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Meetings/Links : Meeting Reports : Biologic Agents and Oral Tazarotene for Psoriasis
Meeting Summary

Biologic Agents and Oral Tazarotene for Psoriasis

Latest Information Presented at a Dermatology Meeting Held
July 28 to August 1, 2004, in New York, New York

Jeffrey M. Weinberg, MD
Director, Clinical Research Center/Dermatopharmacology
St. Luke's - Roosevelt Hospital Center
New York, New York

Bruce E. Strober, MD, PhD
Assistant Professor and Associate Director, Dermatopharmacology Unit
New York University School of Medicine
Ronald O. Perelman Department of Dermatology,
New York University Medical Center
New York, New York

This report will focus on the new information that was presented on biologic agents and oral tazarotene for the treatment of moderate to severe psoriasis.

Alefacept
No new data was presented on the use of alefacept in plaque psoriasis, but a short case series describing the successful treatment of palmoplantar psoriasis with alefacept was presented by Dr. Myers and colleagues.1 Both patients in this series had palmoplantar psoriasis of several years' duration that had failed to respond to topical, systemic, and phototherapies. Both patients achieved significant clinical improvement after 5 to 8 doses of alefacept and continued to improve throughout a 12-week course of treatment.

Efalizumab
Presentations on efalizumab at this meeting included an overview of two separate studies on the long-term use of efalizumab and a discussion of the incidence and management of flare during efalizumab therapy.2,3 In the first study (presented by Dr. Gottlieb and colleagues),2 patients who completed a 12-week, double-blind comparison of efalizumab 2 mg/kg/wk versus placebo and who had achieved PASI 50 or a static Physician's Global Assessment of Mild, Minimal, or Clear could receive efalizumab 1 mg/kg/wk during an open-label extension to 3 years. Efficacy was well maintained throughout this long-term study, with 50% achieving PASI 75 at month 30 as compared to 41% at month 3 ("intent-to-treat" analysis). Patients in the open-label extension portion of this study were allowed to use mid-potency topical steroids and ultraviolet phototherapy (UVB) to help control their psoriasis, but only 3 patients utilized UVB during the 30-month period. In the second long-term study (presented by Dr. Papp and colleagues),3 all patients who completed the first 12 weeks of a double-blind comparison of efalizumab 1 mg/kg/wk with placebo were eligible to receive efalizumab 1 mg/kg/wk during an open-label extension to 72 weeks. This study also allowed patients to use mid-potency topical steroids and ultraviolet phototherapy to help control their psoriasis. Approximately 59% of the patients who received between 37 and 48 weeks of continuous treatment in this study achieved PASI 75 ("as-treated" analysis). There was no increase in adverse events and no emergence of new adverse events with long-term treatment in both studies.

Patients may experience a worsening of their psoriasis during or after discontinuation of efalizumab therapy, and this issue was discussed in several sessions at this meeting. In his overview of the safety of biologic agents, Dr. Menter reviewed the definitions of flare, relapse, and rebound.4 Flare is defined as a worsening of psoriasis at any time and may be either localized or generalized. Localized flares occur at new sites and tend to remain localized, while generalized inflammatory flares tend to involve existing plaques. Relapse is defined as a loss of at least 50% of the improvement seen during therapy. A rebound of psoriasis is defined as a worsening of psoriasis to 125% of the baseline PASI or the appearance of psoriasis variants such as erythrodermic or pustular psoriasis within 12 weeks of discontinuation of therapy.

If a localized flare occurs, it may not be necessary to discontinue efalizumab, but topical therapy should be added until the flare resolves. Dr. Menter presented a case study of a patient who was maintained on efalizumab through a localized flare with excellent long-term results. Dr. Menter indicated, however, that if a generalized inflammatory flare occurs during the first 12 weeks of therapy, the patient should be transitioned to another therapy as quickly as possible. This was illustrated by a separate case study of a patient who did not have an adequate clinical response to efalizumab and who developed inflammatory pityriasiform psoriasis of the trunk and flexures after 10 weeks of treatment. The condition resolved after the patient was switched to cyclosporine. Patients have also been successfully transitioned to other therapies following efalizumab therapy. Those transition therapies that successfully prevented rebound in at least 90% of patients included high-potency topical steroids, phototherapy, systemic corticosteroids, and methotrexate. Therapies that successfully prevented rebound in 75% to 90% of patients included systemic retinoids, vitamin D derivatives, and other topical therapies. It was also noted that the tapering of the dose of efalizumab over many weeks is not recommended as an approach to discontinuation of the drug, as it may increase the risk of rebound occurring.

Etanercept
New information about etanercept included presentations on efficacy in different patient subgroups, as well as the effect of etanercept on PASI subscales, pruritus, and patient-reported outcomes. Long-Term safety data were presented, and a single case study of pyoderma gangrenosum effectively treated with etanercept was described.

Dr. Papp and colleagues presented a study that showed that etanercept was similarly effective in patients from different demographic subgroups (age, race, or sex).5 Similarly, a poster by Dr. Strober and colleagues demonstrated that there was no difference in the response to etanercept in patients with a wide range of different treatment histories (including methotrexate, acitretin, PUVA, or UVB).6 There was some evidence, however, that patients with a history of cyclosporine treatment might respond slightly less well to etanercept therapy than those patients without a cyclosporine treatment history. Dr. Leonardi and colleagues showed that etanercept treatment produced rapid and significant improvements in all PASI subscales (erythema, induration, scaling) and all body area component scores.7 A poster by Dr. Kimball and colleagues showed that etanercept also significantly reduced pruritus in psoriasis patients.8 The beneficial effect of etanercept on patient-reported outcomes was demonstrated in a poster by Dr. Krueger and colleagues.9 This study showed marked improvements in both Dermatology Life Quality Index (DLQI) and Short Form 36 (SF-36) health survey scores after 12 weeks of etanercept treatment. These improvements were seen in all DLQI subscales and in both the physical and mental component summary scores of the SF-36.

An integrated analysis of safety in psoriasis patients was presented in a poster by Dr. Gottlieb and colleagues.10 This analysis pooled the data from one phase 2 and two phase 3 studies and included 364 patients who had been treated for at least 12 months and 52 patients who had been treated for at least 15 months. No new or unanticipated pattern of adverse events was observed with extended use of etanercept in this study. An analysis of the long-term safety of etanercept in rheumatoid arthritis patients was presented in a poster by Dr. Lebwohl and colleagues.11 This analysis included 971 patients who were entering their 6th year of therapy and demonstrated that rates of serious adverse events and serious infections remained low and stable over time and that there was no evidence of cumulative toxicity.

In addition, Dr. Cohen presented a single case of a patient with rheumatoid arthritis and lupus who developed pyoderma gangrenosum that was successfully treated with etanercept.12 The patient's skin lesions had failed to respond after several months of care in a wound clinic but had completely resolved after 4 months of etanercept therapy.

Infliximab
No new data on the use of infliximab in the treatment of psoriasis or psoriatic arthritis were presented. There was a symposium, however, that reviewed previous studies demonstrating the safety and efficacy of infliximab in psoriasis, psoriatic arthritis, rheumatoid arthritis, and inflammatory gastrointestinal diseases.13 This comprehensive review made it clear that infliximab is very effective across a wide range of inflammatory disorders but that "dose-creep" with repeated treatments (possibly due to neutralizing antibodies) is a common problem regardless of the condition being treated. It was also noted that although infliximab appears to be more effective than etanercept in psoriasis patients, its efficacy seems to be somewhat similar to that of etanercept in psoriatic arthritis patients.

Adalimumab
The presentations on adalimumab included the effect of long-term treatment on PASI and patient-reported outcomes, and a preliminary study of the effect of adalimumab on psoriatic arthritis.

In a presentation on psoriasis and psoriatic arthritis clinical trials presented as part of a symposium on the role of TNF in psoriatic disease, Dr. Leonardi described the preliminary results of a long-term study of adalimumab in psoriasis.14 Psoriasis patients completing a double-blind, placebo-controlled adalimumab clinical trial could participate in a double-blind, dose-ranging, extension study to 60 weeks. After 24 weeks of treatment, the percentage of patients who achieved PASI 75 was 64% among patients treated with 40 mg every other week (eow; with an 80-mg loading dose at week 0) and 72% among patients treated with 40 mg weekly (with two 80-mg loading doses at weeks 0 and 1). In a cohort of patients who received placebo for 12 weeks followed by 12 weeks of 40 mg adalimumab eow, 55% of patients achieved PASI 75. Serious adverse events were noted to be higher in the adalimumab-treated cohorts: 6.7% of the 40 mg eow dosing group and 10.0% in the 40 mg weekly group, versus 0.0% in the placebo/adalimumab crossover group. The specific nature of those serious adverse events was not presented.

The effect of adalimumab on patient quality of life is also being evaluated as part of this ongoing, long-term study. Separate posters by Dr. Wallace and colleagues demonstrated that adalimumab produces marked improvements in both DLQI15 and SF-36 scores.16 At week 24, the mean decrease in DLQI was 10.2 after eow dosing and 11.6 after weekly dosing. Moreover, 40% of patients with eow dosing and 54.8% of patients with weekly dosing had DLQI scores of zero after 24 weeks of treatment.15 At week 12, mean improvements in 6 out of the 8 domains of the SF-36 were statistically significant, and these improvements were maintained through week 24.16

Dr. Leonardi also presented the preliminary results from a study of the use of adalimumab in the treatment of psoriatic arthritis that suggested that 12 weeks of adalimumab can produce a 20% improvement in the American College of Rheumatology response (ACR 20) in 66% of patients. Improvements in target lesion response and PASI were also seen in these patients.

Oral Tazarotene
Studies were presented on the effect of once-weekly oral tazarotene on patient satisfaction and difficult-to-treat lesions. The pooled analysis of two placebo-controlled, phase 3 trials and one open-label extension was presented in a poster by Dr. Leonardi and colleagues.17 In this study, oral tazarotene was shown to produce moderate-to-complete clearing of psoriasis in 54% to 64% of patients. Oral tazarotene was well tolerated, and 73% to 80% of patients expressed high satisfaction with their treatment after 12 weeks of therapy. Clinically significant improvements in psoriasis-specific quality of life, as measured by the psoriasis-specific quality-of-life questionnaire (PQOL-12), were also evident in the majority of patients after 12 weeks of therapy. A separate, open-label study (presented by Dr. Menter and colleagues) showed that oral tazarotene could produce significant improvements in target lesions of the knee, elbow, and scalp after 1 to 2 weeks of treatment and in nail lesions after 16 weeks of treatment.18

General
Several symposia, general sessions, and panel discussions at this meeting provided overviews of biologic therapy. Physicians described how the availability of biologic therapies has greatly reduced their use of other, more toxic, psoriasis therapies and allowed them to use simpler treatment regimens. One physician noted that his use of biologic therapy had caused a significant reduction in his use of methotrexate, acitretin, and cyclosporine, and his need for combination therapy similarly had been reduced. Other physicians reported using biologics as their first-line therapy of choice for any patient with moderate to severe psoriasis, provided that insurance coverage was available. Some physicians reported experimenting with the use of biologic agents in combination with phototherapy or other systemic treatments. Other physicians stated that they preferred to try and find the most effective monotherapy for a patient before using combination therapy. If a patient is not doing well on one biologic agent, these physicians will switch the patient to another biologic agent rather than adding another therapy. Combination therapy, for these physicians, is reserved for those patients who do not do well on any monotherapy.

In discussions of specific biologic agents, there was general agreement between speakers regarding the overall clinical profiles of the biologic agents. Alefacept was referred to as safe and capable of producing long remissions but as having a slow onset of efficacy and a lower responder rate than the other biologic agents. Efalizumab was described as safe, with a relatively rapid onset of action and increasing improvement with long-term treatment. Rebound following discontinuation of efalizumab was described as preventable and manageable if patients are transitioned onto other treatment modalities whenever efalizumab needs to be discontinued. Flare during efalizumab therapy was described as uncommon and treatable. Etanercept was described as being effective in both psoriasis and psoriatic arthritis and as being most effective if high doses (50 mg twice weekly) are used during the first 3 months of therapy, after which a "step down" to 50 mg once weekly is recommended. There was general agreement that infliximab provides the most rapid and dramatic improvements in psoriasis but that "dose creep" with repeated treatments can be a problem, especially if another immunomodulatory agent, such as methotrexate, is not used concomitantly. Serious infusion reactions with infliximab are rare, but staff and facilities must be available to deal with them if they do occur. There was also general agreement that anti-TNF biologic agents (etanercept, infliximab, and adalimumab) should be used with caution in patients with a risk of serious infection, heart failure, or central nervous system (CNS) demyelinating disorders. Several presentations described how concerns about an increase in lymphoma with biologic therapy appear to be unfounded. The rate of lymphoma in patients on biologic therapy is greater than that in the general population, but this appears to be due to an increased incidence of lymphoma among the patient populations being treated and not as a result of drug treatment. Some presenters stated that they always perform tuberculosis testing prior to the use of any anti-TNF biologic agent (even though it is neither required nor recommended in the product labeling for etanercept), but other physicians indicated that they did not test for tuberculosis prior to the initiation of etanercept therapy.

In addition, two case series were presented that showed new onset or worsening of psoriasis in a handful of patients treated with anti-TNF biologic agents for either rheumatoid arthritis or ankylosing spondylitis.4 In the first series of 8 patients, the anti-TNF biologic agents used included adalimumab, infliximab, and etanercept, with 5 of the 8 patients receiving more than one anti-TNF agent in the course of their treatment history. In the second case series, 2 patients had been treated with etanercept and 2 had been treated with infliximab. It was generally agreed that all effective therapies for psoriasis will manifest rare cases of psoriasis rebound after their discontinuation, but large, placebo-controlled studies evaluating anti-TNF therapies in psoriasis patients suggest that rebound of disease after discontinuation is not a common feature of these drugs.

The overall view of the use of biologic agents in the treatment of psoriasis was that they are all effective in certain patients and relatively safer than the nonbiologic systemic agents that have been used for moderate to severe psoriasis in the past. Moreover, they offer the potential for the type of continuous control for psoriasis that has long been the goal of treatment in other chronic immunological diseases, such as rheumatoid arthritis and asthma. The overall impact of these therapies is that more patients are able to control their disease without the "on and off" approach to therapy that is required with conventional therapies in order to limit safety problems.

References
  1. Myers W, Christiansen L, Gottlieb AB. Intramuscular alefacept in the treatment of palmoplantar psoriasis. Presented at: Summer Academy 2004 of the American Academy of Dermatology; July 28 - August 1, 2004; New York, New York. Poster.
  2. Gottlieb AB, Hamilton TK, Caro I, et al. Efficacy and safety outcomes of extended efalizumab therapy in patients with moderate to severe chronic plaque psoriasis: an update. Presented at: Summer Academy 2004 of the American Academy of Dermatology; July 28 - August 1, 2004; New York, New York. Poster 77.
  3. Papp KA, Caro I, Chastain R, et al. The safety of continuous subcutaneous efalizumab therapy for moderate to severe chronic plaque psoriasis: preliminary results from an open-label, multicenter study. Presented at: Summer Academy 2004 of the American Academy of Dermatology; July 28 - August 1, 2004; New York, New York. Poster 76.
  4. Menter A. Clinical experience with safe, long-term control: the safety of biologics: clinical experience. Presented at: Summer Academy 2004 of the American Academy of Dermatology; July 28 - August 1, 2004; New York, New York. Poster.
  5. Papp KA, Tyring S, Wang H, et al. Impact of patient demographics on efficacy and safety of etanercept treatment in psoriasis. Presented at: Summer Academy 2004 of the American Academy of Dermatology; July 28 - August 1, 2004; New York, New York. Poster P86.
  6. Strober B, Yamauchi P, Korman N, et al. Psoriasis patients with varying treatment histories respond similarly to etanercept therapy. Presented at: Summer Academy 2004 of the American Academy of Dermatology; July 28 - August 1, 2004; New York, New York. Poster P88.
  7. Leonardi CL, Elewski BE, Wang H, et al. Etanercept improves all PASI subscales in patients with psoriasis. Presented at: Summer Academy 2004 of the American Academy of Dermatology; July 28 - August 1, 2004; New York, New York. Poster P99.
  8. Kimball AB, Wooley JM, Zitnik R. Reductions in pruritus for patients with moderate to severe psoriasis receiving etanercept therapy. Presented at: Summer Academy 2004 of the American Academy of Dermatology; July 28 - August 1, 2004; New York, New York. Poster P95.
  9. Krueger G, Wooley JM, Zitnik R. Etanercept improves patient reported outcomes for patients with moderate to severe psoriasis. Presented at: Summer Academy 2004 of the American Academy of Dermatology; July 28 - August 1, 2004; New York, New York. Poster P94.
  10. Gottlieb A, Goffe B, Nakanishi A, et al. Integrated analysis of the long-term safety of etanercept in patients with psoriasis. Presented at: Summer Academy 2004 of the American Academy of Dermatology; July 28 - August 1, 2004; New York, New York. Poster P91.
  11. Lebwohl MG, Gottlieb AB, Whitmore JB, et al. Global safety and efficacy of more than 6 years of etanercept therapy in rheumatoid arthritis. Presented at: Summer Academy 2004 of the American Academy of Dermatology; July 28 - August 1, 2004; New York, New York. Poster P87.
  12. Cohen DJ. Successful treatment of pyoderma gangrenosum with etanercept. Presented at: Summer Academy 2004 of the American Academy of Dermatology; July 28 - August 1, 2004; New York, New York. Poster.
  13. Krueger GG (moderator). Discovery and applications of biologics. Presented at: Summer Academy 2004 of the American Academy of Dermatology; July 28 - August 1, 2004; New York, New York. Symposium.
  14. Leonardi CL. Psoriasis and psoriatic arthritis clinical trials: emerging differences among agents. In: The critical role of TNF in psoriatic disease: practical applications of using TNF antagonists. Presented at: Summer Academy 2004 of the American Academy of Dermatology; July 28 - August 1, 2004; New York, New York. Satellite symposium.
  15. Wallace K, Heffernan M, Hamlin R, et al. Results of the DLQI dermatology-specific quality of life measure in moderate to severe plaque psoriasis patients receiving 24 weeks of adalimumab therapy. Presented at: Summer Academy 2004 of the American Academy of Dermatology; July 28 - August 1, 2004; New York, New York. Poster.
  16. Wallace K, Miller B, Heffernan M, et al. Results of the SF-36 general health status measure in moderate to severe chronic plaque psoriasis patients treated with adalimumab for 24 weeks. Presented at: Summer Academy 2004 of the American Academy of Dermatology; July 28 - August 1, 2004; New York, New York. Poster.
  17. Leonardi CL, Kowalski JW, Walker PS, et al. Improving patient satisfaction in patients with moderate to severe psoriasis. Presented at: Summer Academy 2004 of the American Academy of Dermatology; July 28 - August 1, 2004; New York, New York. Poster P83.
  18. Menter A, Lew-Kaya D, Beddingfield FC, et al. Efficacy of oral tazarotene on difficult-to-treat psoriatic lesions during 1 year of treatment. Presented at: Summer Academy 2004 of the American Academy of Dermatology; July 28 - August 1, 2004; New York, New York. Poster P84.