Psoriasis: Immunopathogenesis and Evolving Immunomodulators and Systemic Therapies; U.S. Experiences

T. Kormeili; N.J. Lowe; P.S. Yamauchi

Disclosures

The British Journal of Dermatology. 2004;151(1) 

In This Article

Current and Emerging Immunomodulatory Therapies for Psoriasis

Alefacept

Alefacept is a recombinant fusion protein, which is composed of the terminal portion of LFA-3 and the Fc portion of human immunoglobulin (Ig) G1. Alefacept is manufactured by Biogen (Cambridge, MA, U.S.A.) under the trade name AmeviveTM and was approved by the U.S. Food and Drug Administration (FDA) in January 2003 for the treatment of moderate to severe plaque psoriasis.

LFA-3 is expressed on APCs and is the ligand for CD2, which is expressed on mature T lymphocytes and natural killer (NK) cells. Ligation of CD2 by LFA-3 acts as a costimulatory signal and is important in the proliferation and activation of T lymphocytes.[51,52] Psoriatic lesions exhibit a predominance of lymphocytes that are memory effector T cells (CD45RO+).[53] CD2 is upregulated on CD45RO+ T lymphocytes.

Alefacept blocks the interaction between LFA-3 on APCs and CD2 on T lymphocytes through competitive inhibition (Fig. 1). The LFA-3 moiety on alefacept binds to CD2 and prevents transduction of costimulatory signals between APCs and T lymphocytes.[51,52] In addition, there appears to be another mechanism by which alefacept exerts its immunosuppressant effect.[26] Alefacept acts as a bridging molecule between CD2 that is upregulated on CD45RO+ T lymphocytes and the FcIII receptor (CD16) on NK cells. Such an interaction induces apoptosis of T lymphocytes through the release of granzyme by NK cells. Thus, alefacept inhibits the proliferation and activation of memory T lymphocytes through blockage of LFA-3-CD2 interactions and induces apoptosis of T lymphocytes through mediation between T lymphocytes and NK cells. Clinical studies have shown that LFA-3-TIP significantly prolonged primate cardiac allograft survival in baboons.[54]

Figure 1.

Immunomodulatory therapies: mechanism of action.

A multicentre, randomized, placebo-controlled, double-blind study evaluated the effectiveness of alefacept in the treatment of chronic plaque psoriasis.[26] Two hundred and twenty-nine patients received either alefacept or placebo intravenously weekly for 12 weeks with follow-up for 12 additional weeks. There was a reduction in the psoriasis area and severity index (PASI) in patients who had received alefacept vs. control subjects. Twenty-four per cent of patients who had received alefacept were clear or almost clear after 12 weeks of therapy. There were no reports of rebound or flare of psoriasis following cessation of alefacept. The average duration of remission in those who were clear was 8 months, with some lasting up to 17 months. It also demonstrated that there was a dose-dependent reduction in peripheral blood memory effector T lymphocytes (both CD4+ CD45RO+ and CD8+ CD45RO+ cells). The selective depletion of such memory T lymphocytes correlated with the improvement in psoriasis and may contribute to the prolonged remissions seen with alefacept. No serious adverse effects or symptoms of cytokine release or capillary leak syndromes were observed.[26]

A randomized, double-blind, placebo-controlled phase III study evaluated the efficacy and tolerability of two courses of alefacept in patients with chronic plaque psoriasis.[55] Patients were given two 12-week courses of either alefacept (7.5 mg once weekly intravenously) or placebo and followed up for 12 weeks after each course. Data from this study revealed a 75% or greater reduction in PASI scores after the first course in 28% of alefacept-treated patients in contrast to 8% in the placebo group (P < 0.001). After a single course of alefacept, patients who had 75% or greater reduction in their PASI score from baseline maintained a 50% or greater reduction in PASI for a median duration of 7 months, without the use of other systemic therapy or phototherapy. After the second course of treatment with alefacept, 40% of patients achieved a ≥ 75% reduction in PASI, and 71% of patients achieved a ≥ 50% reduction in PASI. Overall, alefacept was well tolerated, with the incidence of transient chills being higher in course 1 and more than 90% of such cases occurring within 24 h of the first few doses.[55] Repeated courses of intravenous alefacept have been shown to be well tolerated, and at least as effective as the initial course of therapy after subsequent courses.[56]

A multicentre, randomized, double-blinded, placebo-controlled phase III trial investigated the efficacy of intramuscular alefacept. A total of 507 patients with chronic plaque psoriasis were randomized into three groups: placebo, alefacept 10 mg or alefacept 15 mg intramuscularly once weekly for 12 weeks. This was followed by a 12-week period of observation. During the study, a higher percentage of patients who received 15 mg of alefacept achieved a significant reduction in PASI than the placebo group. Of patients in the 15 mg alefacept group who achieved at least 75% PASI reduction 2 weeks after the last dose, 71% maintained at least 50% improvement in PASI throughout the 12-week follow-up. There were no opportunistic infections and no cases of disease rebound.[57]

In addition to clinical improvement in the degree of psoriasis, alefacept has been shown to be associated with improvement in patients' quality of life as assessed by the Dermatology Life Quality Index (DLQI) and the Dermatology Quality of Life Scales (DQOLS).[58] Data revealed more significant improvement in quality of life in patients treated with alefacept 15 mg than in those treated with placebo.[59] As expected, the improvement in both DLQI and DQOLS in patients treated with alefacept correlates with the improvement in the PASI scores.

No combination therapy using alefacept and systemic agents have been reported to date. However, there is evidence that narrowband or broadband ultraviolet (UV) B in conjunction with alefacept improves psoriasis better than UVB alone.[60]

Patients who can benefit from alefacept therapy include those who have moderate to severe psoriasis (more than 10% body surface area) or who are candidates for systemic agents or phototherapy. A pretreatment CD4 count must be checked and alefacept is administered intramuscularly weekly at 15 mg for 12 weeks. Should patients require another 12-week course of alefacept, there is a minimum of 12 weeks without alefacept prior to instigating another course. CD4 counts are monitored weekly while patients are receiving the drug and if the CD4 count falls below 250 cells µL-1, the drug must be discontinued until the CD4 count increases above 250 cells µL-1. If the CD4 count remains < 250 cells µL-1 for four continuous weeks, then alefacept treatment must be permanently discontinued. In the first course of the intravenous study, 10% of patients temporarily discontinued treatment and 2% permanently discontinued treatment owing to CD4+ T-lymphocyte counts below the specified threshold of 250 cells µL-1. No opportunistic infections or organ toxicity were reported in the clinical trials.[57] Three reports of lymphomas were reported during the trials.

Efalizumab

Efalizumab is a humanized IgG1 monoclonal antibody directed against the CD11a subunit in LFA-1. Efalizumab is produced in Chinese hamster ovary cells and is humanized to reduce immunogenicity by grafting the murine hypervariable regions into consensus human IgG1/ heavy- and light-chain sequences.[61] Efalizumab is manufactured by Genentech/Xoma (San Francisco CA, U.S.A.) under the trade name RaptivaTM and was approved in October 2003 by the FDA for the treatment of psoriasis. Efalizumab is given once a week subcutaneously. The initial loading dose is 0.7 mg kg-1 followed by weekly continuous doses at 1.0 mg kg-1. The initial loading dose is lower in order to minimize the transient flu-like symptoms that were observed in the clinical trials at the higher doses.

LFA-1 is expressed on T lymphocytes and is a member of the leucocyte ß2 integrin family which functions as adhesion molecules. LFA-1 is a heterodimer composed of two subunits, CD18, which is the common ß-chain present on other ß2-integrin molecules and CD11a, the unique -chain that is targeted by efalizumab. The ligands for LFA-1 are ICAMs including ICAM-1, ICAM-2 and ICAM-3. ICAMs are widely expressed on APCs, endothelial cells, keratinocytes and fibroblasts.

Upon ligation by ICAMs, LFA-1 is important in T-cell trafficking to the skin, T-cell activation, and T-cell adhesion to keratinocytes and endothelial cells (Fig. 1). In vitro studies have demonstrated that blockage of LFA-1 binding to ICAM-1 by monoclonal antibodies directed to LFA-1 prevents signal transduction cascades downstream to LFA-1 and loss of leucocyte function.[62,63,64] ICAM-1 is upregulated on keratinocytes in psoriatic lesions.[65]

In a double-blind, placebo-controlled phase II multicentre study, patients with minimum PASI scores of 12 and affected body surface areas of ≥ 10% were treated with efalizumab at either 0.1 or 0.3 mg kg-1 intravenously.[66] The drug was administered at weekly intervals for 8 weeks. The percentage of patients who attained > 50% reduction of psoriatic plaques was 48% with efalizumab compared with 15% with the placebo group. The Physician Global Assessment of > 75% improvement was greater with the 0.3 mg kg-1 group (25%) vs. the placebo group, which was only 2%. Adverse effects were minimal with flu-like symptoms being the most common complaint.[66]

In an open-label, multicentre study, the effectiveness of a single dose of efalizumab given intravenously at varying doses (0.03-10 mg kg-1) was evaluated in the treatment of moderate to severe psoriasis.[67] Histological analysis demonstrated that doses of efalizumab > 1.0 mg kg-1 completely inhibited CD11a staining for at least 14 days in peripheral blood lymphocytes and psoriatic plaques. Lower doses resulted in complete blockage but for < 14 days. There was a correlative decrease in keratinocyte and endothelial cell expression of ICAM-1, reduction of epidermal and dermal CD3+ T lymphocytes, and atrophy of the epidermis. A dose-dependent drop in the PASI compared with baseline was observed. Patients who had received doses of efalizumab > 1.0 mg kg-1 noted improvement between weeks 2 and 10. Lower concentrations resulted in clearance of psoriatic plaques at later time intervals. The most common adverse events were headache, chills, fever and nausea. These were reversible and were more severe at higher doses. No circulating antibodies to efalizumab were detected and treatment did not decrease the number of circulating lymphocytes.[67]

In a phase III, multicentre, randomized, placebo-controlled, double-blind study, 597 subjects with psoriasis were assigned to receive either subcutaneous efalizumab (1 or 2 mg kg-1 week-1) or placebo for 12 weeks. Depending on the response after 12 weeks, subjects received an additional 12 weeks of treatment with efalizumab or placebo. Study treatments were discontinued at week 24, and subjects were followed for an additional 12 weeks. At the end of week 12, 22% of the subjects who had received efalizumab 1 mg kg-1 week-1 and 28% of those who had received efalizumab 2 mg kg-1 week-1 attained a 75% improvement in PASI, compared with 5% of the subjects in the placebo group. Efalizumab-treated subjects had greater improvement than those in the placebo group as early as week 4. Among the efalizumab-treated subjects who had an improvement of ≥ 75% or more in the PASI score at week 12, improvement was maintained through week 24 in 77% of those who continued to receive efalizumab, compared with 20% of those who were switched to placebo. After the discontinuation of efalizumab at week 24, an improvement of ≥ 50% in the PASI was maintained in approximately 30% of subjects during the 12 weeks of follow-up.[68] Efalizumab is associated with an early onset of action, as early as 14 days after administration. Relapse of psoriasis is usually seen within 60-70 days of discontinuation of therapy and rebound is noted in approximately 5% of patients, as defined by flaring > 125% of baseline. Data indicate that efalizumab can be administered for an extended period of time with most acute adverse reactions occurring at the first or second injections with decreasing incidence with each subsequent administration.[69]

A recent open-label study of efalizumab demonstrated improvement in patients with moderate to severe plaque psoriasis.[70] Patients were randomized to receive a single dose of efalizumab (0.3 mg kg-1 week-1 subcutaneously) or increasing doses of efalizumab (0.5-2.0 mg kg-1 week-1 subcutaneously) for eight weekly doses. Overall PASI scores showed improvement of approximately 40-60% in signs and symptoms of plaque psoriasis by day 56. Mean PASI scores were still declining at the end of the 8-week dosing period, suggesting that a longer duration of treatment would be more effective. By day 91 of the study, PASI scores in the 0.5-1.0 mg kg-1 week-1 group were 16.2 (increased from 14.6 at day 56) and 11.7 in the 1.0-2.0 mg kg-1 week-1 group (also increased from 10.1 at day 56 of study). No serious adverse reactions, including allergic reactions, were noted. The data concluded that subcutaneous administration of efalizumab is safe and effective in the treatment of moderate to severe plaque psoriasis.[70]

Overall, efalizumab is associated with an early onset of action and improvement is noted as early as 14 days. Studies with extended treatment suggest that continuing efalizumab therapy is more beneficial in maintaining and improving responses. The relapse of psoriasis is usually evident about 2 months after discontinuation of therapy, and rebound in approximately 5% of patients (i.e. flare to > 125% of baseline PASI score) was noted.[70]

Etanercept

Etanercept is a recombinant molecule comprising the human TNF- p75 receptor fused to the Fc portion of human IgG1 molecule (Fig. 1). Etanercept is a fully human dimeric fusion protein produced by Chinese hamster ovary cells and functions as a TNF- inhibitor by binding to and inactivating TNF- thereby preventing interactions with its cell surface receptors. Studies have demonstrated that etanercept does not induce complement-mediated cell lysis in vitro. Etanercept is approved for the treatment of rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.[71,72,73,74] Etanercept is manufactured by Amgen Thousand Oaks, CA, U.S.A. under the trade name EnbrelTM.

The dosage of etanercept for adults is 50 mg kg-1 week-1. For paediatric patients with juvenile rheumatoid arthritis (4-17 years), the dosage is 0.8 mg kg-1 week-1 (maximum 50 mg kg-1 week-1). The drug is self-administered by the patients subcutaneously. The frequency of dosing for all indications can be once a week or twice a week. Because etanercept is supplied as 25 mg doses per vial, patients are instructed to administer two shots the same day which can be given at the same time. Alternatively, etanercept can be administered twice a week, spaced every 3-4 days. Paediatric patients can administer etanercept once a week at 0.8 mg kg-1 or in divided doses twice a week at 0.4 mg kg-1. The most common locations for subcutaneous injections are the abdomen, thighs and upper arms. In order to minimize injection site reactions, patients are instructed to place their injections at least an inch apart from the prior injection site or to inject at contralateral sites.

Several studies have demonstrated that TNF- is implicated in the pathogenesis of psoriasis. TNF- levels have been shown to be increased in psoriatic plaques and in the synovial fluid of patients with active psoriatic arthritis. Furthermore, levels of TNF- have been shown to correlate with disease severity, i.e. increasing during worsening of the psoriasis and decreasing after effective therapy.[75,76,77,78] TNF-'s proinflammatory effects are numerous and have been shown to include the following:

  1. Induction of synthesis of other proinflammatory cytokines including IL-1, IL-6, IL-8, transforming growth factor-, granulocyte/macrophage colony stimulating factor and leukaemia inhibitory factor;
     

  2. Stimulation of prostaglandin (PGE2) and leukotriene (LTB4) synthesis;
     

  3. Activation of leucocytes and assistance in extravasation via upregulation of adhesion molecules such as E-selectin, vascular cell adhesion molecule and ICAM;
     

  4. Stimulation of collagenase and matrix metalloproteinase production by neutrophils and fibroblasts;
     

  5. Regulation of apoptosis; and
     

  6. Generation of acute phase reactants.[71,72,74,78]

In a randomized, double-blind, placebo-controlled study, Mease et al.[79] showed that twice weekly subcutaneous injections of etanercept (25 mg) for 12 weeks resulted in substantial remission of both psoriasis and psoriatic arthritis. The median PASI improvement was 46% in etanercept-treated patients vs. 9% in placebo-treated patients. Eighty-seven per cent of patients with psoriatic arthritis had a reduction in their arthritis as measured by the psoriatic arthritis response criteria vs. 23% of placebo-treated patients. Twenty-six per cent of etanercept-treated patients achieved a 75% improvement in the PASI compared with none in the placebo-treated group. Other reports have also shown a reduction in psoriatic arthritis when treated with etanercept.[80,81,82,83,84,85]

Iyer et al. reported six cases of patients with severe recalcitrant psoriasis partially resistant to other ongoing systemic agents whose disease activity showed marked improvement with the addition of etanercept to the treatment regimen.[86] No added toxicity was found with etanercept when added to agents such methotrexate, hydroxyurea, acitretin or ciclosporin. Thus, etanercept can be added as combination therapy to other systemic agents, especially when they are being tapered, so as to prevent any rebound recurrences. In addition, etanercept can be used in psoriatic patients who are also undergoing concomitant UVB or psoralen plus UVA therapy without additional toxicity.[86]

The phase II trial of etanercept as monotherapy treatment for psoriasis has demonstrated significant clearance of psoriatic plaques. This was a 24-week, multicentre, double-blind, placebo-controlled study in which patients with moderate to severe psoriasis (> 10% of their body surface area) and who had received at least prior systemic treatment were enrolled. Patients were randomized to receive 25 mg etanercept twice a week or placebo. At weeks 12 and 24, 30% and 56% of patients who received etanercept achieved a 75% improvement in the PASI score, respectively, vs. 2% and 5% at the same time intervals.[87]

The phase III trial conducted in the U.S.A. was a 24-week, double-blind, multicentre, placebo-controlled study in which patients were randomized to receive either placebo (n = 652) or etanercept subcutaneously at low dose (25 mg once weekly), medium dose (25 mg twice weekly) or high dose (50 mg twice weekly).[88] In the placebo group, after receiving placebo, the patients were crossed over to receive twice-weekly treatment with 25 mg of etanercept. At week 12, 4% of the patients in the placebo group attained a 75% improvement in PASI compared with 14% in the 25 mg weekly dose, 34% in the 25 mg twice-weekly dose, and 49% in the 50 mg twice-weekly dose. There was continued improvement with longer, continuous treatment. At week 24, 25% of the patients attained the PASI 75% improvement in the 25 mg weekly dose, 44% in the 25 mg twice-weekly dose, and 59% in the 50 mg twice-weekly dose. Patients in the original placebo group who were crossed over to receive etanercept 25 mg twice weekly at week 12 exhibited improvement of their psoriasis and 33% of them achieved the PASI 75% improvement - a response rate consistent with that in the 25 mg twice-weekly dose at week 12 (34%).[88]

The most frequent side-effects of etanercept included mild, transient injection site reactions, upper respiratory infections, headaches and rhinitis. The injection site reactions typically occurred 2-3 weeks into treatment but were not severe enough to warrant discontinuation of the subjects during the clinical trials. No opportunistic infections were reported during the clinical trials. Because etanercept does not induce complement-mediated lysis of cells, the frequency of tuberculosis in patients treated with etanercept is similar to the background population incidence. No laboratory monitoring is required for etanercept although rare cases of pancytopenia have been reported. There is also a higher incidence of developing antinuclear antibodies (11% vs. 5% in placebo) and antidouble-stranded DNA antibodies (15% vs. 4% in placebo). Rare incidents of demyelination have been reported with the TNF- inhibitors for the treatment of inflammatory arthritides.[89,90] The neurological events were temporally related to anti-TNF- therapy, with partial or complete resolution on discontinuation.[90] Thus, consideration should be given to avoiding use of TNF- inhibitors in patients with a history of multiple sclerosis or a family history of multiple sclerosis. There have been reports of worsening congestive heart failure (CHF) and rare instances of new onset of CHF without identifiable precipitating factors in patients treated with etanercept.[91] Therefore, the development of new neurological signs and symptoms, as well any evidence of development of CHF, should warrant discontinuation of anti-TNF- therapy.

Infliximab

Infliximab is a human-mouse monoclonal antibody that binds to and inhibits the activity of TNF- (Fig. 1). It is licensed for the treatment of rheumatoid arthritis in conjunction with methotrexate[92,93] and Crohn's disease.[94,95] Infliximab is manufactured by Centocor, Malvern, PA, U.S.A. under the trade name RemicadeTM.

Much like the other anti-TNF- agent, etanercept, infliximab has also been shown to be effective in the treatment of both psoriasis and psoriatic arthritis. A study by Chaudhari et al.[96] demonstrated in a double-blind, randomized trial that patients with moderate to severe psoriasis receiving infliximab intravenously as monotherapy at 5 mg kg-1 or 10 mg kg-1 at weeks 0, 2 and 6 experienced a high degree of clinical improvement and rapid time to response (median time 4 weeks) compared with subjects who had received placebo. Infliximab was well tolerated without serious adverse events. Other reports have also shown that infliximab alone or with combination therapy with methotrexate treats recalcitrant psoriasis.[97,98] In addition, infliximab was found not only to decrease the PASI score in patients with psoriasis, but there was a marked improvement in psoriatic arthritis as well.[80,81,99] Another recent report demonstrated that infliximab was effective in the treatment of recalcitrant psoriasis in two cases.[97]

O'Quinn and Miller have also reported two cases of single 5-10 mg infliximab infusion in patients with recalcitrant psoriatic plaques and erythroderma. Both patients showed rapid and complete clearing of their psoriasis with a disease-free interval of 3-4 months.[100] According to another study of seven patients with plaque psoriasis who received a single 5 mg kg-1 dose of infliximab, the effects of infliximab therapy are prolonged even weeks after the administration of the drug. The patients in this study showed a 69% improvement in PASI scores and 61% improvement in DLQI at 2 weeks after the single dose of infliximab. Four of the seven patients showed sustained improvement at a follow-up at 10 weeks' postinfusion. The infusion was well tolerated.[101]

In an open-label study, eight patients with severe psoriasis received 5 mg kg-1 infliximab infusions at weeks 0, 2 and 6, and biopsies were obtained at weeks 0, 1 and 10 (the endpoint of the treatment phase). Data confirmed a mean PASI decline from 21.8 at week 0 to 3.4 at week 10. At the 14-week follow-up PASI was 7.1 ± 2.7, with a decrease in pruritus from 2.5 at 0 weeks, and 0.43 at 10 weeks to 0.83 at the 14-week follow-up.[102] The same data were reported by Gottlieb et al. after use of infliximab in the treatment of moderate to severe psoriasis.[103]

According to a recent study, 33 patients with moderate to severe plaque psoriasis were treated with three doses of infliximab at 5 or 10 mg kg-1 doses vs. placebo at weeks 0, 2 and 6, and responding patients were retreated with open-label infliximab at the same dose for weeks 10-26 as needed. Placebo nonresponders were then treated with infliximab at the 5 or 10 mg kg-1 dose and followed up through week 26, for a total of 29 patients who received either 5 or 10 mg kg-1 of infliximab in the open-label extension. At week 26, PASI score reductions were sustained at 40% for the 5 mg kg-1 and 73% for the 10 mg kg-1 dose of infliximab, documenting a rapid but sustainable improvement of psoriatic plaque reduction with infliximab therapy.[104]

Clinical trials have shown improvement in both skin as well as synovitis of the joints. Up to 82% of patients treated with infliximab achieved a > 75% response in PASI which correlated with a reduction of synovitis and magnetic resonance imaging findings of the joints within 10 weeks.[105] Al-Salem reports two cases with severe active psoriatic arthritis who both demonstrated dramatic improvement in their psoriatic skin lesions as well as concomitant improvement in their arthritis symptoms after receiving infliximab infusion at a dose of 5 mg kg-1.[106]

Unwanted adverse effects with infliximab included infections, infusion-related effects, headaches, vertigo, flushing, gastrointestinal effects, abnormal hepatic functions and fatigue. Because infliximab is a chimeric antibody (fusion of murine and human antibodies), human antichimeric antibody formation may occur which would result in loss of efficacy. For that reason, methotrexate is used in conjunction with infliximab for the treatment of rheumatoid arthritis. In addition, because infliximab induces complement-mediated lysis of cells, there is a higher incidence of tuberculosis compared with the background population. For this reason, tuberculin skin testing is required on all patients undergoing therapy with infliximab.[106]

Adalimumab

Adalimubab is a human IgG1 human monoclonal antibody directed against TNF- and blocks its interaction with the p55 and p75 cell surface receptors (Fig. 1). Adalimubab also lyses cells that express surface TNF- in the presence of complement. Adalimumab was FDA approved for the treatment of rheumatoid arthritis in December 2002. The dosage of adalimubab for adults with rheumatoid arthritis is 40 mg subcutaneously every other week as a self-injection. As with infliximab, patients who will undergo therapy with adalimubab should have a tuberculin skin test performed. Adalimubab may be used alone or combined with methotrexate for rheumatoid arthritis. Adalimubab is manufactured by Abbott Laboratories (Abbott Park, IL, U.S.A.) under the trade name HumiraTM.

Currently, adalimubab is undergoing phase II clinical trials for psoriasis and phase III studies for psoriatic arthritis.

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