- Email: [email protected]
Long-term management of plaque psoriasis with continuous efalizumab therapy
CLINICAL
REVIEW
Long-term management of plaque psoriasis with continuous efalizumab therapy Alan Menter, MD,a Craig L. Leonardi, MD,b Wolfram Sterry, MD,c Jan D. Bos, MD,d and Kim A. Papp, MD, PhDe Dallas, Texas; St. Louis, Missouri; Berlin, Germany; Amsterdam, The Netherlands; and Waterloo, Ontario, Canada
A
fter a long period with few significant therapeutic advances, the last decade has witnessed a notable increase in the number of therapies that are in development and that have been approved for patients with psoriasis. Although the effectiveness of many traditional systemic therapies was discovered serendipitously,1 advances in molecular research and technology have resulted in the development of a new class of psoriasis therapies. Biologic therapies are designed to specifically target discrete processes, cell types, or cytokines known to be important in the pathogenesis of psoriasis.2 With their targeted mechanisms of action, it is hoped that biologic therapies will provide patients who have psoriasis with effective and safer options.3 Biologic therapies have been studied rigorously in well-designed controlled trials treating significant numbers of patients with psoriasis. Furthermore, some of the biologics (eg, efalizumab) have longterm treatment data for a small subset of patients with psoriasis. The clinical trial experience leading to the relatively recent approval of 3 biologic therapies (alefacept, efalizumab, and etanercept) for psoriasis
From Baylor University Medical Center, Dallasa; St. Louis University School of Medicineb; University Hospital Charite´ Berlinc; Academic Medical Center, University of Amsterdamd; and Probity Medical Research, Waterloo.e Supported by Genentech Inc and Serono International SA. Disclosures: Dr Leonardi has received educational grant support from and served on the speakers bureau and advisory board for Genentech Inc. Dr Menter has received research support and/or is a consultant and/or lecturer for Abbott Laboratories, Amgen Inc, Biogen Idec, Centocor Inc, Genentech Inc, Serono SA, and Xoma LLC. Dr Papp is a consultant, an investigator, and an advisory board member for Genentech Inc, Serono SA, and Xoma LLC; he is on the Serono SA speakers bureau. Drs Bos and Sterry have no conflicts of interest to disclose. Reprint requests: Alan Menter, MD, Texas Dermatology Research Institute, 5310 Harvest Hill Rd, Suite 260, Dallas, TX 75230. E-mail: [email protected]. J Am Acad Dermatol 2006;54:S182-8. 0190-9622/$32.00 ª 2006 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.10.028
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Abbreviations used: GIF: LMB: PASI: PASI-50: PASI-75:
generalized inflammatory flare localized mild breakthrough Psoriasis Area and Severity Index at least 50% reduction in PASI score at least 75% reduction in PASI score
has widened the range of therapeutic options and is altering the way many dermatologists approach psoriasis management. Because biologic therapies for psoriasis exert their therapeutic effects by mechanisms distinct from traditional psoriasis therapies and because they are administered differently—by subcutaneous or intramuscular injection—dermatologists are familiarizing themselves with these newer therapeutic options and are seeking guidance on how to best incorporate them into daily practice. As clinical trial data accumulate, and as more dermatologists prescribe biologic therapies for their patients, valuable experience will accumulate and further define how these therapies can be optimally incorporated into a dermatologist’s psoriasis armamentarium. It is also expected that data contrasting the biologics and evaluating their use in clinical practice rather than according to structured trial protocols would give additional information needed to make proper choices in the management of psoriasis. Extensive clinical trial experience has shown that efalizumab, a humanized recombinant monoclonal immunoglobulin G-1 antibody developed to target multiple T cellemediated processes critical to the pathogenesis of psoriasis,4 provides rapid and sustained efficacy for many patients with psoriasis.5-8 A number of efalizumab clinical trials have been prospectively designed to provide dermatologists with clinical trial data that support and guide clinical decisions concerning efalizumab administration. Psoriasis is a chronic disease without a cure; therefore, most patients will require long-term therapy to control their symptoms. Many patients have been
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Fig 1. Efalizumab patient management guidelines. *Range represents percentage of patients who achieved at least a 50% reduction in the PASI score (PASI-50) by week 12 in pooled data from three randomized, controlled phase III trials (59%), and in an ongoing open-label, 36-month phase III trial (82%).
unable to achieve continuous symptom control because the toxicity associated with traditional therapies has precluded their long-term administration. This supplement discusses a number of relevant aspects of treating patients receiving efalizumab therapy: continuous administration (see article by Gottlieb et al elsewhere in this supplement), management of psoriasis exacerbations during efalizumab therapy and avoiding rebound after discontinuation of treatment (see article by Carey et al elsewhere in this supplement), and retreatment in responding patients in the event that efalizumab is discontinued and reinitiated (see article by Papp et al elsewhere in this supplement). Until now there have been limited clinical trial data to address various issues that may arise during treatment of patients with efalizumab. The results of several efalizumab clinical trials and retrospective analyses provide insight into the treatment of patients receiving efalizumab. This review combines the results of these relevant efalizumab clinical studies and the observations and recommendations from experienced investigators.
Based on the evidence available to date and our collective experiences, we have developed a treatment guideline to assist our colleagues in the clinical treatment of patients receiving efalizumab for psoriasis (Fig 1).
EFALIZUMAB CLINICAL TRIAL EVIDENCE Multiple clinical trials have demonstrated that the majority of patients with psoriasis realize a clinical benefit from efalizumab therapy.5,6,8,9 Phase III randomized clinical studies have demonstrated that a significantly greater proportion of patients treated with efalizumab compared with placebo achieved all primary and secondary efficacy end points at 3 months. For instance, results from the pivotal trial demonstrated that 27% of patients treated with efalizumab achieved at least 75% improvement in their Psoriasis Area and Severity Index (PASI) score (PASI-75) compared with 4% of patients treated with placebo after 3 months (12 weeks).6 When therapy was extended from 3 to 6 months as part of an open-label extension, PASI responses continued
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to improve. Of all patients, 44% achieved PASI-75 after 24 weeks of continuous therapy.7 PASI-75 is the efficacy benchmark used by many regulatory bodies; however, this is a very stringent criterion for success and patients generally achieve meaningful disease and quality-of-life improvements with at least a 50% reduction in PASI score (PASI-50) response.10 In the above-mentioned pivotal trial, 59% of patients achieved PASI-50 after 3 months of efalizumab therapy and 67% achieved PASI-50 after 6 months.6,7 These findings are supported by results from a 36-month open-label, phase III trial involving 339 patients. At the time of submission, data for 170 patients who received up to 27 months of treatment were available for analysis (see article by Gottlieb et al elsewhere in this supplement); 36-month study results were recently reported.11 This trial demonstrated that some patients can maintain their therapeutic responses for at least 27 months and up to 36 months of continuous efalizumab treatment. After the 3-month initial treatment period, 82% of patients achieved PASI-50 and 41% achieved PASI-75. Of patients who qualified for the long-term maintenance treatment period, 76% achieved PASI-50 and 56% achieved PASI-75 after 27 months of therapy. Moreover, the proportion of patients who achieved almost complete clearance of disease, as reflected by at least a 90% reduction in PASI score response rate, continued to increase during the first 18 months of therapy (13% after 3 months to 33% at 18 months), after which time improvement was maintained (30% at month 27). The rate of patient discontinuation was low and stable throughout 27 months of continuous therapy, with the rate of discontinuation during each 3-month analysis period comparable with that observed during the initial 12-week treatment period of other phase III efalizumab trials (4.0%-11.4%).5,6,8,9 Patients discontinued for multiple reasons (eg, lack of efficacy, adverse events, life circumstances). Although the efalizumab clinical trials evaluated PASI-75 as the primary end point, it is unlikely that dermatologists will apply this measure in clinical practice. During the clinical trials, patients treated with efalizumab also demonstrated benefit when assessed by more commonly used measures, including the Physician’s Global Assessment. In addition to improvement on physician-assessed clinical measures, patients treated with efalizumab reported improvements on multiple patient-reported outcome measures that assess the impact of efalizumab on health-related quality of life.12 Most patients treated with efalizumab achieved significant improvement relative to placebo in patient-reported measures of health-related quality of life within
4 weeks of initiating efalizumab. During the pivotal trial, patients receiving efalizumab therapy reported a mean improvement of 47% from baseline on the Dermatology Life Quality Index questionnaire, compared with a 14% improvement for patients in the placebo group.13 Similar improvements were achieved on other patient-reported measures of treatment efficacy, including a visual analog scale for itch and both the frequency and severity subscales of the Psoriasis Severity Assessment. Improvements in these patient-reported measures were sustained throughout 24 weeks of continuous treatment.7 Efalizumab therapy has generally been well tolerated. The most common adverse events are associated with initiation of efalizumab therapy and have been termed acute adverse events.14 These are characterized as flu-like symptoms associated with the first 1 or 2 doses of efalizumab therapy. In clinical trials, few patients discontinued efalizumab because of acute adverse events.14 In a small study, there has been no indication that long-term continuous therapy alters the safety profile of efalizumab (see article by Gottlieb et al elsewhere in this supplement). There is also no evidence of a trend toward an increase in overall incidence of adverse events or evidence of end-organ damage. As new therapeutic agents such as efalizumab are demonstrating efficacy on multiple physicianand patient-assessed end points, the primary cut-off measure currently used to evaluate the efficacy of a psoriasis therapy (PASI-75) appears increasingly arbitrary. Moreover, the PASI measures only improvement in skin condition, thus ignoring possible improvements in patient quality of life. With an increasing number of new therapeutics approved or under development for psoriasis, it becomes increasingly important to consider the multiple dimensions of efficacy and safety that contribute to disease control.
TREATING PATIENTS WHO IMPROVE AND MAINTAIN BENEFIT Collectively, clinical trial results and investigator experiences indicate that patients who achieve a clinical benefit (eg, at least a PASI-50 response or a Physician’s Global Assessment of change of ‘‘good’’ or ‘‘better’’) can receive continuous efalizumab therapy unless an adverse event occurs, efficacy declines substantially, or life circumstances dictate otherwise. It is unlikely that patients will lose symptom control or experience rebound in the event that they miss a dose (see article by Carey et al elsewhere in this supplement); therefore, dermatologists and patients need not be overly concerned in the event that an occasional dose is missed.
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Because psoriasis is a disease that fluctuates in severity over time, patients may experience some variability in their response over time. This is not unique to efalizumab; fluctuation in disease severity is a common occurrence in patients with psoriasis.15 There are a number of factors unrelated to psoriasis treatment that can exacerbate or trigger psoriasis in patients otherwise experiencing symptom control (eg, infection, fluctuations in endocrine factors, hypocalcemia, medications used for other indications, stress, or cutaneous trauma).15 For mild recurrences during treatment with efalizumab, dermatologists can consider adding a course of topical corticosteroids. Some patients will discontinue efalizumab therapy despite a favorable response. Life circumstances that might result in discontinuation of efalizumab include pregnancy, extended holidays or travel plans, or insurance coverage changes. Evidence from multiple studies demonstrates that discontinuation of efalizumab therapy in responding patients typically results in a gradual return of psoriasis; however, rebound has been seen in some of these patients. In one study, the median time to relapse after efalizumab discontinuation in responding patients was approximately 2 months (see article by Carey et al elsewhere in this supplement). Patients should be observed after discontinuation of efalizumab. Upon disease recurrence, patients who were responsive to efalizumab and discontinued treatment because of temporary circumstances may benefit from restarting efalizumab therapy. The results of a clinical trial demonstrated that efalizumab retreatment was effective and well tolerated (see article by Papp et al elsewhere in this supplement). However, because some patients who discontinued efalizumab after a retreatment course may also experience rebound, patients receiving efalizumab retreatment should be assessed for rebound when efalizumab is discontinued. Furthermore, the efficacy of retreatment appears to be similar to that achieved during an initial course of efalizumab (see article by Papp et al elsewhere in this supplement). Therefore, discontinuation from efalizumab therapy does not preclude responding patients from receiving and benefiting from efalizumab therapy in the future.
PRACTICAL CONSIDERATIONS FOR PATIENTS NOT DEMONSTRATING NOTICEABLE IMPROVEMENT Nonresponders are the patients most likely to experience psoriasis adverse events or disease worsening during or rebound after treatment (see article by Carey et al elsewhere in this supplement). Patients who show no noticeable response by approximately 3 months after beginning efalizumab
therapy are unlikely to derive benefit from continued efalizumab and should transition to an alternative psoriasis therapy.
TREATING PATIENTS WHO EXPERIENCE PSORIASIS EVENTS DURING EFALIZUMAB THERAPY During clinical trials with efalizumab, psoriasis adverse events were noted in some patients. Their appearance can be broadly classified into one of two categories: the more common transient localized papular eruption (described as a localized mild breakthrough [LMB]) that is typically papular and limited in nature; or a more infrequent and extensive eruption known as generalized inflammatory flare (GIF). As dermatologists have gained experience with efalizumab in clinical practice and are able to more accurately describe their observations, the description of these events has evolved over time. Dermatologists have previously referred to LMB as a ‘‘transient papular eruption’’ or ‘‘transient neutrophilic dermatoses’’ and referred to GIF as a ‘‘generalized inflammatory exacerbation.’’ In the opinion of the investigators, LMB and GIF are accurate descriptions of the potential psoriasis events that may occur during treatment with efalizumab. It is important to note that the proliferation of terminology appearing in the literature does not represent new events observed during treatment with efalizumab and despite the use of new descriptive terminology, LMB is a form of psoriasis and not a new disease. Some patients may initially demonstrate a favorable response to efalizumab therapy and then experience a psoriasis event during therapy. It is important to distinguish these events from incomplete washout of a prior psoriasis therapy. If a patient has not been completely washed out from a prior psoriasis therapy, a brief period of overlap when efalizumab therapy is initiated is recommended. A GIF as a result of incomplete washout may not necessitate efalizumab discontinuation. In responding patients, dermatologists or patients may observe alterations in the appearance of psoriasis or slight fluctuations in disease control of a papular nature, which may be described as LMB. LMB, when it does occur, generally manifests within 4 to 8 weeks of initiating efalizumab therapy, although it can occur at any time. Typically, existing lesions are not involved, and the LMB is frequently, but not exclusively, localized on the neck, torso, or flexural areas. Based on investigator observations, LMB appears to have no clinical impact in responding patients and may be effectively treated through. Dermatologists may consider adding a topical
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therapy to continued efalizumab therapy until the breakthrough resolves. Although unlikely, should the LMB not respond to topical therapy or worsen, dermatologists may consider adding a short course (eg, 4-6 weeks) of a systemic therapy to efalizumab therapy until resolution, at which time the concomitant systemic therapy can be discontinued. Alternatively, dermatologists may add an alternative systemic psoriasis therapy, and after a period of overlap sufficient to allow the new therapy to become effective, discontinue efalizumab therapy. Dermatologists should educate their patients regarding the potential for LMB or GIF (see below) before initiation of efalizumab therapy. Dermatologists have also noted the infrequent occurrence of GIF, which typically involves existing plaques with or without the development of new lesions. GIF is more commonly observed in nonresponding patients; however, it has been seen in patients who have responded well to efalizumab therapy. Most cases manifest within 6 to 10 weeks of initiating efalizumab therapy. In the event of an inflammatory flare, dermatologists may consider initiation of a short course (eg, 4-6 weeks) of an alternative systemic psoriasis therapy (eg, cyclosporine or methotrexate). If the flare resolves and the underlying psoriasis is improved, the systemic therapy can then be tapered off and efalizumab continued. If the flare is not controlled or the underlying psoriasis is not improved, efalizumab should be discontinued and the patient should be maintained on systemic therapy. Alternatively, dermatologists may elect to simply discontinue efalizumab therapy by transitioning to an alternative psoriasis therapy without a period of overlap. At this time, there is no evidence or sufficient cumulative experience indicating the superiority of one approach over another. Ultimately, it is up to the treating dermatologist to select the approach. It is important that dermatologists educate patients to return to the office immediately if they develop widespread, erythematous, edematous lesions that may also take on a pustular appearance. With careful monitoring and prompt treatment, patients can be safely treated to achieve control of their disease. Anecdotally, some patients who developed a GIF were successfully retreated with efalizumab at a later time. It should be noted that although dermatologists have some experience combining efalizumab with other psoriasis therapies, there are limited data for the safety of such combinations. Most efalizumab clinical trials excluded concomitant psoriasis treatments with the exception of mild topicals (eg, low-potency corticosteroids)14 and, in some
trials, selected forms of phototherapy.16-18 In a randomized, controlled phase II study to evaluate the safety and efficacy of efalizumab for the treatment of patients with psoriatic arthritis, a cohort of patients received efalizumab with concomitant methotrexate for up to 24 weeks.19 The safety profile of patients treated with efalizumab in this trial was consistent with the placebo group, suggesting that concomitant methotrexate use does not adversely affect the efalizumab safety profile. It is recommended to carefully observe patients when overlapping efalizumab with another therapy, particularly another systemic immunosuppressive agent.
TRANSITIONING FROM EFALIZUMAB TO AN ALTERNATIVE PSORIASIS THERAPY The results of the rebound analyses (see article by Carey et al elsewhere in this supplement) suggest that a successful approach to discontinuation in patients who do not respond to, or who worsen on, efalizumab involves immediate transition to an alternative psoriasis therapy. Alternatively, patients may be transitioned by overlapping an alternative systemic agent with efalizumab for a period of time long enough to allow the second agent to achieve maximal effect, then discontinuing efalizumab. Transitioning patients off one psoriasis therapy and onto another is a common treatment strategy used to maintain disease control and avoid treatment-related toxicity. Thus, most dermatologists are familiar with transitioning between, overlapping, and combining different therapeutic agents.20-22 Transition to an alternative agent treats the patient’s psoriatic symptoms and may avoid worsening of disease. The selection of the most appropriate alternative psoriasis therapy is based on a patient’s history of response to and tolerance of prior psoriasis therapies, other concomitant illnesses or medications that might interact with psoriasis therapies, and the severity of the disease. The retrospective analyses presented by Carey et al (article appears elsewhere in this supplement) are supported by a smaller phase III prospective analysis of transition medications.23 Together, these results suggest that transition to other approved psoriasis treatments can prevent worsening of disease or rebound when efalizumab therapy is stopped. The results from a phase III study indicate that tapering efalizumab therapy without having a transition therapy option is not an effective strategy to prevent rebound.24
EFALIZUMAB DISCONTINUATION AND REBOUND Rebound has been observed with many psoriasis therapies.25,26 A retrospective analysis of pooled
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data from multiple efalizumab clinical trials using a definition of rebound adapted from the National Psoriasis Foundation25,26 indicated that rebound occurs in 14% of all patients who abruptly discontinue efalizumab (see article by Carey et al elsewhere in this supplement). Moreover, the results demonstrated that patients who do not respond to efalizumab are most likely to experience rebound. These patients require particular attention when efalizumab is discontinued. Therefore, although dermatologists should be aware of the possibility of rebound in patients responsive to efalizumab, it is most common in those patients who have an inadequate response. Post hoc analyses suggest that when disease begins to recur, progression to rebound may be preventable with the use of available psoriasis therapies (see article by Carey et al elsewhere in this supplement). The majority (91%) of patients who were treated with alternative psoriasis therapies when experiencing active worsening of their psoriasis did not progress to rebound. When patients exhibited early signs of disease worsening after efalizumab discontinuation, the use of a number of psoriasis therapies appeared to be helpful in preventing progression to rebound. Agents that appeared to be effective at preventing rebound when used to treat signs of recurrence include methotrexate, cyclosporine, oral corticosteroids, and even topical corticosteroids (see article by Carey et al elsewhere in this supplement). In these cases, the choice of therapy was based on physician and patient decision. Similar to patients who discontinued efalizumab as a consequence of a GIF, patients who experience rebound are not precluded from reinitiating efalizumab therapy at some point in the future.
Collectively, the clinical trial and investigator experience with efalizumab provides extensive information that serves as the basis for the treatment guideline and treatment principles described herein (Fig 1). Patients who are maintaining efficacy and tolerating efalizumab favorably can receive efalizumab on a continuous basis. Patients who respond can safely discontinue treatment if necessary and restart therapy at some time in the future. Periodic patient assessments are recommended early in efalizumab treatment and throughout the first 3 months of therapy. Dermatologists need to be aware of the various options for management of psoriasis events should they occur during therapy or after discontinuation. As detailed in this article, patients who develop psoriasis events or worsening during therapy can be treated using a variety of approaches. Before initiating efalizumab therapy, dermatologists need to educate their patients regarding the possibility of psoriasis events and the importance of reporting them immediately. In addition, although a missed dose in responding patients is unlikely to be problematic, patients (particularly those who are efalizumab nonresponsive) should be counseled to not discontinue efalizumab therapy without consulting their dermatologists. The accumulating clinical experience with efalizumab indicates that it is an effective therapy for the majority of patients with moderate to severe chronic plaque psoriasis. Furthermore, efalizumab has a demonstrated safety profile, with no evidence suggestive of cumulative toxicity or end-organ damage. Efalizumab is a therapy that may provide hope to many patients with psoriasis seeking continuous control of their psoriasis. The authors thank Barry Lubarsky, PhD, of Helix Medical Communications LLC for editorial assistance in the development of this manuscript.
CONCLUSIONS Efalizumab has been studied extensively in numerous phase I, II, and III trials treating more than 3500 patients with psoriasis, indicating that the majority of patients experience significant improvement in their disease. Many patients with psoriasis who receive efalizumab therapy experience a rapid improvement in their symptoms within 2 to 4 weeks.5,6,8 Improvement in disease severity continues with prolonged efalizumab dosing.23 Efficacy for some patients remaining on continuous therapy appears to be maintained for at least 27 months (see article by Gottlieb et al elsewhere in this supplement) and up to 36 months.11 Moreover, some responding patients may continue to experience improved clearing in their disease for up to the first 18 months of treatment.
REFERENCES 1. Griffiths CE. Immunotherapy for psoriasis: from serendipity to selectivity. Lancet 2002;359:279-80. 2. Krueger JG. The immunologic basis for the treatment of psoriasis with new biologic agents. J Am Acad Dermatol 2002;46:1-23. 3. Singri P, West DP, Gordon KB. Biologic therapy for psoriasis: the new therapeutic frontier. Arch Dermatol 2002;138:657-63. 4. Werther WA, Gonzalez TN, O’Connor SJ, McCabe S, Chan B, Hotaling T, et al. Humanization of an anti-lymphocyte function-associated antigen (LFA)-1 monoclonal antibody and reengineering of the humanized antibody for binding to rhesus LFA-1. J Immunol 1996;157:4986-95. 5. Lebwohl M, Tyring SK, Hamilton TK, Toth D, Glazer S, Tawfik NH, et al. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med 2003;349:2004-13. 6. Gordon KB, Papp KA, Hamilton TK, Walicke PA, Dummer W, Li N, et al. Efalizumab for patients with moderate to severe
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7.
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plaque psoriasis: a randomized controlled trial. JAMA 2003; 290:3073-80. Menter A, Gordon K, Carey W, Hamilton T, Glazer S, Caro I, et al. Efficacy and safety observed during 24 weeks of efalizumab therapy in patients with moderate to severe plaque psoriasis. Arch Dermatol 2005;141:31-8. Leonardi CL, Papp KA, Gordon KB, Menter A, Feldman SR, Caro I, et al. Extended efalizumab therapy improves chronic plaque psoriasis: results from a randomized phase III trial. J Am Acad Dermatol 2005;52:425-33. Papp KA, Sobell J, Toth D, Walicke PA, Wang X, Garovoy MR, et al. Safety of subcutaneous efalizumab therapy in patients with moderate to severe plaque psoriasis. Poster presented at: American Academy of Dermatology Summer Meeting; July 25-29, 2003; Chicago, Ill. Carlin CS, Feldman SR, Krueger JG, Menter A, Krueger GG. A 50% reduction in the Psoriasis Area and Severity Index (PASI 50) is a clinically significant endpoint in the assessment of psoriasis. J Am Acad Dermatol 2004;50:859-66. Gottlieb AB, Gordon KB, Hamilton TK, Caro I, Kwon P, Compton P, et al. Maintenance of efficacy and safety with continuous efalizumab therapy in patients with moderate to severe chronic plaque psoriasis: final phase IIIb study results. Poster 4 presented at: 63rd Annual Meeting of the American Academy of Dermatology; February 18-22, 2005; New Orleans, La. Menter A, Kosinski M, Bresnahan BW, Papp KA, Ware JE Jr. Impact of efalizumab on psoriasis-specific patient-reported outcomes: results from three randomized, placebo-controlled clinical trials of moderate to severe plaque psoriasis. J Drugs Dermatol 2004;3:27-38. Gordon KB, Siegfried E, Carey W, Walicke P, Li N, Garovoy M, et al. Impact of 24 weeks of continuous efalizumab therapy on patient-reported outcomes in patients with moderate to severe plaque psoriasis. Poster presented at: American Academy of Dermatology Summer Meeting; July 25-29, 2003; Chicago, Ill. Raptiva [efalizumab] [package insert]. South San Francisco, Calif: Genentech Inc; June 2005. De Jong EM. The course of psoriasis. Clin Dermatol 1997; 15:687-92. Gottlieb AB, Gordon KB, Lebwohl MG, Caro I, Walicke PA, Li N, et al. Extended efalizumab therapy sustains efficacy without increasing toxicity in patients with moderate to severe chronic plaque psoriasis. J Drugs Dermatol 2004;3:614-24.
17. Cohen DJ, Fivenson D, Kimball AB, Tharp M, Turner J, Caro I, et al. Safety and tolerability of efalizumab therapy: a phase IIIb open-label study including patients using concurrent topical or phototherapy or recently transitioning from nonbiologic systemic psoriasis therapies. Poster presented at: 63rd Annual Meeting of the American Academy of Dermatology; February 18-22, 2005; New Orleans, La. 18. Menter A, Hamilton TK, Caro I, Kwon P, Papp K. Safety and tolerability of efalizumab therapy for patients with moderate to severe chronic plaque psoriasis: results of an open-label phase IIIb multicenter trial. Poster presented at: 63rd Annual Meeting of the American Academy of Dermatology; February 18-22, 2005; New Orleans, La. 19. Papp KA, Mease PJ, Garovoy MR, Kardatzke D, Leonardi CL. Efalizumab in patients with psoriatic arthritis: results of a phase II, randomized, double-blind, placebo-controlled study. Presented at: 10th International Psoriasis Symposium; June 10-13, 2004; Toronto, Ontario, Canada. 20. Maryles S, Rozenblit M, Lebwohl M. Transition from methotrexate and cyclosporine to other therapies including retinoids, ultraviolet light and biologic agents in the management of patients with psoriasis. J Dermatol Treat 2003; 14(Suppl):7-16. 21. Koo JY. Current consensus and update on psoriasis therapy: a perspective from the US. J Dermatol 1999;26:723-33. 22. Weinstein GD, White GM. An approach to the treatment of moderate to severe psoriasis with rotational therapy. J Am Acad Dermatol 1993;28:454-9. 23. Menter A, Kardatzke D, Rundle AC, Kwon P, Garovoy MR, Leonardi CL. Incidence and prevention of rebound upon efalizumab discontinuation. Poster presented at: 10th International Psoriasis Symposium; June 10-13, 2004; Toronto, Ontario, Canada. 24. Carey W, Rundle AC, Kwon P, Leonardi CL. Taper regimens in the management of patients discontinuing efalizumab therapy. Poster 29 presented at: 10th International Psoriasis Symposium; June 10-13, 2004; Toronto, Ontario, Canada. 25. Gordon KB, Koo JYM, Feldman SR, Menter A, Krueger G. Definitions of measures of effect duration for psoriasis treatments. Psoriasis Forum 2002;8:1-5. 26. Gordon KB, Feldman SR, Koo JY, Menter A, Rolstad T, Krueger G. Definitions of measures of effect duration for psoriasis treatments. Arch Dermatol 2005;141:82-4.
REVIEW
Long-term management of plaque psoriasis with continuous efalizumab therapy Alan Menter, MD,a Craig L. Leonardi, MD,b Wolfram Sterry, MD,c Jan D. Bos, MD,d and Kim A. Papp, MD, PhDe Dallas, Texas; St. Louis, Missouri; Berlin, Germany; Amsterdam, The Netherlands; and Waterloo, Ontario, Canada
A
fter a long period with few significant therapeutic advances, the last decade has witnessed a notable increase in the number of therapies that are in development and that have been approved for patients with psoriasis. Although the effectiveness of many traditional systemic therapies was discovered serendipitously,1 advances in molecular research and technology have resulted in the development of a new class of psoriasis therapies. Biologic therapies are designed to specifically target discrete processes, cell types, or cytokines known to be important in the pathogenesis of psoriasis.2 With their targeted mechanisms of action, it is hoped that biologic therapies will provide patients who have psoriasis with effective and safer options.3 Biologic therapies have been studied rigorously in well-designed controlled trials treating significant numbers of patients with psoriasis. Furthermore, some of the biologics (eg, efalizumab) have longterm treatment data for a small subset of patients with psoriasis. The clinical trial experience leading to the relatively recent approval of 3 biologic therapies (alefacept, efalizumab, and etanercept) for psoriasis
From Baylor University Medical Center, Dallasa; St. Louis University School of Medicineb; University Hospital Charite´ Berlinc; Academic Medical Center, University of Amsterdamd; and Probity Medical Research, Waterloo.e Supported by Genentech Inc and Serono International SA. Disclosures: Dr Leonardi has received educational grant support from and served on the speakers bureau and advisory board for Genentech Inc. Dr Menter has received research support and/or is a consultant and/or lecturer for Abbott Laboratories, Amgen Inc, Biogen Idec, Centocor Inc, Genentech Inc, Serono SA, and Xoma LLC. Dr Papp is a consultant, an investigator, and an advisory board member for Genentech Inc, Serono SA, and Xoma LLC; he is on the Serono SA speakers bureau. Drs Bos and Sterry have no conflicts of interest to disclose. Reprint requests: Alan Menter, MD, Texas Dermatology Research Institute, 5310 Harvest Hill Rd, Suite 260, Dallas, TX 75230. E-mail: [email protected]. J Am Acad Dermatol 2006;54:S182-8. 0190-9622/$32.00 ª 2006 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.10.028
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Abbreviations used: GIF: LMB: PASI: PASI-50: PASI-75:
generalized inflammatory flare localized mild breakthrough Psoriasis Area and Severity Index at least 50% reduction in PASI score at least 75% reduction in PASI score
has widened the range of therapeutic options and is altering the way many dermatologists approach psoriasis management. Because biologic therapies for psoriasis exert their therapeutic effects by mechanisms distinct from traditional psoriasis therapies and because they are administered differently—by subcutaneous or intramuscular injection—dermatologists are familiarizing themselves with these newer therapeutic options and are seeking guidance on how to best incorporate them into daily practice. As clinical trial data accumulate, and as more dermatologists prescribe biologic therapies for their patients, valuable experience will accumulate and further define how these therapies can be optimally incorporated into a dermatologist’s psoriasis armamentarium. It is also expected that data contrasting the biologics and evaluating their use in clinical practice rather than according to structured trial protocols would give additional information needed to make proper choices in the management of psoriasis. Extensive clinical trial experience has shown that efalizumab, a humanized recombinant monoclonal immunoglobulin G-1 antibody developed to target multiple T cellemediated processes critical to the pathogenesis of psoriasis,4 provides rapid and sustained efficacy for many patients with psoriasis.5-8 A number of efalizumab clinical trials have been prospectively designed to provide dermatologists with clinical trial data that support and guide clinical decisions concerning efalizumab administration. Psoriasis is a chronic disease without a cure; therefore, most patients will require long-term therapy to control their symptoms. Many patients have been
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Fig 1. Efalizumab patient management guidelines. *Range represents percentage of patients who achieved at least a 50% reduction in the PASI score (PASI-50) by week 12 in pooled data from three randomized, controlled phase III trials (59%), and in an ongoing open-label, 36-month phase III trial (82%).
unable to achieve continuous symptom control because the toxicity associated with traditional therapies has precluded their long-term administration. This supplement discusses a number of relevant aspects of treating patients receiving efalizumab therapy: continuous administration (see article by Gottlieb et al elsewhere in this supplement), management of psoriasis exacerbations during efalizumab therapy and avoiding rebound after discontinuation of treatment (see article by Carey et al elsewhere in this supplement), and retreatment in responding patients in the event that efalizumab is discontinued and reinitiated (see article by Papp et al elsewhere in this supplement). Until now there have been limited clinical trial data to address various issues that may arise during treatment of patients with efalizumab. The results of several efalizumab clinical trials and retrospective analyses provide insight into the treatment of patients receiving efalizumab. This review combines the results of these relevant efalizumab clinical studies and the observations and recommendations from experienced investigators.
Based on the evidence available to date and our collective experiences, we have developed a treatment guideline to assist our colleagues in the clinical treatment of patients receiving efalizumab for psoriasis (Fig 1).
EFALIZUMAB CLINICAL TRIAL EVIDENCE Multiple clinical trials have demonstrated that the majority of patients with psoriasis realize a clinical benefit from efalizumab therapy.5,6,8,9 Phase III randomized clinical studies have demonstrated that a significantly greater proportion of patients treated with efalizumab compared with placebo achieved all primary and secondary efficacy end points at 3 months. For instance, results from the pivotal trial demonstrated that 27% of patients treated with efalizumab achieved at least 75% improvement in their Psoriasis Area and Severity Index (PASI) score (PASI-75) compared with 4% of patients treated with placebo after 3 months (12 weeks).6 When therapy was extended from 3 to 6 months as part of an open-label extension, PASI responses continued
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to improve. Of all patients, 44% achieved PASI-75 after 24 weeks of continuous therapy.7 PASI-75 is the efficacy benchmark used by many regulatory bodies; however, this is a very stringent criterion for success and patients generally achieve meaningful disease and quality-of-life improvements with at least a 50% reduction in PASI score (PASI-50) response.10 In the above-mentioned pivotal trial, 59% of patients achieved PASI-50 after 3 months of efalizumab therapy and 67% achieved PASI-50 after 6 months.6,7 These findings are supported by results from a 36-month open-label, phase III trial involving 339 patients. At the time of submission, data for 170 patients who received up to 27 months of treatment were available for analysis (see article by Gottlieb et al elsewhere in this supplement); 36-month study results were recently reported.11 This trial demonstrated that some patients can maintain their therapeutic responses for at least 27 months and up to 36 months of continuous efalizumab treatment. After the 3-month initial treatment period, 82% of patients achieved PASI-50 and 41% achieved PASI-75. Of patients who qualified for the long-term maintenance treatment period, 76% achieved PASI-50 and 56% achieved PASI-75 after 27 months of therapy. Moreover, the proportion of patients who achieved almost complete clearance of disease, as reflected by at least a 90% reduction in PASI score response rate, continued to increase during the first 18 months of therapy (13% after 3 months to 33% at 18 months), after which time improvement was maintained (30% at month 27). The rate of patient discontinuation was low and stable throughout 27 months of continuous therapy, with the rate of discontinuation during each 3-month analysis period comparable with that observed during the initial 12-week treatment period of other phase III efalizumab trials (4.0%-11.4%).5,6,8,9 Patients discontinued for multiple reasons (eg, lack of efficacy, adverse events, life circumstances). Although the efalizumab clinical trials evaluated PASI-75 as the primary end point, it is unlikely that dermatologists will apply this measure in clinical practice. During the clinical trials, patients treated with efalizumab also demonstrated benefit when assessed by more commonly used measures, including the Physician’s Global Assessment. In addition to improvement on physician-assessed clinical measures, patients treated with efalizumab reported improvements on multiple patient-reported outcome measures that assess the impact of efalizumab on health-related quality of life.12 Most patients treated with efalizumab achieved significant improvement relative to placebo in patient-reported measures of health-related quality of life within
4 weeks of initiating efalizumab. During the pivotal trial, patients receiving efalizumab therapy reported a mean improvement of 47% from baseline on the Dermatology Life Quality Index questionnaire, compared with a 14% improvement for patients in the placebo group.13 Similar improvements were achieved on other patient-reported measures of treatment efficacy, including a visual analog scale for itch and both the frequency and severity subscales of the Psoriasis Severity Assessment. Improvements in these patient-reported measures were sustained throughout 24 weeks of continuous treatment.7 Efalizumab therapy has generally been well tolerated. The most common adverse events are associated with initiation of efalizumab therapy and have been termed acute adverse events.14 These are characterized as flu-like symptoms associated with the first 1 or 2 doses of efalizumab therapy. In clinical trials, few patients discontinued efalizumab because of acute adverse events.14 In a small study, there has been no indication that long-term continuous therapy alters the safety profile of efalizumab (see article by Gottlieb et al elsewhere in this supplement). There is also no evidence of a trend toward an increase in overall incidence of adverse events or evidence of end-organ damage. As new therapeutic agents such as efalizumab are demonstrating efficacy on multiple physicianand patient-assessed end points, the primary cut-off measure currently used to evaluate the efficacy of a psoriasis therapy (PASI-75) appears increasingly arbitrary. Moreover, the PASI measures only improvement in skin condition, thus ignoring possible improvements in patient quality of life. With an increasing number of new therapeutics approved or under development for psoriasis, it becomes increasingly important to consider the multiple dimensions of efficacy and safety that contribute to disease control.
TREATING PATIENTS WHO IMPROVE AND MAINTAIN BENEFIT Collectively, clinical trial results and investigator experiences indicate that patients who achieve a clinical benefit (eg, at least a PASI-50 response or a Physician’s Global Assessment of change of ‘‘good’’ or ‘‘better’’) can receive continuous efalizumab therapy unless an adverse event occurs, efficacy declines substantially, or life circumstances dictate otherwise. It is unlikely that patients will lose symptom control or experience rebound in the event that they miss a dose (see article by Carey et al elsewhere in this supplement); therefore, dermatologists and patients need not be overly concerned in the event that an occasional dose is missed.
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Because psoriasis is a disease that fluctuates in severity over time, patients may experience some variability in their response over time. This is not unique to efalizumab; fluctuation in disease severity is a common occurrence in patients with psoriasis.15 There are a number of factors unrelated to psoriasis treatment that can exacerbate or trigger psoriasis in patients otherwise experiencing symptom control (eg, infection, fluctuations in endocrine factors, hypocalcemia, medications used for other indications, stress, or cutaneous trauma).15 For mild recurrences during treatment with efalizumab, dermatologists can consider adding a course of topical corticosteroids. Some patients will discontinue efalizumab therapy despite a favorable response. Life circumstances that might result in discontinuation of efalizumab include pregnancy, extended holidays or travel plans, or insurance coverage changes. Evidence from multiple studies demonstrates that discontinuation of efalizumab therapy in responding patients typically results in a gradual return of psoriasis; however, rebound has been seen in some of these patients. In one study, the median time to relapse after efalizumab discontinuation in responding patients was approximately 2 months (see article by Carey et al elsewhere in this supplement). Patients should be observed after discontinuation of efalizumab. Upon disease recurrence, patients who were responsive to efalizumab and discontinued treatment because of temporary circumstances may benefit from restarting efalizumab therapy. The results of a clinical trial demonstrated that efalizumab retreatment was effective and well tolerated (see article by Papp et al elsewhere in this supplement). However, because some patients who discontinued efalizumab after a retreatment course may also experience rebound, patients receiving efalizumab retreatment should be assessed for rebound when efalizumab is discontinued. Furthermore, the efficacy of retreatment appears to be similar to that achieved during an initial course of efalizumab (see article by Papp et al elsewhere in this supplement). Therefore, discontinuation from efalizumab therapy does not preclude responding patients from receiving and benefiting from efalizumab therapy in the future.
PRACTICAL CONSIDERATIONS FOR PATIENTS NOT DEMONSTRATING NOTICEABLE IMPROVEMENT Nonresponders are the patients most likely to experience psoriasis adverse events or disease worsening during or rebound after treatment (see article by Carey et al elsewhere in this supplement). Patients who show no noticeable response by approximately 3 months after beginning efalizumab
therapy are unlikely to derive benefit from continued efalizumab and should transition to an alternative psoriasis therapy.
TREATING PATIENTS WHO EXPERIENCE PSORIASIS EVENTS DURING EFALIZUMAB THERAPY During clinical trials with efalizumab, psoriasis adverse events were noted in some patients. Their appearance can be broadly classified into one of two categories: the more common transient localized papular eruption (described as a localized mild breakthrough [LMB]) that is typically papular and limited in nature; or a more infrequent and extensive eruption known as generalized inflammatory flare (GIF). As dermatologists have gained experience with efalizumab in clinical practice and are able to more accurately describe their observations, the description of these events has evolved over time. Dermatologists have previously referred to LMB as a ‘‘transient papular eruption’’ or ‘‘transient neutrophilic dermatoses’’ and referred to GIF as a ‘‘generalized inflammatory exacerbation.’’ In the opinion of the investigators, LMB and GIF are accurate descriptions of the potential psoriasis events that may occur during treatment with efalizumab. It is important to note that the proliferation of terminology appearing in the literature does not represent new events observed during treatment with efalizumab and despite the use of new descriptive terminology, LMB is a form of psoriasis and not a new disease. Some patients may initially demonstrate a favorable response to efalizumab therapy and then experience a psoriasis event during therapy. It is important to distinguish these events from incomplete washout of a prior psoriasis therapy. If a patient has not been completely washed out from a prior psoriasis therapy, a brief period of overlap when efalizumab therapy is initiated is recommended. A GIF as a result of incomplete washout may not necessitate efalizumab discontinuation. In responding patients, dermatologists or patients may observe alterations in the appearance of psoriasis or slight fluctuations in disease control of a papular nature, which may be described as LMB. LMB, when it does occur, generally manifests within 4 to 8 weeks of initiating efalizumab therapy, although it can occur at any time. Typically, existing lesions are not involved, and the LMB is frequently, but not exclusively, localized on the neck, torso, or flexural areas. Based on investigator observations, LMB appears to have no clinical impact in responding patients and may be effectively treated through. Dermatologists may consider adding a topical
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therapy to continued efalizumab therapy until the breakthrough resolves. Although unlikely, should the LMB not respond to topical therapy or worsen, dermatologists may consider adding a short course (eg, 4-6 weeks) of a systemic therapy to efalizumab therapy until resolution, at which time the concomitant systemic therapy can be discontinued. Alternatively, dermatologists may add an alternative systemic psoriasis therapy, and after a period of overlap sufficient to allow the new therapy to become effective, discontinue efalizumab therapy. Dermatologists should educate their patients regarding the potential for LMB or GIF (see below) before initiation of efalizumab therapy. Dermatologists have also noted the infrequent occurrence of GIF, which typically involves existing plaques with or without the development of new lesions. GIF is more commonly observed in nonresponding patients; however, it has been seen in patients who have responded well to efalizumab therapy. Most cases manifest within 6 to 10 weeks of initiating efalizumab therapy. In the event of an inflammatory flare, dermatologists may consider initiation of a short course (eg, 4-6 weeks) of an alternative systemic psoriasis therapy (eg, cyclosporine or methotrexate). If the flare resolves and the underlying psoriasis is improved, the systemic therapy can then be tapered off and efalizumab continued. If the flare is not controlled or the underlying psoriasis is not improved, efalizumab should be discontinued and the patient should be maintained on systemic therapy. Alternatively, dermatologists may elect to simply discontinue efalizumab therapy by transitioning to an alternative psoriasis therapy without a period of overlap. At this time, there is no evidence or sufficient cumulative experience indicating the superiority of one approach over another. Ultimately, it is up to the treating dermatologist to select the approach. It is important that dermatologists educate patients to return to the office immediately if they develop widespread, erythematous, edematous lesions that may also take on a pustular appearance. With careful monitoring and prompt treatment, patients can be safely treated to achieve control of their disease. Anecdotally, some patients who developed a GIF were successfully retreated with efalizumab at a later time. It should be noted that although dermatologists have some experience combining efalizumab with other psoriasis therapies, there are limited data for the safety of such combinations. Most efalizumab clinical trials excluded concomitant psoriasis treatments with the exception of mild topicals (eg, low-potency corticosteroids)14 and, in some
trials, selected forms of phototherapy.16-18 In a randomized, controlled phase II study to evaluate the safety and efficacy of efalizumab for the treatment of patients with psoriatic arthritis, a cohort of patients received efalizumab with concomitant methotrexate for up to 24 weeks.19 The safety profile of patients treated with efalizumab in this trial was consistent with the placebo group, suggesting that concomitant methotrexate use does not adversely affect the efalizumab safety profile. It is recommended to carefully observe patients when overlapping efalizumab with another therapy, particularly another systemic immunosuppressive agent.
TRANSITIONING FROM EFALIZUMAB TO AN ALTERNATIVE PSORIASIS THERAPY The results of the rebound analyses (see article by Carey et al elsewhere in this supplement) suggest that a successful approach to discontinuation in patients who do not respond to, or who worsen on, efalizumab involves immediate transition to an alternative psoriasis therapy. Alternatively, patients may be transitioned by overlapping an alternative systemic agent with efalizumab for a period of time long enough to allow the second agent to achieve maximal effect, then discontinuing efalizumab. Transitioning patients off one psoriasis therapy and onto another is a common treatment strategy used to maintain disease control and avoid treatment-related toxicity. Thus, most dermatologists are familiar with transitioning between, overlapping, and combining different therapeutic agents.20-22 Transition to an alternative agent treats the patient’s psoriatic symptoms and may avoid worsening of disease. The selection of the most appropriate alternative psoriasis therapy is based on a patient’s history of response to and tolerance of prior psoriasis therapies, other concomitant illnesses or medications that might interact with psoriasis therapies, and the severity of the disease. The retrospective analyses presented by Carey et al (article appears elsewhere in this supplement) are supported by a smaller phase III prospective analysis of transition medications.23 Together, these results suggest that transition to other approved psoriasis treatments can prevent worsening of disease or rebound when efalizumab therapy is stopped. The results from a phase III study indicate that tapering efalizumab therapy without having a transition therapy option is not an effective strategy to prevent rebound.24
EFALIZUMAB DISCONTINUATION AND REBOUND Rebound has been observed with many psoriasis therapies.25,26 A retrospective analysis of pooled
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data from multiple efalizumab clinical trials using a definition of rebound adapted from the National Psoriasis Foundation25,26 indicated that rebound occurs in 14% of all patients who abruptly discontinue efalizumab (see article by Carey et al elsewhere in this supplement). Moreover, the results demonstrated that patients who do not respond to efalizumab are most likely to experience rebound. These patients require particular attention when efalizumab is discontinued. Therefore, although dermatologists should be aware of the possibility of rebound in patients responsive to efalizumab, it is most common in those patients who have an inadequate response. Post hoc analyses suggest that when disease begins to recur, progression to rebound may be preventable with the use of available psoriasis therapies (see article by Carey et al elsewhere in this supplement). The majority (91%) of patients who were treated with alternative psoriasis therapies when experiencing active worsening of their psoriasis did not progress to rebound. When patients exhibited early signs of disease worsening after efalizumab discontinuation, the use of a number of psoriasis therapies appeared to be helpful in preventing progression to rebound. Agents that appeared to be effective at preventing rebound when used to treat signs of recurrence include methotrexate, cyclosporine, oral corticosteroids, and even topical corticosteroids (see article by Carey et al elsewhere in this supplement). In these cases, the choice of therapy was based on physician and patient decision. Similar to patients who discontinued efalizumab as a consequence of a GIF, patients who experience rebound are not precluded from reinitiating efalizumab therapy at some point in the future.
Collectively, the clinical trial and investigator experience with efalizumab provides extensive information that serves as the basis for the treatment guideline and treatment principles described herein (Fig 1). Patients who are maintaining efficacy and tolerating efalizumab favorably can receive efalizumab on a continuous basis. Patients who respond can safely discontinue treatment if necessary and restart therapy at some time in the future. Periodic patient assessments are recommended early in efalizumab treatment and throughout the first 3 months of therapy. Dermatologists need to be aware of the various options for management of psoriasis events should they occur during therapy or after discontinuation. As detailed in this article, patients who develop psoriasis events or worsening during therapy can be treated using a variety of approaches. Before initiating efalizumab therapy, dermatologists need to educate their patients regarding the possibility of psoriasis events and the importance of reporting them immediately. In addition, although a missed dose in responding patients is unlikely to be problematic, patients (particularly those who are efalizumab nonresponsive) should be counseled to not discontinue efalizumab therapy without consulting their dermatologists. The accumulating clinical experience with efalizumab indicates that it is an effective therapy for the majority of patients with moderate to severe chronic plaque psoriasis. Furthermore, efalizumab has a demonstrated safety profile, with no evidence suggestive of cumulative toxicity or end-organ damage. Efalizumab is a therapy that may provide hope to many patients with psoriasis seeking continuous control of their psoriasis. The authors thank Barry Lubarsky, PhD, of Helix Medical Communications LLC for editorial assistance in the development of this manuscript.
CONCLUSIONS Efalizumab has been studied extensively in numerous phase I, II, and III trials treating more than 3500 patients with psoriasis, indicating that the majority of patients experience significant improvement in their disease. Many patients with psoriasis who receive efalizumab therapy experience a rapid improvement in their symptoms within 2 to 4 weeks.5,6,8 Improvement in disease severity continues with prolonged efalizumab dosing.23 Efficacy for some patients remaining on continuous therapy appears to be maintained for at least 27 months (see article by Gottlieb et al elsewhere in this supplement) and up to 36 months.11 Moreover, some responding patients may continue to experience improved clearing in their disease for up to the first 18 months of treatment.
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17. Cohen DJ, Fivenson D, Kimball AB, Tharp M, Turner J, Caro I, et al. Safety and tolerability of efalizumab therapy: a phase IIIb open-label study including patients using concurrent topical or phototherapy or recently transitioning from nonbiologic systemic psoriasis therapies. Poster presented at: 63rd Annual Meeting of the American Academy of Dermatology; February 18-22, 2005; New Orleans, La. 18. Menter A, Hamilton TK, Caro I, Kwon P, Papp K. Safety and tolerability of efalizumab therapy for patients with moderate to severe chronic plaque psoriasis: results of an open-label phase IIIb multicenter trial. Poster presented at: 63rd Annual Meeting of the American Academy of Dermatology; February 18-22, 2005; New Orleans, La. 19. Papp KA, Mease PJ, Garovoy MR, Kardatzke D, Leonardi CL. Efalizumab in patients with psoriatic arthritis: results of a phase II, randomized, double-blind, placebo-controlled study. Presented at: 10th International Psoriasis Symposium; June 10-13, 2004; Toronto, Ontario, Canada. 20. Maryles S, Rozenblit M, Lebwohl M. Transition from methotrexate and cyclosporine to other therapies including retinoids, ultraviolet light and biologic agents in the management of patients with psoriasis. J Dermatol Treat 2003; 14(Suppl):7-16. 21. Koo JY. Current consensus and update on psoriasis therapy: a perspective from the US. J Dermatol 1999;26:723-33. 22. Weinstein GD, White GM. An approach to the treatment of moderate to severe psoriasis with rotational therapy. J Am Acad Dermatol 1993;28:454-9. 23. Menter A, Kardatzke D, Rundle AC, Kwon P, Garovoy MR, Leonardi CL. Incidence and prevention of rebound upon efalizumab discontinuation. Poster presented at: 10th International Psoriasis Symposium; June 10-13, 2004; Toronto, Ontario, Canada. 24. Carey W, Rundle AC, Kwon P, Leonardi CL. Taper regimens in the management of patients discontinuing efalizumab therapy. Poster 29 presented at: 10th International Psoriasis Symposium; June 10-13, 2004; Toronto, Ontario, Canada. 25. Gordon KB, Koo JYM, Feldman SR, Menter A, Krueger G. Definitions of measures of effect duration for psoriasis treatments. Psoriasis Forum 2002;8:1-5. 26. Gordon KB, Feldman SR, Koo JY, Menter A, Rolstad T, Krueger G. Definitions of measures of effect duration for psoriasis treatments. Arch Dermatol 2005;141:82-4.