Long-term data in the treatment of psoriasis

Authors


  • Conflicts of interest
    The author has acted as a Consultant for Abbott Laboratories, Essex Pharmaceuticals, Novartis and Wyeth, and has received grants/research support from Abbott, Novartis, Essex/Schering Plough. He has received honoraria for presentations/lectures from Abbott, Biogen, Essex/Schering Plough, Novartis, Almiral/Hermal, Serono and Wyeth.

D. Thaçi.
Tel: +49 69 63 01 65 56
Fax: +49 69 63 01 73 75
E-mail: thaci@em.uni-frankfurt.de

Summary

Moderate-to-severe plaque psoriasis is associated with a considerable disease burden and treatment needs are often unmet. Several conventional systemic drugs are available as treatments, including methotrexate, ciclosporin, retinoids and psoralen ultraviolet A, which, although effective, are associated with considerable toxicity that limits their long-term use. Recent developments in more targeted therapies involving biological agents, such as anti-T-cell agents and inhibitors of tumour necrosis factor-alpha, offer an alternative treatment approach with the possibility of longer continuous therapy, which may translate into disease control and improved quality of life. Although the majority of data supporting the use of biological agents have been obtained in short-term studies of 3–6 months’ duration, some agents have been evaluated for longer periods of continuous administration. Comparison of efficacy among these agents may better define their role as long-term therapy. This article discusses the data currently available on both conventional and biological systemic therapies for psoriasis, in terms of short-term and long-term use.

Psoriasis is a chronic, inflammatory skin disease with a remitting/recurring course that requires active, lifelong management in most patients. Approximately 20–30% of affected individuals require continuous, long-term, systemic therapy to achieve effective symptom control.1 The burden of psoriasis is substantial, with effects on quality of life (QoL) comparable with those observed with major chronic diseases such as cancer, arthritis and depression.2 Although conventional systemic treatments for psoriasis [e.g. methotrexate, ciclosporin, oral retinoids, psoralen ultraviolet A (PUVA)] may be effective for short-term symptom relief, they are associated with serious toxicities that limit their long-term use,3 and patients using such treatments are faced with the inconvenience of rotational, intermittent or step-wise treatment regimens and regular safety monitoring.4 Furthermore, symptom control with conventional agents is often suboptimal. For example, extended follow-up of patients treated with PUVA, a standard agent in clinical practice that is generally considered effective, and intermittent methotrexate revealed no long-term improvements in disease severity and that 50% of patients still had moderate-to-severe psoriasis despite treatment.5 Additionally, patient dissatisfaction with current treatments is high,6,7 and a substantial proportion of patients with moderate-to-severe psoriasis do not receive any systemic treatment.8

Further elucidation of the molecular and cellular pathways involved in psoriasis has led to the development of target-specific biological therapies.9,10 Due to their targeted mode of action, biological therapies have improved safety and, thus, have an improved benefit-to-risk profile compared with conventional systemic treatments.4 Biological therapies offer the possibility of long-term, continuous therapy – a new treatment paradigm in psoriasis.10 The integration of such agents into the clinical management of patients with moderate-to-severe psoriasis requires an appreciation of their relative efficacy, in particular when used as continuous and/or long-term therapy. This is confounded by the fact that data on the use of conventional systemic therapies for long-term treatment are sparse, with most randomized controlled trials (RCTs) involving small samples.3,11 In addition, there is a lack of direct comparator studies on systemic treatments in psoriasis, with only two active comparator trials in the published literature.12,13

This article will present an overview of the available efficacy data on both conventional and biological systemic therapies for the treatment of moderate-to-severe psoriasis, emphasizing, where possible, their efficacy as long-term or continuous therapy. It should be borne in mind that comparisons between studies are complicated by the lack of standardized efficacy assessments, which may include percentage improvements in the Psoriasis Area and Severity Index (PASI), mean change in PASI over time, and QoL scores.11 More recent RCTs of biological agents have typically used a 75% improvement in PASI (PASI-75) as a primary endpoint, which is the measure used here to compare efficacy across studies and agents, although reference is made to other measurements, where appropriate. PASI-75 response data from such studies are summarized in Table 1.13–35

Table 1.   PASI-75 response rates for biological agents in psoriasis
AgentLength of treatment
12–16 weeks24 weeks48–60 weeks15 months24 months27 months36 months
Patients achieving PASI-75 (%)
  1. N/A, data not available; PASI-75, 75% improvement in Psoriasis Area and Severity Index.

  2. aThis study used an unlicensed etanercept treatment schedule of 50 mg twice a week.

Alefacept28–3314,15N/AN/AN/AN/AN/AN/A
Efalizumab28–3916–2039–4417–1957215821552256224523
Etanercept34–4924–2844–5926,276328N/A51a29N/AN/A
Infliximab70–8030–3264–8232,3344–6132,33N/AN/AN/AN/A
Adalimumab71–8013,34,35703556–6434N/AN/AN/AN/A

Non-biological systemic therapies

Methotrexate is a folate antagonist that inhibits DNA synthesis, thereby affecting epidermal cell replication, with additional actions that lead to suppression of T-cell activity. Although methotrexate is a well-established systemic therapy for moderate-to-severe psoriasis, long-term efficacy data are limited,3,11 and the rationale for its use has been based largely on clinical experience.36 A direct comparator study involving 88 patients found methotrexate and ciclosporin to be equally effective, with approximately 60% of patients achieving PASI-75 after 16 weeks of either treatment.12

More data are available on the efficacy of the immunosuppressant ciclosporin, although variation in the outcomes reported complicates direct comparisons.11 In placebo-controlled studies, notable improvements in disease scores were found after short-term use of ciclosporin as induction therapy.3,37,38 Published reports on ciclosporin as maintenance therapy found clinically significant improvements in 86–95% of patients (as measured by improvements in baseline PASI) when ciclosporin was used as continuous therapy or dosed intermittently over 6–17 months,39–41 with improved QoL scores also demonstrated.42 Although ciclosporin has been used in longer treatment courses,43,44 the occurrence of treatment-related toxicity limits continuous therapy with ciclosporin to a recommended maximum of 2 years.44

The other traditional systemic therapy for psoriasis is the retinoid acitretin, although it is difficult to draw conclusions regarding its efficacy as monotherapy because of the heterogeneity among clinical studies evaluating its use, particularly at doses that do not result in clinically significant adverse effects.45 One systematic review concluded that acitretin as monotherapy is modestly effective.3 In clinical practice, acitretin is used most often in combination with other agents such as PUVA, with which a synergistic response has been seen.3,46 As is the case with other conventional systemic treatments for psoriasis, there is a lack of published long-term data for acitretin.

Fumaric acid esters (FAE) are licensed for short-term (< 6 months) use in patients with severe psoriasis in Germany, but not in other countries, which limits data on this therapy. Clinical trials have reported a reduction in PASI score of between 50% and 80% after 12–16 weeks of treatment with FAE,47,48 but use of these agents is limited by gastrointestinal complaints (in up to 60% of patients) and flushing (in 30–50%), which can be severe. Although there is a lack of published controlled studies, clinical experience suggests that treatment with FAE can be maintained for up to 2 years.

The clinical use of conventional systemic agents as continuous therapy is complicated by treatment-related toxicity, most notably end-organ toxicity to liver (e.g. with methotrexate) and kidney (e.g. with ciclosporin)1,3,36,44 and, especially in patients previously treated with ciclosporin, an increased risk of non-melanoma skin cancer in patients exposed to PUVA, particularly with long-term administration.1,3,44 In addition, there are practical considerations, such as the need for frequent monitoring of hepatic and renal function, and the likelihood of drug–drug interactions. Such constraints have limited the use of these agents to an intermittent basis, in lower doses as combination therapy, or in rotational or sequential regimens,46 which explains to some extent the paucity of long-term data for single-agent use.

Biological therapies

Efficacy and safety of alefacept

Alefacept is a chimeric fusion protein of leukocyte function-associated antigen (LFA)-3 and the Fc region of immunoglobulin (Ig) G1 that targets CD2+  cell populations, including T cells and natural killer cells, by blocking LFA-3/CD2 interaction and inducing T-cell apoptosis.9

The efficacy of alefacept as induction therapy has been demonstrated in placebo-controlled studies.14,15,49 In one Phase III study involving 367 patients receiving a 12-week course of alefacept (75 mg administered intravenously once weekly), 28% of patients achieved PASI-75, rising to 40% in those patients receiving a second treatment course.14 Another Phase III study comparing alefacept and placebo in 507 patients reported that 28–33% of patients achieved PASI-75 with 12 weeks of alefacept 10 or 15 mg, administered intramuscularly once weekly.15 It has been suggested that a 16-week course of induction therapy is more effective than a 12-week course.49

Data for longer treatment with alefacept are based on reports of repeated 12-week treatment courses. Follow-up data from both Phase III studies reported on response to successive treatment courses.50,51 After one course of therapy, 29% of patients achieved PASI-75.50 Among 647 patients who received at least two courses of alefacept, an incremental response was seen after successive courses, with 54% of the 89 patients who received five courses achieving PASI-75.50 For patients who responded, remission lasted an average of 7 months. Continuous treatment is not prescribed in clinical practice; rather, alefacept is given as intermittent 12-week treatment courses, either as monotherapy or in combination with other agents.51

Although there are still concerns about treatment-related lymphopenia, specifically a reduced CD4+  T-cell count, the incidence of serious infection was < 1% across the alefacept clinical trials.51 Monitoring CD4+ cell counts is necessary prior to and during alefacept therapy. The most common adverse events (AEs) included headache, upper respiratory tract infection and pruritus. Safety data for alefacept are limited mainly to those derived from approximately 2000 patients in 13 clinical trials.51 Longer-term data are needed to establish the safety profile of this agent, particularly with regard to the theoretical increased risk of malignancy and serious infection.

Efficacy and safety of efalizumab

Efalizumab is a humanized monoclonal IgG1 antibody that binds to the α subunit (CD11a) of LFA-1, blocking its interaction with intercellular adhesion molecule-1, and inhibiting both T-cell activation and migration into the dermis, where subsequent T-cell reactivation and interaction with keratinocytes are inhibited. Thus, efalizumab acts at multiple stages in the immune cascade involved in the pathogenesis of psoriasis.9 The short-term efficacy of efalizumab has been demonstrated in pivotal studies involving over 1600 patients, of whom 1172 received efalizumab.16–20 These studies report PASI-75 being achieved in 28–39% of patients after 12 weeks of efalizumab treatment, administered at doses of 1 or 2 mg kg−1 wk−1.16–20 Furthermore, an increased response was found with extended therapy, with 39–44% of patients achieving PASI-75 after 24 weeks of continuous treatment.17–19 In these studies, a rapid improvement in symptoms was seen within 2–4 weeks. Efalizumab is particularly effective in ‘high-need’ patients (i.e. patients for whom at least two systemic treatments had failed or were contraindicated), as demonstrated by the CLEAR study in 793 patients (529 receiving efalizumab), of whom 526 (342 receiving efalizumab) were ‘high-need’.52 After 12 weeks, 30% of patients receiving efalizumab achieved PASI-75, with little difference in PASI response between ‘high-need’ patients and other patients with moderate-to-severe psoriasis.52 Statistically significant improvements in Dermatological Life Quality Index scores were also reported.53 In an open-label extension to this study,54 in 308 patients who had not achieved PASI-75, treatment for an additional 12 weeks resulted in 27% of this group attaining PASI-75. Within this group, the greatest improvement in response with extended treatment was seen among patients (n = 118) who had achieved PASI-50 after 12 weeks of treatment but had not achieved PASI-75, with almost half (47·5%) of these patients achieving PASI-75 at week 24.

Longer-term efficacy data for efalizumab are available from an open-label study, with reports demonstrating continued efficacy for up to 3 years of treatment.21–23 In the initial study cohort, 339 patients with moderate-to-severe chronic plaque psoriasis were treated with efalizumab (2 mg kg−1 wk−1 for 12 weeks), with 41% of patients achieving PASI-75. In the maintenance phase, 290 patients reaching at least PASI-50 at 12 weeks continued with efalizumab (75% of whom received 1 mg kg−1 weekly dosing). Among 228 patients receiving continuous treatment for 15 months, 58% achieved PASI-75 and 29% achieved PASI-90, demonstrating continued efficacy over this period.21 Among 170 patients treated for 27 months, 56% achieved PASI-75 and 30% achieved PASI-90, confirming and extending previous reports that continuous efalizumab treatment improves and maintains responses with long-term therapy in patients with chronic plaque psoriasis.22 Using an as-treated analysis at the end of the maintenance phase (i.e. including only those 151 patients who entered the month 30–33 treatment segment), after continuous treatment for 33 months, 74·8% achieved a PASI-75 response and 41·1% achieved PASI-90.23 Of the 113 patients who entered the transition treatment segment (months 33–36), at the end of 3 years of continuous treatment, 73% achieved PASI-75 and 40% achieved PASI-90.23 These data represent the longest reported period of continuous treatment with a biological agent in psoriasis thus far.

The safety data for efalizumab derived from clinical trials and post-marketing surveillance involve a cumulative total of 28 000 patient-years (as of April 2007) and represent one of the largest safety databases for any biological therapy in psoriasis.55 Efalizumab is generally well tolerated, with transient, mild, influenza-like symptoms being the most common AE reported.10,16–20 Six cases of serious thrombocytopenia related to efalizumab therapy have been reported from the clinical development trials,56 and it is recommended that platelet counts are monitored. The incidence of serious infection is low (≤ 0·5%) and no increase has been reported in the incidence of serious infection or malignancy.57,58 Importantly, data from extended use and continuous treatment studies suggest that long-term treatment does not increase the incidence of AEs, including infections and malignancies: in clinical trials, there were no cases of opportunistic infection (including tuberculosis), multiple sclerosis and congestive heart failure.21–23 There is no evidence of end-organ toxicity associated with efalizumab.58,59 Worsening of psoriasis (disease flare) has been reported with efalizumab therapy, and an increase in disease severity following discontinuation of short-term treatment (rebound) has also been documented.60 Rebound is seen more commonly in patients with a poor response to treatment,60 and several authors have reported strategies for the management of disease flare without stopping efalizumab treatment or a successful reintroduction of efalizumab therapy once the flare event has stabilized.61–64 In contrast to termination of short-term treatment, personal experience has indicated that rebound events may not occur following long-term treatment with efalizumab.

Efficacy and safety of etanercept

Etanercept is a human recombinant fusion protein of the Fc IgG1 receptor and the extracellular domain of the tumour necrosis factor (TNF)-α receptor that acts as a competitive inhibitor to circulating TNF-α by blocking interaction with the cell surface receptor.9 In two Phase II studies24,25 and subsequent larger Phase III studies involving over 1700 patients26–28 in whom the short-term efficacy of etanercept was investigated, PASI-75 was reached by 34–49% of patients after 12 weeks of treatment. These responses were mirrored by improvements in global assessments by physicians and patients, and in QoL measures. In one study, etanercept therapy led to reductions in depression and fatigue scores.28 Etanercept treatment response has been found to be dose dependent, with a greater proportion of patients achieving PASI-75 with the 50-mg twice-weekly dosing regimen than with the 25-mg twice-weekly regimen over 12 weeks. Extending treatment to 24 weeks also improves response, with 44–45% of patients achieving PASI-75 with the 25-mg twice-weekly regimen and 59% with the 50-mg twice-weekly regimen.26,27

Longer-term data for up to 60 weeks of etanercept treatment have been reported: an open-label extension study of a Phase III trial found that continued treatment improved responses among patients initially not achieving a PASI-50 response.26,65 Non-responders from the Phase III trial (n = 157) received continued treatment with etanercept 25, 50 or 100 mg wk−1.65 At week 36, among 145 patients, 43% had achieved PASI-50 and 12% had achieved PASI-75. At week 60 (n = 112), 55% had achieved PASI-50 and 23% had achieved PASI-75. These data suggest that continuation of etanercept treatment in patients whose initial response is poor may be beneficial in the longer term. Another long-term, open-label extension study using etanercept 50 mg wk−1 reported that, after initial efficacy at 12 weeks, 63% of 591 patients who continued treatment reached PASI-75 at week 48.28 However, a modest reduction in response was seen with longer-term treatment, and at 96 weeks a PASI-75 response was seen in only 51% of patients.29

Although the body of safety data for etanercept is substantial, the majority of the data are derived from studies in conditions other than psoriasis, including rheumatoid arthritis. Available data in psoriasis indicate that etanercept is generally well tolerated, with injection site reactions being the most common AE.10,25,27,28 Other commonly reported AEs include headache, upper respiratory tract infection and influenza-like symptoms.25,27,28 As a TNF-α blocker, etanercept is contraindicated in patients with severe heart failure or a history of demyelinating disease, and has been associated with reactivation of hepatitis B viral infection and latent tuberculosis, as well as the occurrence of de novo tuberculosis infections.10 Additional data for complications related to TNF-α blockade with etanercept are derived from its use in other conditions, chiefly rheumatoid arthritis, and include an increased risk of serious infections and lymphoma, but not of other malignancies.66,67

Efficacy and safety of infliximab

Infliximab is a human/murine chimeric monoclonal antibody that binds specifically to TNF-α, neutralizing it and thus blocking interaction with cell surface receptors.9 The short-term efficacy of infliximab has been demonstrated in two Phase II studies30,31 and a subsequent larger Phase III study (EXPRESS study),32 involving a total of 660 patients, which found that treatment with infliximab (administered intravenously in doses of 3, 5 or 10 mg at weeks 0, 2 and 6) resulted in achievement of PASI-75 after 10 weeks in 70–80% of patients. Rapid clinical improvements were observed in all three studies.

Longer-term data from the EXPRESS study have been reported, with treatment continued (as an intravenous infusion of 5 mg kg−1 at weeks 0, 2 and 6, and then every 8 weeks) through to week 46.32 Of 271 patients receiving continued infliximab, a sustained response was observed at week 24, with 82% of patients attaining PASI-75, after which a moderate reduction in efficacy was noted, falling to 61% of patients reaching PASI-75 at week 50.32 Similar findings were reported in a more recent comparison of continuous and intermittent infliximab therapy over 1 year, which involved an initial 835 patients.33 In an initial placebo-controlled induction phase of this study, in the active treatment arm (intravenous infusions of 3 or 5 mg kg−1 at weeks 0, 2 and 6), PASI-75 was achieved in 70% and 75% of patients who had been treated with 3 mg kg−1 and 5 mg kg−1 of infliximab, respectively. Patients were then randomized to receive continuous treatment (as intravenous infusions every 8 weeks) or intermittent ‘as-needed’ dosing (given when a PASI-75 response was lost). With continuous therapy up to week 26, PASI-75 scores were maintained in 64% of patients receiving the 3-mg kg−1 dose and in 78% of patients receiving the 5-mg kg−1 dose. Subsequently, a reduced response to continuous 8-weekly infusion therapy was observed, with PASI-75 achieved by 44% of patients receiving 3 mg kg−1 and 54% of patients receiving 5 mg kg−1 at week 50. Patients receiving continuous dosing had consistently higher PASI-75 scores than those treated with intermittent dosing, and PASI scores were greater with the higher dose of infliximab.33 The reduction in efficacy with treatment duration may be related to the development of neutralizing antibodies to infliximab, a phenomenon noted in these studies, although the mechanism behind loss of efficacy remains unclear. These data suggest that infliximab is effective as continuous treatment for up to 1 year, with some loss of response over time. Its benefits beyond this time frame are not known owing to the lack of longer-term data.

In common with etanercept, although a substantial body of safety data exists for infliximab, much of this is derived from its use in conditions other than psoriasis, and psoriasis-specific safety data are limited. Although treatment is generally well tolerated, infusion reactions are seen in approximately 20% of patients and are more common in patients who develop an anti-infliximab antibody response.10,32,33 Raised liver enzyme levels are also noted with infliximab treatment, most commonly elevated aspartate aminotransferase levels.32 As a TNF-α blocker, infliximab should not be given to patients with severe heart failure or a history of demyelinating disease. Screening for hepatitis B virus infection and latent tuberculosis should also be performed.10 As discussed for etanercept, infliximab therapy is associated with an increased risk of serious infection and lymphoma.66,67

Efficacy and safety of adalimumab

Adalimumab is a fully human monoclonal antibody against TNF-α that both neutralizes TNF-α and blocks receptor interaction.9 The short-term efficacy of adalimumab therapy has been demonstrated in placebo-controlled Phase II/III studies,34,35 as well as in an active comparator RCT.13 An initial Phase II study involving 95 patients treated with adalimumab 40 mg, administered subcutaneously weekly or every other week (eow), demonstrated dose-dependent efficacy. After 12 weeks, PASI-75 was reached in 80% of patients with weekly dosing and 53% with eow dosing.34 A subsequent Phase III study (REVEAL) involving 1212 patients found that, after 16 weeks of treatment with adalimumab (40 mg eow), 71% of patients achieved PASI-75.35 In the CHAMPION study, which compared adalimumab (40 mg eow) with methotrexate (7·5 mg orally, increased as needed and as tolerated to 25 mg weekly) and placebo in 271 patients, 80% of patients receiving adalimumab and 36% of patients receiving methotrexate achieved PASI-75 after 16 weeks, confirming the efficacy of adalimumab and its superiority over methotrexate.13 Adalimumab treatment also improved QoL and patient-reported outcomes, with superior results for Patient Global Assessment, pain and pruritus scores when compared with methotrexate treatment.68

Compared with other biological agents, longer-term efficacy data for adalimumab are more limited. In the larger Phase III study, among patients reaching PASI-75 after treatment with adalimumab, a loss of response was observed following re-randomization to placebo, suggesting that continuous treatment is necessary to maintain a response.35 This study reported that, after 24 weeks of continuous treatment, 70% of patients achieved PASI-75, and at 33 weeks, 89% achieved this response. However, PASI scores for longer treatment duration were not reported. In an open-label extension to the initial Phase II study,34 in which 106 patients received continued treatment for 60 weeks, PASI-75 was achieved by 64% of patients receiving continuous weekly dosing and by 56% receiving adalimumab eow.

Safety data for adalimumab in psoriasis are also limited compared with other biological agents. Data from clinical trials suggest that the overall incidence of AEs may be higher with adalimumab than with placebo.13,34,35 The most commonly reported AEs in patients treated with adalimumab were nasopharyngitis, upper respiratory tract infection and headache. However, the incidence of severe AEs was low and comparable in the adalimumab and placebo treatment groups. Until more data are available, the caveats for use of adalimumab should be considered to be the same as those for other TNF-α blockers.

Conclusion

As psoriasis is a chronic disease with no known cure, it is critical that long-term data on the efficacy and safety of available therapies are available to guide clinical decision-making. Toxicities associated with conventional systemic therapies for psoriasis preclude their long-term use in the majority of patients.1,3,4 In addition, there is a lack of valid data to define the efficacy of these agents in the long term. Biological therapies are being used increasingly in the management of patients with moderate-to-severe psoriasis, with data from RCTs showing that all classes and individual agents (i.e. efalizumab, etanercept, infliximab, adalimumab, alefacept) are effective in inducing a clinical response with short-term use. In addition, efalizumab, etanercept, infliximab and adalimumab have demonstrated efficacy as maintenance therapy, whereas alefacept is effective for intermittent dosing. As such, biological therapies offer a realistic alternative to conventional intermittent systemic therapies. Some data, however, suggest that certain agents have limitations in clinical practice; for example, there may be a tendency towards reduced efficacy over longer periods of maintenance treatment with TNF-α blockers (e.g. etanercept, infliximab).29,32,33 Obesity may also affect the efficacy of biological agents, which is important given the strong association between obesity and psoriasis.69 Infliximab and efalizumab are administered according to body weight and have been shown to be consistently effective across weight ranges; some data suggest that fixed-dose agents, including etanercept and alefacept, may be less effective in patients who are obese.70

Currently, the most robust data for long-term use and sustained efficacy and safety in patients with psoriasis are available for efalizumab. In a large cohort, published data are available for up to 3 years of continuous treatment.21–23 Efalizumab was effective in maintaining improved PASI scores over this period, suggesting its suitability for continuous long-term administration. A good safety and tolerability profile for continuous efalizumab therapy has also been documented across these studies.22,57–59

Acknowledgments

The author takes full responsibility for the content of the paper, but thanks Iain O’Neill (supported by Merck Serono International S.A., Geneva, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany) for assistance in preparing the initial draft of the manuscript and collating comments.

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