Download Biologic agents in psoriasis

Blackwell Publishing AsiaMelbourne, AustraliaAJDAustralasian Journal of Dermatology0004-8380© 2006 The Australasian College of Dermatologists? 2006474217230MiscellaneousBiologic
agents in
psoriasisMR Lee and AJ Cooper
Australasian Journal of Dermatology (2006) 47, 217–230
doi: 10.1111/j.1440-0960.2006.00286.x
PROFESSIONAL DEVELOPMENT PROGRAM
Biologic agents in psoriasis
Michael R Lee and Alan J Cooper
Department of Dermatology, Royal North Shore Hospital, Pacific Highway, St Leonards, New South Wales,
Australia
SUMMARY
This paper reviews the new biologic agents that
selectively block the immunologic steps implicated in
the pathogenesis of psoriasis. Four strategies have
been targeted: reduction of the number of pathogenic
T cells; inhibition of T-cell activation and migration;
modulation of the immune system; and blockage of
the activity of inflammatory cytokines. There are
three classes: monoclonal antibodies, fusion proteins
and recombinant cytokines or growth factors. The
actions, efficacy and side-effect profile of the biologic
agents, alefacept, efalizumab, etanercept and infliximab, are reviewed.
Key words: alefacept, efalizumab, etanercept,
fusion protein, infliximab, monoclonal antibody,
psoriasis area and severity index, recombinant
cytokine.
INTRODUCTION
There is currently an unmet need for a treatment for psoriasis that is readily available, safe, efficacious, and
provides long-term remission. Advances in molecular
biotechnology have resulted in the emergence of new targeted biologic therapies in dermatology, in parallel with
other areas in medicine. These new biologic agents have
yielded tangible results that meet some of the criteria of the
ideal therapy. They offer the hope for safe, long-term control of psoriasis because, to date, biologics have no known
nephrotoxicity or hepatotoxicity. It is desirable for drugs to
have the least global immunosuppression in treating psoriasis and biologics selectively block immune pathways
implicated in the pathogenesis. This paper reviews the new
Correspondence: Dr Michael R Lee, Department of Dermatology,
Royal North Shore Hospital, Pacific Highway, St Leonards, NSW
2065, Australia. Email: [email protected]
Michael R Lee, MB BS. Alan J Cooper, FACD.
Conflict of interest declaration: Both authors have been chief and
co-investigators for Biogen Idec trials.
Submitted 20 June 2005; accepted 4 May 2006.
© 2006 The Australasian College of Dermatologists
biologic agents in the context of these cellular and molecular immune pathways.
IMMUNOMODULATION BY BIOLOGIC
THERAPY
The US Department of Health and Human Services defines
‘biologic response modifiers’ as a generic term for hormones, neuroactive compounds and immunoreactive compounds that act at the cellular level. The FDA Centre for
Biologics Evaluation and Research defines biologics as
those agents derived from living material: human, plant,
animal or microorganism. There are three distinct classes
of biologic agents: monoclonal antibodies, fusion proteins
and recombinant cytokines or growth factors. 1 Antibodies
can be classified as chimeric where the antibody is composed of human and murine sequences, humanized where
individual amino acids in a human backbone are replaced
with specific murine sequences, or human sequence.1
Fusion proteins consist of a human receptor domain, so it
has capacity to bind to its ligand, which is fused to the
constant portion of IgG thus allowing solubility in plasma. 1
A strict nomenclature for the generic names of the biologics
has been developed. Generic names of chimeric monoclonal antibodies have the suffix -ximab, humanized monoclonal antibodies have the suffix -zumab and human
monoclonal antibodies have the suffix -umab. Receptor–
antibody fusion proteins have the suffix -cept. The strategies for immunomodulation in psoriasis are outlined in
Abbreviations:
CD
DLQI
FDA
IFN
Ig
IL
iNOS
LFA
PASI
PGA
PSA
TGA
TGF
Th
TNF
cluster of differentiation
dermatology life questionnaire index
Food and Drug Administration
interferon
immunoglobulin
interleukin
inducible nitric oxide synthase
lymphocyte function associated antigen
psoriasis area and severity index
physician’s global assessment
Psoriasis Symptom Assessment
Therapeutic Goods Administration
transforming growth factor
T-helper
tumour necrosis factor
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MR Lee and AJ Cooper
Table 1 Strategies for immunomodulation in psoriasis
Strategy
Biologic agent
Reduction of the number of pathogenic T cells
Inhibition of T-cell activation and migration
Alefacept, denileukin diftitox
CTLA4Ig, galiximab, efalizumab, daclizumab,
OKTcdr4a, HuMax-CD4, siplizumab
Ilodecakin, oprelvekin
Etanercept, infliximab, adalimumab, ABX-IL8
Modulation of the immune system
Blockage of the activity of inflammatory cytokines
Figure 1 Actions of alefacept: (1) The
LFA-3 portion binds to CD2 on the surface of T cells and blocks the interaction of CD2 with natural LFA-3. (2) The
IgG1 portion binds to the FcγRI and
FcγRIII receptors of NK cells or monocytes, inducing granzyme-mediated
apoptosis of memory effector T cells.
This illustration has been provided by
Biogen Idec. APC, antigen presenting
cell; CD, cluster of differentiation;
IgG1, immunoglobulin G1; LFA, lymphocyte function associated antigen;
MHC, major histocompatibility complex; NK, natural killer; TCR, T-cell
receptor.
Table 1. Evidence is lacking for the use of biologics in pregnancy and lactating mothers. Therefore, these agents
should not be used in pregnant or lactating mothers. It is
advised that women of child-bearing potential should use
contraception during treatment.
Strategy 1: Reduction of the number of pathogenic
T cells
Alefacept, LFA-3TIP (Amevive; Biogen Idec, Cambridge,
MA, USA) is a fusion protein combining two binding sites
of LFA-3 with the hinge, CH2 and CH3 sequences of IgG1.
The LFA-3 segment binds to CD2 on memory T cells
(Fig. 1), thereby inhibiting the activation and proliferation
of T cells.2–4 CD2 is constitutively expressed on all T-lymphocytes; however, it is up-regulated on the surface of
memory T cells.5,6 The constant portion of IgG1 additionally
binds to FcγRIII/CD16 on natural killer cells and monocytes
which triggers granzyme-mediated apoptosis of those T
cells expressing high levels of CD2 (Fig. 1). Since CD45RO+
memory effector T cells express more CD2 than do
CD45RA+ naïve T cells, alefacept binds preferentially to
memory effector T cells.7 Alefacept is currently approved
by the TGA in Australia for the treatment of adult patients
© 2006 The Australasian College of Dermatologists
with moderate to severe chronic plaque psoriasis who are
candidates for systemic agents or phototherapy.
Alefacept is administered intramuscularly. The recommended regimen is a 12-week course of weekly injections
(15 mg). This is then followed by a 12-week rest period and
a subsequent second course comprising weekly injections
(15 mg) for a further 12 weeks may be considered. The
results of a phase IV multicentre study in five sites within
Australia to determine whether patients with chronic
plaque psoriasis are able to go beyond the second 12-week
rest period before requiring alefacept or an alternative
therapy in patients are eagerly anticipated. It is recommended that a baseline CD4+ T-lymphocyte count be performed and fortnightly thereafter. Should the CD4+ counts
fall below 250 cells/mL, then dosing should be withheld
until CD4+ counts recover. If the CD4+ counts continuously
remain below 250 cells/mL for four consecutive weeks,
then the drug should be ceased.
In a randomized, double-blind, placebo-controlled phase
III study, the clinical efficacy of alefacept given intramuscularly was demonstrated.7 A total of 507 patients were
randomized to receive i.m. placebo ( n = 168), 10 mg of alefacept (n = 173) or 15 mg of alefacept (n = 166) weekly for
12 weeks followed by 12 weeks of observation. Throughout
Biologic agents in psoriasis
the study, a significantly (P < 0.001) higher percentage of
patients in the 15 mg group (33%) or 10 mg group (28%)
than in the placebo group (13%) achieved at least 75% PASI
reduction from baseline. The percentage of patients achieving at least 50% reduction in PASI throughout the study
period was 57% in the 15 mg alefacept group compared
with 35% in the placebo group ( P < 0.001). The same endpoint was achieved by 53% of patients in the 10 mg alefacept group (P = 0.002 vs placebo).
The results of the clinical trials have shown that alefacept
significantly improves the symptoms of psoriasis. In the
phase III trials, the DLQI was compared to the PGA status
and PASI scores.8 Those who achieved a PGA status of ‘clear
or almost clear’ and at least a 75% reduction in the PASI
score from baseline achieved a >70% improvement in DLQI
scores. Those with at least a 50% reduction in the PASI
score from baseline also demonstrated a marked improvement (60%) in their DLQI score.
While the onset of action is slow, a major benefit of alefacept is that it has the potential for long-term remission.
The clinical response to alefacept has shown to be durable
during follow up. It has been demonstrated that of those
who receive 12 weeks of 15 mg intramuscular alefacept,
74% are able to maintain at least a 50% reduction in PASI
during the 12-week follow-up period. Of those who receive
15 mg intramuscular alefacept and achieve a 50–75% PASI
reduction from baseline 2 weeks after the last dose, 79%
maintain at least a 25% reduction in PASI during the 12week follow-up period.7
Adverse events reported from clinical trials include headache, pruritus, infection, rhinitis, injection site pain and
injection site inflammation.7,9,10 The trials have shown that
alefacept does cause transient decreases in CD45RO + memory T cells.7,9,10 Alefacept does not interfere with the primary
219
and secondary responses to a newly encountered antigen
and the acquired immune response to a recall antigen. 11
Whether problems occur with continuous courses longer
than 12 weeks remains to be seen. These results are
encouraging because one of the concerns of other immunosuppressive therapies is that they are non-specific in terms
of targeting particular T-cell subsets. Biogen Idec has
reported that two of the 1357 patients treated with alefacept
developed lymphoma (Hodgkin and folliculo-centric lymphoma) while on or after ceasing alefacept. 8 These patients
had been treated with various systemic agents before starting alefacept. The clinical data demonstrate that alefacept
exhibits a low potential for immunogenecity and there were
no reports of hypersensitivity in those few patients that did
develop antialefacept antibodies. 7,9
Strategy 2: Inhibition of T-cell activation
and migration
Efalizumab (Raptiva; Genentech and XOMA, South San
Francisco, CA, USA) is a humanized form of a murine antibody targeted against CD11a, a subunit of LFA-1. Lymphocyte function associated antigen-1, composed of the
subunits CD11a and CD18, is responsible for T-cell activation, cytotoxic T-cell function, and T-cell adhesion to keratinocytes and vascular endothelium. 12,13 Efalizumab can
therefore interfere with development of psoriatic plaques
by blocking T-cell migration into the skin and by inhibiting
T-cell activation (Fig. 2).
Efalizumab is currently approved by the TGA in Australia
for the treatment of adult patients with moderate to severe
chronic plaque psoriasis who are candidates for systemic
agents or phototherapy. Efalizumab is administered subcutaneously. The recommended dose is 0.7 mg/kg for the ini-
Figure 2 Efalizumab inhibits T-cell
activation, cytotoxic T-cell function,
and T-cell adhesion to keratinocytes
and vascular endothelium by targeting
against CD11a, the subunit of lymphocyte function associated antigen-1. This
illustration has been provided by
Serono. CD, cluster of differentiation;
ICAM, intercellular adhesion molecule;
LFA, lymphocyte function associated
antigen.
© 2006 The Australasian College of Dermatologists
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MR Lee and AJ Cooper
tial dose followed by 1 mg/kg weekly thereafter. Treatment
is of a continuous nature.
In a phase III, randomized, double-blind, parallel group,
placebo-controlled, multicentre, 12-week study,14 weekly
subcutaneous efalizumab (1 mg/kg) improved psoriasis.
Efalizumab therapy resulted in significant improvements in
PASI scores, PGA, overall DLQI, Itching Visual Analog Scale
(ranges from 0 [no impairment] to 10 [severe itching]) and
PSA score. By week 12, 27% of efalizumab-treated patients
achieved a PASI-75 response compared with 4% of placebotreated patients (P < 0.001). Patients in the efalizumab
group showed improvement in the mean DLQI scores by
the second week compared with the placebo group
(P < 0.001). Efalizumab-treated patients reported greater
improvements in their attitudes about their disease, their
ability to participate in daily activities (including leisure
and work) and their personal relationships. There was a
trend towards improvement across all symptoms in both
frequency and severity in the efalizumab group as shown
by mean improvements in the PSA score. With respect to
severity, or how bothersome the symptoms were, the largest absolute improvements occurred in both the itching
(mean improvement of 1.1 for efalizumab vs 0.3 for placebo
[P < 0.001]) and scaling (1.2 for efalizumab vs 0.4 for placebo [P < 0.001]) components.
In a phase III, multicentre, randomized, placebo-controlled, double-blind study, extending efalizumab treatment
from 12 to 24 weeks demonstrated ongoing benefit.15 The
study involved three consecutive phases: the first treatment
phase (weeks 0–12), the extended treatment phase (weeks
13–24) and the follow-up phase (weeks 25–36). In the first
phase, patients were randomized to 1 mg/kg subcutaneous
efalizumab per week, 2 mg/kg subcutaneous efalizumab
per week, or placebo. In the second phase, subjects who
had received efalizumab were stratified into three subgroups based on their week 12 PASI score improvement
from baseline (≥75%, 50–74%, or <50%). Subjects in the
first two strata were randomized to 2 mg/kg of efalizumab
either weekly or every other week or to placebo. Subjects
in the third stratum (<50% improvement) were randomized
to either an increased dose of efalizumab 4 mg/kg per week
or placebo. Those randomized to placebo in the first phase
were discontinued after week 12. At week 12, there was at
least a 75% improvement in the PASI score from baseline
of 22% in those who had received 1 mg/kg of efalizumab
per week, 28% in those who had received 2 mg/kg of efalizumab per week as compared with 5% of those who
received placebo (P < 0.001 for both comparisons). Efalizumab-treated patients had greater improvement than
those receiving placebo as early as week 4 ( P < 0.001). Continued efalizumab therapy provided continued benefit.
Among the efalizumab group who had an improvement of
at least 75% in their PASI scores from baseline at week 12,
improvement was maintained through week 24. At week 36,
12 weeks after the discontinuation of efalizumab, at least
50% improvement in the PASI scores from baseline
achieved during treatment was maintained in 30% of the
subjects who had received continuous efalizumab for
24 weeks. The time to relapse (loss of at least 50% of the
© 2006 The Australasian College of Dermatologists
improvement in PASI score that had been achieved between
baseline and week 24) among subjects who had an
improvement of at least 50% at week 24 was approximately
84 days.
Long-term administration of efalizumab is currently
being evaluated in an ongoing open-label, phase III study.16
In the initial 12-week treatment period, patients received
weekly subcutaneous efalizumab 2 mg/kg. Patients who
achieved at least a 50% improvement in their PASI score
from baseline or an overall PGA grading of mild, minimal
or clear were eligible to enter the open-label maintenance
period, comprising an additional 33 months of treatment.
During maintenance treatment, the subjects received
weekly doses of subcutaneous efalizumab 1 mg/kg and in
the event of relapse (loss of at least 50% improvement in
their PASI score from baseline at month 3), the dose was
increased to 2, 3 or 4 mg/kg weekly. At 12 weeks, 41% and
82% of patients achieved at least a 75% or 50% improvement in their PASI score from baseline, respectively. At
15 months, 50% and 65% of patients achieved at least a
75% or 50% improvement in their PASI score from baseline,
respectively.
The most frequent adverse events reported in the clinical
trials were fever, nausea, vomiting, headaches, chills,
asthenia, myalgia and pharyngitis. 14–19 These occurred on
the day or within 2 days after the administration of the drug
and were most frequent after the first dose and decreased
in frequency over time and by the third dose, the percentage of these adverse events were similar to placebo. Transient increases in circulating T-lymphocytes were noted in
the efalizumab-treated group during studies and returned
to reference range upon completion of treatment. 15,16,18,19
Treatment with efalizumab has been associated with
thrombocytopaenia. Therefore, platelet counts are recommended every month for the first 3 months and every
3 months thereafter. One major concern with the use of
efalizumab is the rebound of psoriasis. Formulating a plan
of transition to address the issue of rebound before discontinuing efalizumab is necessary. A post-hoc analysis of the
effectiveness of treatments in preventing rebound during
the observation period from 1014 participants in the phase
II and III trials showed that cyclosporin was completely
successful in preventing rebound. High-potency topical corticosteroids were shown to be successful with only 7%
(8/111) of patients achieving rebound status. The least
helpful strategies included psoralen and UVA and systemic
retinoids with rebound rates of 25% (2/8) and 21% (5/24),
respectively.20
Strategy 3: Modulation of the immune system
Two distinct lines of T-cell differentiation are possible.
Under the influence of IL-12 and IFN-γ, CD4 T cells differentiate into a Th1 phenotype and CD8 T cells differentiate
into a Tc1 phenotype. Both of these phenotypes produce
type-1 cytokines which include IL-1α, IL-1β, IL-2, IL-6,
IL-8, IFN-γ, TNF-α and TNF-β, TGF-α and TGF-β, and granulocyte colony stimulating factor.21–25 Psoriasis is characterized by an over-expression of the pro-inflammatory type-1
Biologic agents in psoriasis
221
Figure 3 Recombinant human IL-10,
a Th-2 cytokine, down-regulates the
Th-1 cytokine response. This illustration has been provided by Biogen Idec.
IL, interleukin; Th, T-helper.
cytokines. Alternatively, under the influence of IL-4, IL-6
and IL-10, CD4 T cells differentiate into a Th2 phenotype
and CD8 T cells differentiate into a Tc2 phenotype. Both of
these phenotypes produce type-2 cytokines which include
IL-4, IL-6, IL-10 and IL-11.26,27 An alternative strategy to
blocking the immunological process is to deviate the
immune response to a type-2 cytokine pattern.
Ilodecakin (Tenovil, Schering-Plough, Berlin, Germany), a human recombinant IL-10, is an important Th2cytokine that is responsible for the down-regulation of the
Th1-cytokine response (IL-2, IL-12, TNF and IFN- γ;
Fig. 3).21–23 There is a relative deficiency of IL-10 in psoriasis.27 In a double-blind, placebo-controlled study,28 seven
patients received human recombinant IL-10 subcutaneously (10 µg/kg) three times per week until relapse or
study termination after 4 months. Remission (defined as
PASI < 5) was achieved by UV light (type not specified) in
combination with topical calipotriol and/or topical dithranol before entry into the study. Nine of 10 in the placebo
group and only two of seven in the human recombinant IL10-treated group showed a relapse during the observation
period (P < 0.05). Moreover, the mean duration of remission in the human recombinant IL-10 group was higher
than in the placebo group (101 days vs 66.4 days). Several
other studies report improvements in skin lesions. 27,29–31
However, in a randomized, double-blind, placebocontrolled trial32 involving 28 patients, 18 patients treated
with subcutaneous human recombinant IL-10 (20 µg/kg)
three times weekly for 12 weeks resulted in only temporary clinical improvement. The mean percentage improvement in PASI scores from baseline at week 8 for the human
recombinant IL-10-treated group was significantly higher
than that for the placebo group (36% vs 13.3%, P = 0.03).
However, most patients receiving human recombinant IL-
10 experienced a rebound following week 8 as reflected in
the mean percentage improvement in PASI scores from
baseline at week 12 despite sustained decreases in proinflammatory type-1 cytokine production (17% for the
human recombinant IL-10 treated group vs 12.9% for the
placebo group, P = 0.69). Treatment with human recombinant IL-10 has been shown to lead to anaemia, thrombocytopaenia and a reduction in serum cholesterol. Studies for
ilodecakin are ongoing.
Oprelvekin (Neumega; Genetics Institute, Cambridge,
MA, USA) is a human recombinant IL-11 and has demonstrated improvement in psoriasis in seven of 12 patients
when administered daily subcutaneous injections for
8 weeks in an open-label, phase I dose escalation study.33
Intraepidermal T cells and total lesional T cells are reduced
and synthesis of intercellular adhesion molecule-1 by epidermal keratinocytes is eliminated by human recombinant
IL-11. In addition, IL-11 decreases the expression of the
products of disease-related genes, including keratin 16,
inducible nitric oxide synthase, IFN- γ, IL-8, IL-12, TNF-α,
IL-1β and CD8 and with increased expression of endogenous IL-11. Studies for oprelvekin are ongoing.
Strategy 4: Blockage of the activity
of inflammatory cytokines
Tumour necrosis factor-α plays a critical role in the pathogenesis of psoriasis. Increased production of TNF-α is seen
in psoriasis and psoriatic arthritis that leads to chronic
inflammation, tissue damage and hyperproliferation of
keratinocytes. Tumour necrosis factor-α is a pleiotropic,
pro-inflammatory cytokine which is detected in eccrine
sweat gland epithelium of normal skin and the epidermis
and dermis of psoriatic skin lesions. It is released from T
© 2006 The Australasian College of Dermatologists
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MR Lee and AJ Cooper
cells, keratinocytes, dermal dendrocytes, macrophages and
mast cells.34
The anti-TNF-α agent etanercept (Enbrel; Immunex
Corporation, Seattle, WA, USA) is a recombinant human
TNF-α receptor(p75) fused with the Fc portion of IgG1 that
binds to the soluble and membrane-bound TNF-α (Fig. 4).
Etanercept has demonstrated efficacy in the treatment of
inflammatory diseases such as rheumatoid arthritis, 35 juvenile rheumatoid arthritis, psoriatic arthritis 36,37 and psoriasis.38–43 Etanercept is currently TGA-approved for moderate
to severe chronic plaque psoriasis, rheumatoid arthritis,
psoriatic arthritis and juvenile chronic arthritis in Australia.
Etanercept is administered subcutaneously. The recommended regimen is 50 mg twice weekly for the first
12 weeks and then 50 mg weekly thereafter. Dosing is
continuous.
In a 24-week, placebo-controlled, double-blind, parallelgroup, phase III study,39 patients with plaque psoriasis were
randomized to receive placebo (n = 166) or etanercept subcutaneously at a low dose (25 mg once weekly, n = 160), a
medium dose (25 mg twice weekly, n = 162), or a high dose
(50 mg twice weekly, n = 164). After 12 weeks, patients in
the placebo group began twice weekly treatment with
25 mg of etanercept. The primary measure of efficacy was
the proportion of patients who achieved at least 75%
improvement from baseline in the PASI score at week 12.
There was such an improvement in 4% in the placebo
group, 14% in the low-dose etanercept group, 34% in the
medium-dose etanercept group and 49% in the high-dose
etanercept group (P < 0.001 for all three comparisons to
placebo). The mean percentage improvements in the PASI
score from baseline were significant for all three etancerept
groups as early as week 2 of the study. The clinical response
of etanercept continued to improve with longer treatment.
At week 24, there was at least a 75% improvement in the
PASI score from baseline in 25% of patients in the low-dose
group, 44% in the medium-dose group and 59% in the highdose group. At week 12, the percentage of patients who
were ‘clear’ or ‘almost clear’ in the PGA were 23% in the
low-dose group, 34% in the medium-dose group and 49%
in the high dose group as compared with 5% in the placebo
group (P < 0.001 for all three comparisons to placebo).
These differences were significant as early as week 4 and
continued to improve with longer treatment. The mean
percentage improvement from baseline in the DLQI was
significant in all etanercept groups by week 2. By week 12,
the mean improvement was 47.2% in the low-dose group,
50.8% in the medium-dose group and 61% in the high-dose
group as compared with 10.9% in the placebo group
(P < 0.001 for all three comparisons to placebo). The study
demonstrated that etanercept produced significant dosedependent improvements in the PASI score from baseline
which were evident as early as week 2.
Of the 573 patients who completed 24 weeks of the initial
blinded treatment, 157 (27.4%) failed to achieve at least a
50% improvement in their PASI scores from baseline. They
entered a 12-week open-label extension and 42.1% (61 of
the 145 incomplete responders, 12 dropouts) achieved at
least a 50% improvement in their PASI scores from baseline
and 11.7% (17 of the 145 incomplete responders) achieved
at least a 75% improvement in their PASI score from baseline.40 This suggests that psoriasis patients who fail to
achieve at least 50% improvement in PASI from baseline
may continue to improve with further etanercept treatment
and they may achieve a clinically meaningful response.
Patients (at the end of week 24) who achieved at least
50% improvement in their PASI score from baseline discontinued etanercept and entered a drug withdrawal study
period until their disease relapsed. 43 The durability of treatment was defined as the time period from the discontinua-
Figure 4 Activity of TNF-α is blocked
by recombinant human TNF-α receptor
fusion
protein
(etanercept)
and
chimeric antibody (infliximab). This
illustration has been provided by Biogen Idec. TNF, tumour necrosis factor.
© 2006 The Australasian College of Dermatologists
Biologic agents in psoriasis
tion of etanercept (week 24) until the first visit at which at
least 50% of PASI improvement that occurred between
baseline and week 24 was lost. Seventy-one per cent (409
of the 573 patients who completed 24 weeks) entered the
study withdrawal phase. The median time to disease
relapse was 85 days, with 25% not relapsing until at least
141 days. The study showed that withdrawal from etanercept following a clinical response results in the return of
signs and symptoms in a gradual manner with treatment
response maintained for approximately 3 months.
Mild to moderate injection site reactions characterized by
pain, swelling and erythema are the most frequent adverse
effects associated with etanercept. 39 Post-marketing studies
have identified serious infections, sepsis and fatalities.
Many of these infections occurred in those who were
predisposed to infections because of an underlying
immunosuppressive state brought on by previous
immunosuppressive therapies. Rare cases of tuberculosis
have been reported. Therefore, etanercept should not be
administered to those with sepsis or active infections,
including chronic and localized infections, 44 and tuberculosis screening is mandatory before initiating etanercept.
Eighteen cases of non-Hodgkin lymphoma occurring after
the initiation of etanercept have been reported to the FDA
between 1999 and 2000.45 However, patients with psoriasis
and rheumatoid arthritis have an increased risk of lymphoma (Hodgkin and non-Hodgkin type) compared with
the general population.46,47
In post-marketing surveillance, rare cases of aplastic
anaemia and central nervous system demyelinating disorders, transverse myelitis, optic neuritis and multiple sclerosis and new onset or exacerbation of seizure disorders
have been reported. In those cases, a causal relationship to
etanercept is not established. There may also be an
increased risk of skin malignancies. A greater percentage
(11%) of patients treated with etanercept developed a new
positive ANA titre of 1:40 or greater compared with 5% of
patients receiving placebo. Additionally, a greater percentage (15%) of patients treated with etanercept developed
anti-dsDNA antibodies compared with 4% of patients
receiving placebo.48 Drug-induced systemic lupus erythematosus and subacute cutaneous lupus erythematosus have
been reported.49,50 Before therapy, patients should have
baseline HIV (in high-risk groups) and hepatitis serology,
tuberculin skin testing, full blood count, liver function and
biochemical investigations.48
In a case series of six patients, etanercept in combination
with other systemic medications and topical medications
demonstrated additional benefit to patients with severe
recalcitrant psoriasis.51 All the six patients were treated
with a variety of systemic agents and topical therapies: two
received oral methotrexate 20 mg and 15 mg weekly, one
received oral acitretin 25 mg on alternate days and oral
hydroxyurea 1.5 g daily, one received oral acitretin 25 mg
on alternate days and UVB (type not specified) weekly, one
received oral cyclosporin 200 mg daily, and one received
topical calcipotriene ointment. The PASI scores before etanercept treatment were 29, 24, 28, 14, 27 and 22, respectively.
In each case, the disease activity showed marked improve-
223
ment after the addition of etanercept therapy. The PASI
scores after etanercept therapy were 10, 12, 10, 7, 14, and
10, respectively. No added toxicity was found. Psoriasis and
psoriatic arthritis were successfully treated with etanercept
and methotrexate in a patient unresponsive to infliximab.52
Methotrexate, 15 mg orally every week was combined with
etanercept 25 mg administered subcutaneously twice every
week. After 12 weeks, the patient’s psoriasis and psoriatic
arthritis were completely resolved.
Infliximab (Remicade; Centocor Inc., Malvern, PA, USA)
is a mouse/human chimeric antibody to TNF-α comprising
a mouse variable region and a human IgG1-α constant
region.53 Infliximab is able to bind to the soluble and transmembrane TNF-α molecules, thereby neutralizing the
effects of TNF-α (Fig. 4). Infliximab is currently licensed in
Australia and the USA for the treatment of fistulizing
Crohn’s disease, rheumatoid arthritis and ankylosing
spondylitis. Infliximab is also being investigated for the
treatment of hidradenitis suppurativa 54 and Sjögren’s
disease.55
Infliximab is administered intravenously at a dose of
5 mg/kg over 2 hours at weeks 0, 2 and 6. Subsequent infusions may be given every 8 weeks at a dose of 5 mg/kg.
Recent case reports have demonstrated the effectiveness of
infliximab with marked improvement in psoriasis as demonstrated by the PASI score.56–62
In a randomized controlled trial, the response to infliximab was similar to cyclosporin in terms of the high proportion of patients achieving clearance and the rapidity of
clearance.63 Thirty-three patients with moderate to severe
psoriasis were randomized to intravenous placebo (n = 11),
infliximab 5 mg/kg (n = 11) or infliximab 10 mg/kg (n = 11)
at weeks 0, 2 and 6. The PGA at week 10 was the defined
primary efficacy end-point. Nine of 11 (82%) patients in the
infliximab 5 mg/kg group and 10 of 11 (91%) patients in the
infliximab 10 mg/kg group achieved the primary end-point
of a good, excellent, or clear rating on the PGA, compared
with only two of 11 (18%) patients in the placebo group.
The change in PASI was a secondary end-point. Nine of 11
(82%) patients in the infliximab 5 mg/kg group and eight
of 11 (73%) patients in the infliximab 10 mg/kg group had
at least 75% improvement in the PASI score from baseline,
compared with two of 11 (18%) patients in the placebo
group. The mean percentage PASI score improvements
from baseline were significantly higher among those who
received infliximab as early as week 2. The median time to
response was 4 weeks. This demonstrates that one of the
advantages of infliximab is that it is able to provide a rapid
response.
Infliximab provides a sustainable effect through week 26
as demonstrated in an open-label extension study from
that above.64 Non-responders in the placebo group were
assigned (1:1) to receive open-label 5 or 10 mg/kg of infliximab at weeks 10, 12 and 16. Responders in the placebo
group were followed up for relapse (loss of 50% or more of
improvement attained in the PASI at week 10) and then
offered infliximab in the same manner as the nonresponders in the placebo group. Non-responders in the
5 mg/kg group were offered a single infusion of 10 mg/kg
© 2006 The Australasian College of Dermatologists
224
MR Lee and AJ Cooper
of infliximab and followed up for response, whereas nonresponders in the 10 mg/kg were discontinued from the
study. Those who responded to treatment with 5 or 10 mg/kg
in the first part of the study were followed up for relapse
and offered single-dose infusions of infliximab on relapse
(loss of at least half of the improvement in PASI scores
achieved at week 10). Among all patients treated with
infliximab, 57% (17 of 30) maintained at least 50%
improvement in their PASI score from baseline and 50%
(15 of 30) maintained at least 75% PASI improvement at
week 26. For those who received 5 mg/kg of infliximab,
40% maintained at least a 50% improvement and 33%
maintained at least a 75% improvement from baseline
through week 26. For those who received 10 mg/kg of
infliximab, 73% maintained at least a 50% improvement
and 67% maintained at least a 75% improvement from
baseline through week 26. The study demonstrated that
infliximab produces a rapid, effective and sustainable
(through week 26) effect and may be used as an infrequent
dosing regimen.
Alternatively, a maintenance dose of every 8 weeks
rather than infrequent dosing may be considered after the
initial week 0, 2 and 6 induction regimen. This was shown
in a double-blind, placebo-controlled trial comprising a 3dose induction regimen followed by a further single infusion at week 26.65 Eligible patients were randomized in a
1:2:2 ratio to intravenous infusions of placebo (n = 51),
infliximab (3 mg/kg, n = 99) or infliximab (5 mg/kg, n = 99)
and were treated at weeks 0, 2 and 6. At week 26, patients
with a PGA of moderate to severe disease activity were
eligible for a single additional intravenous infusion. At
week 10, 72% (71/99) of patients treated with infliximab
(3 mg/kg) and 88% (87/99) of patients treated with infliximab (5 mg/kg) achieved a PASI-75 compared with 6%
(3/51) of patients treated with placebo (P < 0.001). At week
10, 84% (83/99) of patients treated with infliximab (3 mg/kg)
and 97% (96/99) of patients treated with infliximab
(5 mg/kg) achieved a PASI-50 compared with 22% (11/51)
of patients treated with placebo (P < 0.001). The response
was evident after the first infusion and at week 2, 34% and
40% of patients in the 3 mg/kg and 5 mg/kg infliximab
treatment groups, respectively, already achieved PASI-50
compared with 4% of patients in the placebo group
(P < 0.001). By week 4, 35% and 47% of patients in the
3 mg/kg and 5 mg/kg infliximab treatment groups, respectively, achieved PASI-75 compared with no patients in the
placebo group (P < 0.001). Patients in the 3 mg/kg and
5 mg/kg groups began to lose response after week 10 and
week 14, respectively. This suggests that a regimen of
maintenance dosing every 8 weeks should be considered
for patients. Four weeks after re-treatment at week 26,
38%, 64% and 18% of patients who were re-treated in the
3 mg/kg, 5 mg/kg and placebo groups, respectively,
achieved a PGA of mild, minimal or clear.
The efficacy of infliximab has also been demonstrated in
improvements in the DLQI. Patients who receive a dose of
5 mg/kg at weeks 0, 2 and 6 can expect an improvement in
the DLQI of 61% as early as week 2. 56 By week 10, patients
can expect a an improvement in the DLQI of 91%. 66
© 2006 The Australasian College of Dermatologists
The most commonly reported adverse events from trials
include infusion-related reactions (dyspnoea, urticaria,
hypotension, flushing and headache). Antibodies produced
by the patient to infliximab may potentially neutralize the
drug and block its effect, leading to dose escalation. Methotrexate may be co-administered with infliximab to prevent
the development of neutralizing antibodies. 67 Erythema
multiforme and a lichenoid eruption have been reported. 68
Pulmonary tuberculosis may be reactivated by treatment
with infliximab, hence patients should be screened for
tuberculosis before infliximab treatment.69,70 Infliximab is
contraindicated in patients with moderate to severe congestive heart failure (New York Heart Association class III/IV)
because of infusion-related reactions of hypotension and
dyspnoea.71 Eight cases of non-Hodgkin lymphoma occurring after the initiation of infliximab have been reported to
the FDA between 1999 and 2000. 45
Three patients have been reported using infliximab in
combination with other immunosuppressants. 72 The first
two patients received cyclosporin (100–150 mg daily) and
infliximab at weeks 0, 2 and 6, and the third patient
received intramuscular methotrexate 25 mg weekly and
narrowband UVB once weekly and infliximab at weeks 0, 2
and 6. The first patient’s skin had a significant but not
complete improvement at week 8. The second patient’s skin
was completely clear at week 4; however, she suffered a
relapse on her hands and feet at week 15. The third
patient’s skin was completely clear by week 7 and she
enjoyed prolonged remission of 30 weeks post initial infusion. In another case report, the beneficial effects of the
combination of infliximab with oral methotrexate in
the treatment of severe psoriasis was demonstrated. 73 The
patient’s baseline PASI score was 27.2 and he received a
single does of infliximab intravenously while he continued
methotrexate 20 mg weekly and emollients. Improvement
in his skin was noted within 3 days of the infusion when his
PASI score had reduced to 15.2, and 3 weeks post infusion
his PASI score was 4.1. Eight weeks post infusion his psoriasis was still clear.
Adalimumab (Humira; Abbott Laboratories, Abbott Park,
IL, USA) is the first fully human anti-TNF-α monoclonal
antibody. It binds specifically to soluble and membranebound TNF-α and blocks its interaction with the p55 and
p75 cell surface TNF receptors. It is currently approved in
the USA for rheumatoid arthritis.
A case report of two patients with long-standing psoriasis
both responded to adalimumab after multiple treatment
failures with conventional and experimental antipsoriatic
medications.74 The first patient received fortnightly subcutaneous injections of adalimumab 40 mg. The PASI score
after the first 8 weeks (three injections) was 46.5 and
improved to 12 after six injections (12 weeks following
commencement of therapy). At 20 weeks after commencement of therapy, her PASI score was 5.7 and after 40 weeks
her disease remains quiescent with a PASI score of 2.2. The
second patient also received fortnightly subcutaneous
injections of adalimumab 40 mg, at which time his psoriasis
involved approximately 50% of his body surface area with
a PASI score of greater than 18. His PASI score was 5 at
Biologic agents in psoriasis
16 weeks after the initial dose and after 6 months of therapy, his PASI score was less than 5. This improvement continues to be maintained at 18 months post treatment. Both
patients tolerated adalimumab with no adverse events
reported.
From the clinical trials for rheumatoid arthritis, the most
common adverse events reported were headache, injection
site pain and nausea.75 Adalimumab is currently undergoing clinical trials for psoriasis and psoriatic arthirits.
OTHER BIOLOGIC AGENTS IN
EXPERIMENTAL PHASE
Table 2 outlines those biologics that are on or close to
market and are approved by the FDA or TGA for psoriasis
and other indications. Recently, alefacept, efalizumab and
etanercept have been approved by the TGA in Australia
for the treatment of moderate to severe psoriasis in adults.
Efalizumab and etanercept are now listed as part of the
Pharmaceutical Benefits Scheme in Australia, but only for
PASI > 15. Other biologics for psoriasis that are still in the
early phase of clinical trial development are listed in
Table 3. Readers are referred to the provided references
for further discussion.
225
CONCLUSION
Systemic therapies for the treatment of psoriasis up until
now have been limited by their safety profile. New advances
in genetic engineering have led to the exciting development
of biologic therapies which have demonstrated a safer
approach to the treatment of psoriasis and hold significant
promise for those who are severely debilitated by this
disease.
There is obvious potential for the use of biologic agents
in combination with existing therapies. Such an approach
may be synergistic and may offer the advantage of minimizing the side-effects of other systemic therapies in the treatment of patients with psoriasis. Combinations of biologic
agents with one another, with other systemic immunosuppressive therapies, with topical treatments, or with phototherapy open the door to a world where control of psoriasis,
more prolonged remission and improved psychosocial
well-being may be achieved.
ACKNOWLEDGEMENT
The authors would like to acknowledge Biogen Idec
(Figs 1,3 and 4) and Serono (Fig. 2) for providing the
illustrations.
Table 2 Biologic agents on or close to market for the treatment of psoriasis in the USA and Australia
Biologic
Trade name
FDA-approved indication
TGA-approved indication
Alefacept
Efalizumab
Etanercept
Amevive
Raptiva
Enbrel
Infliximab
Remicade
Adalimumab
Humira
Chronic plaque psoriasis: moderate to severe
Chronic plaque psoriasis: moderate to severe
Rheumatoid arthritis
Psoriatic arthritis
Ankylosing spondylitis
Chronic plaque psoriasis: moderate to severe
Crohn’s disease
Rheumatoid arthritis
Ankylosing spondylitis
Rheumatoid arthritis
Chronic plaque psoriasis: moderate to severe
Chronic plaque psoriasis: moderate to severe
Rheumatoid arthritis
Psoriatic arthritis
Juvenile chronic arthritis
Chronic plaque psoriasis: moderate to severe
Crohn’s disease
Rheumatoid arthritis
Ankylosing spondylitis
–
FDA, Food and Drug Administration; TGA, Therapeutic Goods Administration.
Table 3 Other biologic agents for psoriasis in experimental phase
Biologic
Action
Reference
Status
Denileukin diftitox, DAB389IL-2
(Ontak; Ligand Pharmaceuticals,
San Diego, CA, USA)
A fusion protein consisting of IL-2 and a
portion of the diphtheria toxin molecule. Denileukin
diftitox is specifically toxic to T-lymphocytes
bearing high affinity IL-2 receptors.
A fully human monoclonal anti-CD4 antibody. Induces a
dose-dependent reduction in the CD4 cell count, with
reduction primarily in the memory T-cell subset with only
a minor decrease in the native T-cell subset.
76
Approved for
cutaneous
T-cell lymphoma
77
Ongoing phase II
study
HuMax-CD4
(Genmab A/S, Copenhagen,
Denmark)
CD, cluster of differentiation; IFN, interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; K16, keratin 16; Th, T-helper; TNF,
tumour necrosis factor.
© 2006 The Australasian College of Dermatologists
226
MR Lee and AJ Cooper
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? 2006474••••Continuing Professional Development ReviewBiologic agents in psoriasis
Biologic agents in psoriasis
229
PROFESSIONAL DEVELOPMENT PROGRAM
Select the most correct answers – multiple answers possible for questions 1–11
1. Biologic response modifiers:
a. Include immunoreactive compounds
b. Include hormones
c. Include neuroactive compounds
d. May be derived from human and animal sources
e. May be derived from plant material
2. Concerning the generic names for biologic agents:
a. Receptor–antibody fusion proteins have the suffix – cept
b. Humanized monoclonal antibodies have the prefix – ximab
c. Human monoclonal antibodies have the suffix – zumab
d. Chimeric monoclonal antibodies have the suffix – umab
e. Chimeric monoclonal antibodies have the suffix – ximab
3. Regarding fusion proteins:
a. Fusion proteins consist of a human receptor domain that
allows solubility in plasma
b. The constant portion of immunoglobulin G allows solubility
in plasma
c. Alefacept is a fusion protein combining two binding sites of
human TNF-α with the hinge, CH2 and CH3 sequences of
IgG1
d. Currently marketed fusion proteins are available for oral
administration
e. The use of fusion proteins is well studied in pregnant women
4. Strategies for immunomodulation therapy for psoriasis include:
a. Stimulation of T helper cell activation
b. Reduction of the number of pathogenic T cells
c. Inhibition of T-cell migration
d. Stimulate activity of inflammatory cytokines
e. Inhibition of interleukin 13 release from B cells
5. Concerning alefacept:
a. Onset of clinical effect in psoriasis is slow
b. Trials have shown transient decreases in CD45RO+ memory T
cells
c. Monitoring CD8+ T lymphocyte at baseline and fortnightly
thereafter is recommended
d. Therapy should be ceased if the CD8+ T lymphocyte count
remains below 250 cells/µl for four consecutive weeks
e. May have the potential to induce long-term remission
6. Efalizumab can interfere with the development of psoriatic plaques
by:
a. Binding to soluble and membrane bound TNF-α
b. Blocking T-cell migration into the skin
c. Inhibiting T-cell activation
d. Modulating the immune system to a type-2 cytokine pattern
e. Stimulating interleukin 13 release from B cells
7. Concerning efalizumab:
a. Is a humanized form of a porcine antibody targeted against
CD11a
b. Can be administered orally
c. Fever, nausea, vomiting, headaches, chills, asthenia myalgia
and pharyngitis are included in the most frequent adverse
events reported in clinical trials
d. The adverse events are most frequently reported after the
third dose
e. Symptomatic improvement in itch is not shown in phase III
studies
8. Etanercept:
a. Is a human receptor-antibody fusion protein
b. Is released from T cells, dermal dendrocytes and
macrophages
c. Is a recombinant murine TNF-α receptor fused with the Fc
portion of IgG1
d. Binds to soluble and membrane bound TNF-α
e. Causes increased serum levels of free TNF-α by blocking the
receptor
9. Etanercept post-marketing studies have reported:
a. Tuberculosis
b. Central nervous system demyelination disorders including
transverse myelitis, optic neuritis and multiple sclerosis
c. Frequent cases of aplastic anaemia
d. Anti-dsDNA antibodies more frequently than in the placebo
patients but no cases of drug-induced systemic lupus
erythematosus
e. New onset or exacerbation of seizure disorders
10. Infliximab:
a. Is the only biologic agent studied widely in lactating women
b. Is approved by the FDA and TGA for use in palmoplantar
pustular psoriasis
c. Binds to soluble and transmembrane TNF-α molecules
d. Has a rapid, effective and sustainable effect on PASI scores
e. May induce antibodies that neutralize the agent and block its
effect
11. Recommended dosing regimens for treatment of chronic plaque
psoriasis include:
a. Alefacept is continuous dosing as weekly subcutaneous
injections
b. Efalizumab is administered as a weekly intravenous infusion
c. Adalimumab is given as an ongoing weekly intramuscular
injection
d. Infliximab is used as an intravenous infusion at weeks 0, 2
and 6 then every 8 weeks
e. Etanercept is administered as a subcutaneous injection once
or twice each week
Directions for questions 12–23: For each numbered item, choose the
appropriate lettered item. There is only one correct answer, but the same
letter can be chosen more than once in any one question.
With respect to questions 12–15:
a. Etanercept
b. Infliximab
c. Efalizumab
d. Adalimumab
12. Is a mouse/human chimeric antibody to TNF-α
13. Is a fully human anti TNF-α monoclonal antibody
14. Is a recombinant human TNF-α receptor fused with the Fc portion
of IgG1
15. Is a humanized antibody directed against CD11a
With respect to questions 16–19:
a. Efalizumab
b. Adalimumab
c. Infliximab
d. Etanercept
16. Crohn’s disease is a TGA approved indication
17. Ankylosing spondylitis is a TGA approved indication
18. Psoriatic arthritis is a TGA approved indication
19. Rheumatoid arthritis is the only FDA approved indication currently
With respect to questions 20–23:
a. Efalizumab
b. Infliximab
c. Alefacept
d. Etanercept
20. Treatment has been associated with thrombocytopaenia
21. Subcutaneous injections have been associated with serious infection, including tuberculosis, sepsis and fatalities
22. Treatment is contraindicated in patients with moderate to severe
congestive heart failure due to infusion related reactions of
hypotension and dyspnoea
23. Weekly intramuscular injections for 12 weeks has the potential for
long-term remission
Answers to PDP questions
1. a,d
6. a,c,d,
2. a,d,e
7. a,b,d
3. b,c,d,e
8. a,b,e
4. a,b,c,e
9. b,d,e
5. b,c,e
10. b,d
from Vol. 47, No. 3:
11. a,b,e
16. b
12. d
17. c
13. c
18. a
14. a
19. d
15. b
20. b
21. c
22. a
23. d
© 2006 The Australasian College of Dermatologists
Blackwell Publishing LtdMelbourne, AustraliaAJDAustralasian Journal of Dermatology0004-83802005 Blackwell Publishing LtdApril 2005462MR Lee and AJ Cooper
Standard basal cell carcinoma surgery
230
MR Lee and AJ Cooper
The Australasian College of Dermatologists
Professional Development Program
Category B
Australasian Journal of Dermatology
Volume 47, No. 4, 2006
Name: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PDP No.: . . . . . . . . . . . . . . . . . . .
State:. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Questions 1–11
Circle the most appropriate answers — multiple
answers possible. Each question must have all
correct answers circled in order to receive points.
Questions 12–23
Circle the correct answer.
1.
A
B
C
D
E
12.
A
B
C
D
2.
A
B
C
D
E
13.
A
B
C
D
3.
A
B
C
D
E
14.
A
B
C
D
4.
A
B
C
D
E
15.
A
B
C
D
5.
A
B
C
D
E
16.
A
B
C
D
6.
A
B
C
D
E
17.
A
B
C
D
7.
A
B
C
D
E
18.
A
B
C
D
8.
A
B
C
D
E
19.
A
B
C
D
9.
A
B
C
D
E
20.
A
B
C
D
10.
A
B
C
D
E
21.
A
B
C
D
11.
A
B
C
D
E
22.
A
B
C
D
23.
A
B
C
D
Pass Mark: 75% (if you obtain this mark or higher you will be granted 1.5 hours Category B PDP credit).
If you feel the need to indicate ambiguity in a question, please do not write comments on the answer sheet.
Please return your answer sheet to College by
1 January 2007. Answer sheets received after
this date will not be accepted.
© 2006 The Australasian College of Dermatologists