean change in score at 24 weeks was 9.3 units in the etanercept group and 0.7 in the placebo group.¹⁰² Improvement in health-related quality of life was also evident from the feeling thermometer scores; patients receiving etanercept experienced a mean improvement of 14.3 units, compared with 2.1 units in patients receiving placebo.

Treatment with etanercept is generally well tolerated; mild injection site reactions are the most common adverse events reported in patients with psoriasis and PsA.⁴⁹ A similar safety and tolerability profile has been observed in patients with rheumatoid arthritis treated with etanercept.^{103 - 106} In general, biologic agents that inhibit TNF are associated with certain risks. For example, rare cases have been reported outside of clinical trials describing the development of demyelinating conditions, opportunistic infections, aplastic anemia, pancytopenia, and lupuslike conditions during treatment with etanercept.^{107 - 108} Further analyses are necessary to determine whether etanercept increases the probability of developing these conditions above the frequency that is seen in patients with rheumatoid arthritis who are not being treated with this biologic agent.

Although not approved by the FDA for the treatment of either psoriasis or PsA, infliximab holds promise in treating these diseases. For example, observations from a randomized, double-blind, placebo-controlled trial of 33 patients with plaque-type psoriasis indicated that treatment with infliximab results in clinical benefit.⁵² In this small investigator-initiated trial, patients received placebo, infliximab (5 mg/kg), or infliximab (10 mg/kg) at weeks 0, 2, and 6. The primary end point, the physician's global assessment, was determined at week 10. In the infliximab groups (5 mg/kg and 10 mg/kg), 82% and 91% of the patients, respectively, had an excellent or clear rating on the physician's global assessment. In contrast, only 18% of the patients in the placebo group achieved these ratings.⁵² Furthermore, 82% of the patients in the 5-mg/kg infliximab group and 73% in the 10-mg/kg infliximab group had at least a 75% improvement in the PASI score compared with 18% of patients in the placebo group.

Clinical benefit in infliximab-treated PsA patients has also been reported. In a study of 9 patients with psoriasis and PsA, a regimen of 5 infusions of infliximab, 3 mg/kg, given over 22 weeks was examined for effects on disease symptoms.¹⁰⁹ After 2 weeks of therapy, the median swollen and tender joint counts decreased from 5.3 and 17.8 to 1.44 and 9.77, respectively. Over the entire treatment period, the mean PASI score changed from 19.04 to 4.91, indicating more than a 74% reduction in PASI score.¹⁰⁹ Efficacy in PsA was also observed in a recent study by Ogilvie and colleagues.⁵¹ Patients (N = 6) with progressive joint disease and psoriatic skin lesions despite treatment with methotrexate (5 patients) or sulfasalazine (1 patient) were treated with infliximab, 5 mg/kg, at weeks 0, 2, and 6. These patients also continued to receive methotrexate or sulfasalazine during the study period. At the end of 10 weeks, PASI scores indicated that improvement occurred in all patients. Improvement in joint disease was also noted. Similarly, an open-label pilot study involving 21 patients with spondyloarthropathy, including 8 patients with PsA, found that treatment with infliximab reduced the symptoms of joint disease.¹¹⁰ Again, skin disease as measured by PASI improved significantly. Preliminary data from a multicenter, randomized, placebo-controlled, double-blind clinical trial involving 102 patients with PsA support the findings from uncontrolled trials and case reports.¹¹¹ Patients in the infliximab arm were given infliximab, 5 mg/kg, at weeks 0, 2, 6, and 14. Concomitant disease-modifying antirheumatic drug therapy at stable doses was allowed. At 16 weeks, 70.6% of infliximab-treated patients achieved ACR20 response criteria compared with 9.8% of placebo-treated patients. A mean reduction of 80.9% in PASI scores was observed in the infliximab group. Infliximab thus appears to be efficacious in improving both joint and skin symptoms.

Treatment with infliximab is generally well tolerated. The most common adverse events reported in patients receiving infliximab are mild headache, upper respiratory tract infections, and infusion reactions.^{52 ,112 - 114} The long-term use of infliximab is associated with the development of human antichimeric antibodies, which is the reason why infliximab is coadministered with methotrexate in patients with rheumatoid arthritis.¹¹⁵ The development of human antichimeric antibodies may potentially reduce the effectiveness of therapy over time, perhaps leading to dose escalation.¹¹⁶ Rare cases have been reported outside of clinical trials describing the association of infliximab with the development of demyelinating disease, lupuslike conditions, and opportunistic infections, including tuberculosis.^{107 ,117} In the multicenter infliximab PsA trial, 1 case of joint infection was observed in the first 16 weeks of therapy.¹¹¹

The cytokine TNF is a key regulator of inflammation, exerting effects on the expression of adhesion molecules, the recruitment of inflammatory cells, and the release of other cytokines and chemical messengers. As such, the aberrant regulation of TNF function plays a major role in the development of chronic inflammatory diseases, including psoriasis and PsA. This makes TNF an excellent target for intervention strategies (ie, TNF-neutralizing therapies) for these diseases.

Most traditional therapies for psoriasis and PsA, such as methotrexate, cyclosporine, and corticosteroids, broadly target T-cell activity. While these therapies do not cure psoriasis and PsA, they do provide varying levels of patient and physician satisfaction. On the other hand, concerns over major adverse effects, such as liver toxic effects with methotrexate and renal toxic effects with cyclosporine, continue to be problematic with the long-term use of these traditional therapies.^{118 - 119} The development of biologic agents that specifically inhibit TNF, such as etanercept and infliximab, has provided clinicians with a valuable alternative to traditional disease-modifying antirheumatic drugs. Tumor necrosis factor–neutralizing therapies are well tolerated and appear to be effective in treating psoriasis and PsA.

Corresponding author and reprints: Gerald Krueger, MD, University of Utah School of Medicine, Department of Dermatology, 30 N 1900 East–4B454SOM, Salt Lake City, UT 84132 (e-mail: krueger@derm.med.utah.edu).

Accepted for publication June 18, 2003.