Approaches to discontinuing efalizumab: an open-label study of therapies for managing inflammatory recurrence
© Papp et al; licensee BioMed Central Ltd. 2006
Received: 11 May 2006
Accepted: 26 October 2006
Published: 26 October 2006
Efalizumab is a humanised recombinant monoclonal IgG1 antibody for the treatment of moderate-to-severe plaque psoriasis. When treatment discontinuation is necessary, however, some patients may experience inflammatory recurrence of the disease, which can progress to rebound if untreated. This analysis evaluated approaches for managing inflammatory recurrence after discontinuation of efalizumab.
An open-label, multicentre, investigational study was performed in 41 patients with moderate-to-severe plaque psoriasis who had recently completed clinical studies with efalizumab and had developed signs of inflammatory recurrence following abrupt cessation of treatment. Patients were assigned by the attending physicians to receive one of five standardised alternative systemic psoriasis treatment regimens for 12 weeks. Efficacy of the different therapy options was assessed using the physician's global assessment (PGA) of change over time.
More favourable PGA responses were observed in patients changing to cyclosporin (PGA of 'good', 'excellent' or 'cleared': 7/10 patients, 70.0%) or methotrexate (9/20, 45.0%), compared with those receiving systemic corticosteroids (2/8, 25.0%), retinoids (0/1, 0.0%) or combined corticosteroids plus methotrexate (0/2, 0.0%). While the majority (77.8%) of patients showed inflammatory morphology at baseline, following 12 weeks of the alternative therapies the overall prevalence of inflammatory disease was decreased to 19.2%.
Inflammatory recurrence after discontinuation of efalizumab therapy is a manageable event, with a number of therapies and approaches available to physicians, including short courses of cyclosporin or methotrexate.
Psoriasis is an inflammatory skin disorder that affects approximately 2–3% of the population  and has a profound impact on quality of life, equivalent to that of other major diseases . Patients with the disease present with well-defined, thickened erythematous patches, typically covered with a silver scale, and the condition is characterised by epidermal hyperplasia, dermal angiogenesis, infiltration of activated T-cells and increased cytokine levels . Chronic psoriasis is a condition requiring long-term medication. Systemic therapies are required by patients with moderate-to-severe disease; a variety of systemic therapies are available, but many of the current agents have serious side-effects that limit long-term administration [4, 5].
The aetiology and pathology of psoriasis are not well understood, but it has been established that T-cells are centrally involved in its development . Recent understanding of the inflammatory pathways in psoriasis has led to the development and use of new biologic agents to treat the condition. One such biologic therapy, efalizumab, is a humanised recombinant monoclonal IgG1 antibody. Efalizumab binds to the alpha-subunit, CD11a, of the T-cell adhesion molecule, leukocyte function-associated antigen-1 (LFA-1), preventing binding with its ligand, intercellular adhesion molecule-1 (ICAM-1), on target cells. This action blocks several T-cell processes important in the pathogenesis of psoriasis, including T-cell activation, T-cell trafficking from the circulation into the skin, and T-cell reactivation in the dermis and epidermis [3, 6, 7].
Definitions of commonly-used terminology used by the US National Psoriasis Foundation (NPF), the European Medicines Agency (EMEA) and this study.
Typical or unusual worsening of disease during treatment and/or the occurrence of new psoriasis morphologies.
Following treatment discontinuation
The EMEA recommend the use of recurrence as an endpoint in long-terms studies provided that it is clearly defined.
The term 'inflammatory recurrence' includes (a) patients with worsening of psoriasis within 2 months of discontinuation from efalizumab treatment to a level less severe than a rebound and (2) patients who have discontinued a psoriasis treatment due to an inflammatory disease flare but, following discontinuation, require treatment to prevent a rebound.
Loss of 50% of PASI improvement from baseline in patients who achieve a clinically meaningful response (≥ 50% improvement in PASI score from baseline).
A reduction of >50% in PASI from the achieved maximal improvement in PASI score.
Subjective alternative: a relapse of psoriasis necessitating the re-initiation of treatment.
A simple worsening of psoriasis beyond 2 months of therapy may represent the natural course of the disease (relapse) rather than a rebound associated with drug.
A PASI of 125% of baseline or new generalized pustular, erythrodermic, or more inflammatory psoriasis occurring within 3 months of stopping therapy.
Worsening occurring after 3 months of therapy may represent the natural course of the disease rather than a rebound associated with the drug.
Worsening of psoriasis over baseline value (e.g. PASI>125%) or new pustular, erythrodermic or more inflammatory psoriasis occurring within 2 months of stopping therapy.
A 2-month boundary separating relapse and rebound is drawn on theoretical grounds and is more or less arbitrary.
This study was intended to mimic current practice and hence a naturalistic approach, in which the physician chose the most appropriate therapy, was pursued. The main objective was to provide guidance for appropriate management of inflammatory recurrence before its progression to rebound.
This was an open-label, investigational study carried out in nine centres on patients with moderate-to-severe plaque psoriasis. The study was carried out according to Good Clinical Practice guidelines and the Declaration of Helsinki; the protocol was approved by Research Review Board, Inc., and all patients provided signed informed consent. Patients were enrolled in the study if: (1) they had worsening of psoriasis within 2 months of discontinuation from efalizumab treatment in other studies, which in the opinion of the investigator had not worsened sufficiently to constitute a rebound but that required re-initiation of treatment or, (2) had previously discontinued an efalizumab study due to an inflammatory disease flare. To cover both these scenarios, the term 'inflammatory recurrence' has been used. Patients were included if the recurrence was related to the disease previously treated with efalizumab and were excluded if the recurrence was considered to be part of the natural disease progression, which occurs more slowly (i.e. a relapse; see Table 1 for the EMEA definition of 'relapse').
Eligible patients received 12 weeks of systemic psoriasis therapy during the study as soon as inflammatory recurrence had been identified by the investigator. In order for the study to closely reflect routine clinical practice, attending physicians were free to judge which patients had worsening of disease that had not progressed to rebound and subsequently to choose the therapy they considered most appropriate for each individual patient from five pre-defined regimens. Physicians could switch among these therapies during the course of the study if it was deemed necessary. The standard approved psoriasis therapy regimens were:
cyclosporin: initial dose 4.0–5.1 mg/kg/day until clinical improvement (as judged by the investigator), followed by a 50% reduction in dose every 2 weeks
retinoids: initial dose 25–50 mg/day until clinical improvement (as judged by the investigator), followed by a 50% reduction in dose continuing for 8 weeks, at which time therapy was stopped
corticosteroids: initial dose 0.25–0.5 mg/kg/day until clinical improvement (as judged by the investigator), followed by a 50% reduction in dose every 2 weeks
methotrexate: initial dose 20–25 mg/week until clinical improvement (as judged by the investigator), followed by a 25% reduction in dose every 2 weeks
combined therapy: systemic corticosteroids plus methotrexate, utilising both of the above regimens in combination.
The physician's global assessment (PGA) is a simple and quick-to-use assessment of clinical status in patients with psoriasis. The PGA is familiar to physicians and is the standard measure of disease severity in current clinical practice. Therefore, PGA of change was considered to be the simplest and most appropriate measure to assess treatment efficacy in the present study. PGA of change was categorised according to seven ratings: 'clear' (100% improvement from baseline), 'excellent' (75–99%), 'good' (50–74%), 'fair' (25–49%), 'slight' (1–24%), 'unchanged' (no change in clinical signs and symptoms from baseline) and 'worse' (deterioration of clinical signs and symptoms from baseline). The disease was classified according to the morphology as inflammatory, plaque, papular/pustular, erythrodermic or inverse psoriasis and individual patients could have more than one type. The proportion of patients with each type was evaluated at the start and end of treatment.
This was a pilot investigation designed to collect information that would help plan future management strategies for patients who experience inflammatory recurrence after discontinuing efalizumab. There was no randomisation, all patients were analysed as treated and no formal statistical analysis was carried out. Owing to the need for treatment to control psoriasis, some patients were already allocated to one of the study drugs at the time of enrolment into the study. For these patients, baseline data were collected retrospectively, while data were collected prospectively for patients who were prescribed their initial psoriasis treatment at the time of enrolment. As the results were qualitatively similar for the two subgroups, the results are presented only for the two subgroups analysed together.
Patient demographics at baseline, according to systemic therapy prescribed as first treatment.
Methotrexate (N = 20)
Cyclosporin (N = 10)
Corticosteroids (N = 8)
Combineda(N = 2)
Retinoids (N = 1)
All patients (N = 41)
Mean ± SD
49 ± 10
43 ± 12
44 ± 11
47 ± 3
46 ± 11
Gender (n (%))
Ethnicity (n (%))
There were five patients in total who discontinued treatment before completing 12 weeks of the study. Three of these patients were from the methotrexate group: two discontinued due to patient decision and one was lost to follow-up; of the remaining two patients who discontinued prematurely, one discontinued from the cyclosporin group due to lack of efficacy, and one discontinued from the combined methotrexate plus corticosteroid group due to patient decision.
Assessment of PGA response
Patients with a PGA changea of 'good', 'excellent' or 'cleared', according to first treatment (assigned at baseline) and last treatment (the treatment that was being received at Week 12)*.
First treatment (n (%))
Last treatment (n (%))
Changes in psoriasis morphology
Disease morphology at start of treatment (baseline) and at Week 12 or withdrawal (endpoint), by last treatment prescribeda.
Methotrexate (N = 13)
Cyclosporine (N = 8)
Corticosteroids (N = 4)
Combinedb(N = 2)
All patients (N = 27)
Inflammatory (n (%))
Plaque (n (%))
Papular/pustular (n (%))
Inverse (n (%))
Erythrodermic (n (%))
The adverse event profile associated with each of the medications has been well documented, and the safety results were consistent with the known profiles. Across all treatment groups, 14 patients (34.1%) had at least one adverse event. Adverse events were considered to be possibly or probably related to treatment in eight patients (19.5%). During the study, there were no deaths, serious adverse events, or discontinuations due to adverse events.
Efalizumab has been developed for long-term treatment of psoriasis, and clinical studies have shown increasing response with longer treatment duration. However, on discontinuation of treatment there have been reports of rebound of psoriasis symptoms, mainly in non-responding patients [11, 14]. Rebound can occur with other psoriasis medications as was shown many years ago after stopping systemic corticosteroids  as well as cyclosporin [16, 17]. If alternative therapies are instituted immediately when inflammatory recurrence is observed, development of rebound may be prevented. This analysis was a preliminary exploration of appropriate alternative therapeutic regimens for control of inflammatory disease recurrence in patients discontinuing efalizumab, such that progression to rebound can be avoided. As an exploratory study, there are a number of inherent limitations that should be accounted for when interpreting the results, including the small number of patients included in each of the treatment groups. It should also be noted that, due to the need for treatment to control psoriasis, some patients were already allocated to one of the study drugs at the time of enrolment into the study. Therefore, baseline data were collected retrospectively for these patients.
In clinical trials, the Psoriasis Area and Severity Index (PASI) is the most commonly used measure of disease severity, but in a clinical setting it is difficult to use due to its complexity. The PGA, which is more simple and quick to use compared with the PASI is, therefore, the more commonly used assessment in current clinical practice. In a placebo-controlled clinical study of efalizumab for the treatment of patients with moderate-to-severe plaque psoriasis, close agreement was found between the PASI and PGA when both were used to measure improvement in psoriasis . In addition, a double-blind trial directly compared ratings with the PASI, PGA and a National Psoriasis Foundation scoring system and found a strong concordance between them . Therefore, PGA was considered to be the simplest and most appropriate measure for use in the present study.
The results from the present analysis indicated that methotrexate and cyclosporin were effective in alleviating the symptoms of recurrence of psoriasis. Systemic corticosteroids and retinoids appeared less effective in treating inflammatory recurrence, but the small number of patients means that further studies with these therapies are still necessary.
The results from this study indicate that inflammatory recurrence after discontinuation of efalizumab therapy is a manageable event. In order to prevent progression to established rebound, a number of therapies and approaches are available to physicians, including short courses of cyclosporin or methotrexate. Further larger-scale studies are required to confirm the present results.
The authors are grateful to the following investigators who also contributed data to this study: Dr Wayne Carey, Montreal, Quebec, Canada; Dr Charles Lynde, Markham, Ontario, Canada; Dr Yves P. Poulin, Sainte-Foy, Quebec, Canada; Dr Zohair Tomi, St John's, Newfoundland, Canada; Dr Ronald B. Vender, Hamilton, Ontario, Canada. The authors would like to thank Peter Bates and Juergen Wiehn for their support in preparing this manuscript. Philippe Fonjallaz is appreciated by the authors for assisting in review and in making editorial comments. The study and manuscript preparation were sponsored by Serono International S.A.
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