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Abstract During the last 30 years, the tremendous progress in our knowledge of the pathogenesis of
psoriasis has led to the development of new agents, the so-called biologics, that have revolutionized the
management of severe psoriasis. Dermatologists and patients see this emerging therapy as a new
perspective in the state of the art in managing moderate to severe psoriasis. After a few years of use in
daily practice, we may begin to analyze the power of the currently available biologic agents in the
management of severe psoriasis from the perspective of facts.
© 2010 Elsevier Inc. All rights reserved.
Therapies effective enough to provide reasonable ther- significant. Even more important are secondary effects and
apeutic perspectives in the management of patients with the risk of serious cumulative toxicity leading to end organ
moderate to severe psoriasis have only been available in damage that usually limits their long-term use.2
recent decades. Since the early 1970s when methotrexate The recent introduction of the so-called biologics
began to be used in the management of psoriasis, the represented a new perspective in the state of the art in
armamentarium of systemic drugs for treating this disease managing moderate to severe psoriasis.3 They are a new
has increased with the appearance of phototherapy, retinoids, generation of drugs, designed by genetic engineering
and cyclosporine. As a consequence, the possibilities of a techniques based on an improved understanding of the
better and long-term management of the disease have also immunogenesis of psoriasis and targeting the activity of T-
improved.1 Still, several issues limit a favorable long-term lymphocytes and cytokines responsible for the inflammatory
outcome with the traditional therapies that currently avail- nature of this disease. From a theoretic point of view,
able. Among them, lack of consistent efficacy (acitretin), dermatologists and patients have seen them as a new hope for
inconvenience associated with time-consuming issues and their unfulfilled desires in the treatment of psoriasis.4,5
unavailability (phototherapy), or frequent monitoring After a few years using them in daily practice, we may
requirements (cyclosporine and methotrexate) are the most begin to analyze the biologics in the management of psoriasis
from the perspective of facts. From this point of view, we
☆
Disclosures: Dr C. Ferrándiz has received honoraria and grants for may ask ourselves how many of the unmet medical needs in
research, consultancy, or lecturing from Merkc-Serono, Wyeth, Abbott, antipsoriatic therapy in the prebiologic era have now been
Schering-Plough, and Janssen-Cilag. Dr J. M. Carrascosa has received fulfilled, and otherwise, which of them still remain elusive.
honoraria and grants for research, consultancy, or lecturing from Merkc-
Serono and Wyeth.
In this review, we will assess the power of facts in biologics
⁎ Corresponding author. when trying to fulfill our patients’ wishes in an attempt to
E-mail address: cferrandiz.germanstrias@gencat.cat (C. Ferrándiz). define the ideal profile of the antipsoriatic therapy.
0738-081X/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.clindermatol.2009.03.002
82 C. Ferrándiz et al.
If dermatologists and patients were asked about the ideal maintained by infliximab14 and adalimumab but tend to
drug for psoriasis therapy, we would probably be able to find increase moderately with etanercept15 and efalizumab.16
several points of agreement. The chosen candidate should be Considering all these data together from the point of view
effective as monotherapy and have a rapid onset of action. It of short-term efficacy, we can conclude that biologics will
might address specific targets operating at psoriasis patho- undoubtedly be used for the induction of clearance of
genesis rather than work in an unspecific anti-inflammatory patients with moderate to severe disease, reaching, in the
or immunosuppressive way, with a low risk of organ toxicity, best possible scenario, an excellent short-term control in up
malignancy, and infection. The safety profile should allow it to 80% of treated patients. Although comparisons among
to be administrated to patients of all ages and life stages as different biologic drugs are difficult because no head-to-
well as to difficult-to-treat patients such as are those with head trials have been performed, significant differences
chronic infections such as hepatitis C (HCV) and B (HBV) among them do exist. Similar results can apparently be
virus and HIV. achieved with classical therapies such as cyclosporine,17
The ideal antipsoriatic drug should not only clear the methotrexate,18 or psoralen and long-wave ultraviolet A
disease but also definitively cure it. But even when (PUVA) therapy,19-21 but it is extremely difficult to compare
considering this latest end point as unattainable at present, biologic with prebiologic therapy because of the scarcity of
the drug should be able to be administered long-term to double-blind, randomized comparative clinical studies.22 In
provide continuous effective control, because continued this sense, only adalimumab has been directly compared
remission after successful treatment is as important as with methotrexate, with results for efficacy significantly
successful induction of remission. Moreover, it should be better for adalimumab.5
easy to use, well accepted by patients, have minimal drug-
to-drug interactions, and should have minimal monitoring
requirements because convenience is also an important Long-term efficacy
issue when dealing with chronic diseases that require
prolonged treatments. Despite biologics being effective in the short-term control
Finally, the cost of the drug should be affordable by most of psoriasis, questions still remain about the long-term
patients, by the national health services of the different effectiveness of these agents. This should be a key point
countries, and by insurance companies. when dealing with chronic diseases such as psoriasis, for
which there is no cure.
The results of a 3-year continuous dosing study with
efalizumab showed an ascending curve of responders during
The facts the first 18 months that was maintained until the end of the
study, with 45.4% with PASI-75 response at 36 months.23
Short-term efficacy (induction of clearance) Etanercept response, at doses of 50-mg twice weekly, peaked
at week 48 with PASI-75 reached in 63%, and then showing
The first step is to decide the primary measurement to a slight decrease to 52% by week 96.24 The extremely high
define efficacy. The Psoriasis Area and Severity Index 90 short-term efficacy of infliximab was sustained when used
(PASI -90), defined as proportion of patients with a more every 8 weeks after the induction period through week 24 but
than 90% decrease in the basal PASI score in the short-term decreased to 60.5% with a PASI-75 response at week
(week 10 to 16), represents the ideal situation of being 50.4,14,25 Although data are limited for adalimumab, about
cleared, or almost cleared, and would be close to the main 5% of patients in continuous therapy lost adequate response
objective of any ideal therapy. We will mainly refer to during weeks 33 to 52.7
PASI-75 because it has been considered as the gold These data indicate that biologics are reasonably capable
standard for the evaluation of the short-term efficacy of of providing long-term control of the disease, although some
different therapies in the management of moderate to severe loss of efficacy can be expected with some of them, mainly
psoriasis, and patients and physicians consider this target as with infliximab and etanercept. The differences in response
more than satisfactory. rates among the approved biologics generally seem to
Taking into account this objective in the short-term (week become less pronounced with increasing duration of
10 to 16), and according to results of double-blind, placebo- treatment; however, the longer the treatment period the
controlled clinical trials, infliximab is the most effective, weaker the evidence base for such indirect comparisons.
with approximately 80% of patients achieving a PASI-75 An alternative to continuous treatment for the long-term
response at week 10,6 followed by adalimumab (71% to 79% control of the diseases could be intermittent therapy effective
at week 16),7,8 etanercept (34% for the doses of 25-mg twice enough to allow for extended drug holidays or to induce
weekly and 49% when using 50-mg twice weekly, at week long-lasting remissions. The advantages would be to reduce
12),9 efalizumab (22% to 39% at week 12),10-12 and exposure to immunosuppressive agents, leading to a lower
alefacept (20% at week 12).13 After an additional 12 risk of long-term adverse events and lower costs. This
weeks of treatment (week 24), the initial response rates are strategy is the common way we use traditional systemics
A new era in the management of psoriasis 83
drugs for psoriasis, because toxicity to organs often limits (0.3%) and single cases of hemolytic anemia have also
continuous use of these agents. been reported.32,33 Psoriasis-related adverse events repre-
Among approved biologic agents, alefacept produced the sent a new class of secondary effects directly induced by
longest posttreatment clinical benefits in responders (7 to 8.6 efalizumab, with a wide spectrum varying from mild
months after a 12-week course), followed by infliximab (4.7 lesions (transient papular eruption on the trunk and body
months after a 6-week, 3-dose induction period), etanercept folds easily managed with topical therapy34 ) to the
(2.8 to 3.5 months after 12 weeks of therapy), and efalizumab unusual but severe generalized inflammatory flare.35,36
(2.8 months after 24 weeks of therapy).26 The duration of New-onset or worsening arthritis has been infrequently
remission achieved with biologics can be considered quite reported during clinical trials and postmarketing surveil-
similar to those of traditional systemic drugs, being alefacept lance, but its relationship with efalizumab therapy needs to
among the biologics and PUVA among the traditional be clarified.37,38
therapies the only ones that can be considered as remitive Agents that block tumor necrosis factor (TNF) have been
(vs suppressive) therapies. associated with an increased risk of reactivation of latent
Concerns about the intermittent use of biologic therapy infections such as tuberculosis, which can be successfully
include the rebound phenomenon reported with some of minimized with adequate prophylaxis,39 and induction or
them after the treatment is discontinued (particularly with exacerbation of demyelinating conditions and may cause
efalizumab in up to 14% of patients27) and a decreased clinical worsening in patients with moderate to severe
degree of response compared with the first treatment cardiac failure.40,41 Injection site reactions have to be
(particularly with infliximab24), even though most patients considered for etanercept, and occasionally severe infusional
responded well to reintroduction of the biologic agents.28,29 reactions, including anaphylaxis, occur in up to 10% of
Therefore, due to these concerns and the short duration of patients with psoriasis who are prescribed infliximab.42,43
remission, biologic agents seem to work better in a Rare cases of severe liver toxicity or even lethal liver failure
continuous than in an as-needed setting.30 have also been observed.44,45
Regarding malignancy, there are currently no signs of a
clear increase in the number of neoplasias associated with the
Safety use of biologics in psoriasis. A higher risk for the
development of nonmelanoma skin cancer and solid cancers
Safety, mainly related to organ toxicity, is the main has been reported in patients with rheumatoid arthritis treated
concern in the long-term control of psoriasis with traditional with anti-TNF drugs.46,47
systemic drugs. Toxic thresholds often limit a prolonged use The primary concern with alefacept is T-lymphocyte
of these agents or at least oblige careful dosing adjustment in depletion, so that monitoring of CD4+ cells is required, and
long-term use that has led to the development of incon- treatment should be discontinued if the CD4+ T-cell count
venience strategies such as combination, rotation, sequential, drops below 250/μL.48,49
and intermittent approaches to optimize long-term out-
comes.31 Another common problem with classic therapies is
frequent drug-to-drug interactions with many drugs of Can biologics be used in all ages and life stages?
common use that can limit therapeutic options in some
patients, mainly the elderly, who are likely to have Ideally, antipsoriatic therapies should be safely adminis-
concomitant illnesses. tered to patients of all ages and life stages. Except for
Given the apparent lack of end-organ toxicity secondary etanercept, no randomized clinical trials have been per-
to prolonged use, biologics may be administered for formed in patients with psoriasis during childhood and
significant periods of time. Available data generally suggest adolescence.50 The experience available with other biologics
that when used according to contemporary guidelines and in this age group is limited to individual cases and small
with appropriate monitoring, approved biologic therapy can series, as is also the case with traditional systemic drugs.
be considered safe and well tolerated in the short-term (12 to Although elderly patients with psoriasis have been safely
24 weeks). Results of the extended studies also support their treated with different biologics—significantly, no dose-
safety and tolerability for longer periods. adjustment has to be done—this group is likely to have
Although the overall rates of adverse events and concomitant illnesses in which any severe secondary effect
withdrawals from treatment are similar among the different may have dramatic consequences.
biologics, these agents differ substantially in the rates of All biologics approved are pregnancy category B, except
specific events and some of them, which are occasionally efalizumab, considered as pregnancy category C. As a
severe, still have to be considered. consequence, pregnancy should be avoided during efalizu-
Efalizumab, for example, can cause common but mild mab therapy as with methotrexate and retinoids because of
adverse events like transitory flu like syndrome or mild their teratogenicity.51 This also applies to lactation, because
transitory nonclinically significant leucocytosis; however, it is not known whether any of the licensed biologics are
infrequent but occasionally severe thrombocytopenia excreted in human milk.
84 C. Ferrándiz et al.
Considering that biologics target the immune system, it characterized adverse event described in patients receiving
seems reasonable to think that the immunologic response to therapy with TNF-blockers, particularly in patients with
vaccines can be partially impaired, as has been shown in rheumatoid arthritis.65,66
some small studies.52 As a consequence, live vaccines must
be avoided during treatment with all biologics, and this is Convenience
also applies to vaccines with attenuated microorganisms in
the case of efalizumab, which could represent a limitation in Therapies that are more convenient than classic systemic
plans for long-term therapy. treatments are needed to improve patient compliance with
The use of biologic agents is also limited in patients with treatment, thus improving therapeutic outcomes. Conveni-
chronic infections such as HBV and HCV or HIV. Evidence ence therapy includes treatments with an easy route and
from limited studies shows that TNF inhibitors, particularly frequency of administration, a minimal need for monitoring,
etanercept, appear to be safe and well tolerated in the setting and requiring few visits to the physician or treatment center.67
of chronic HCV, without a negative effect on the underlying An important advance has been achieved in this area,
HCV infection.53,54 Conversely, chronic HBV may reacti- because, except for infliximab, all the approved biologics
vate during therapy with TNF-blockers.55 The use of anti- have been designed to be subcutaneously self-administered
TNF agents in short series of HIV-infected patients has not at home from twice weekly to once every 2 weeks.
been associated with significant clinical adverse effects or a Infliximab is more inconvenient to administer because it
negative effect in CD4 counts and HIV viral load levels, but requires intravenous perfusion in a hospital outpatient
no definitive counselling or guidelines are available.56 setting. The dosing frequency (once every 8 weeks) after
Finally, for patients with a history of malignancy resulting the induction period is well accepted by the patients.
from nonmelanoma skin cancer, a clear statement indicating Monitoring has been improved with the biologic agents
the interval of time free of recurrence that should be compared with traditional systemic drugs used in the
considered safe before the different biologics could be treatment of psoriasis because the lack of end-organ toxicity
initiated is still lacking.57 makes the need for monitoring less cumbersome.68 Despite
Although all the approved biologics have been demon- the few evidence-based studies on monitoring practices for
strated to be generally safe and well tolerated, secondary patients with psoriasis receiving biologic therapies, a detailed
effects—occasionally severe—may occur as a direct con- medical history, physical examination, and chemistry screen
sequence of the drug. This remains a concern mainly in long- with liver function tests, complete blood cell count, and
term use. In addition, experience is scarce regarding safety in platelet count, as well as tuberculosis testing are mandatory
particular groups such as children, older patients, pregnant at baseline and with variable frequencies thereafter.52
women, and patients with chronic infections or a history
of cancer.
Cost
Can biologics be used in psoriasis other than The cost of biologics is a key issue to be considered and
plaque psoriasis? can lead to restrictions of prescriptions by health care
providers. A comprehensive and adequate evaluation of the
The approved indication of all biologics is for moderate to effect of the new biologics in the global cost of psoriasis is
severe plaque psoriasis, which represents more than 80% of complex. In addition to direct costs from resources
all psoriasis.58 Psoriasis has many different clinical pre- attributable to the therapeutic intervention, indirect costs
sentations and can affect different areas of the body surface. resulting from reduced productivity and intangible costs
In this sense, limited psoriasis poorly controlled with incurred from pain and emotional suffering should also be
topical therapy and affecting the vulnerable areas of the face, taken into account.69 The annual direct cost of any of the
scalp, palms and soles, genitalia, and nails can cause approved biologic agents—about $12,800 for efalizumab
significant disability or impairment in physical or mental (the least expensive) to $34,800 for etanercept (50 mg, twice
functioning, with a severe effect on the quality of life.59 This weekly)—far exceeds the direct cost of any of the classic
is also the case with some peculiar clinical presentations such therapies, estimated to be from $1200 for methotrexate to
are pustular and inverse psoriasis. The usefulness of $10,000 for cyclosporine (5 mg/kg).70
biologics in such circumstances has not been proved. Only Biologics may also reduce health care resource utilization,
infliximab has been approved for nail psoriasis, and few case absenteeism, and caregiver assistance in psoriatic patients,
reports and short published series only allow the supposition which could translate into savings in both direct and indirect
that efalizumab might be a good option in patients with hand costs as well as improvements in health-related quality of life
and foot psoriasis.60-62 for patients.71 Thus, because the number of patients being
With respect to pustular psoriasis, some successful but prescribed biologic agents is dramatically increasing, studies
anecdotal cases have been reported.63,64 The development of to assess the cost-effectiveness of the use of biologics are
new cases of pustular psoriasis is also an uncommon but well mandatory. Different perspectives may include the evalua-
A new era in the management of psoriasis 85
tion of the efficiency of biologic agents in cost per patient in 4. Sterry W, Barker J, Boehncke WH, et al. Biological therapies in the
achieving a minimally significant difference in the Derma- systemic management of psoriasis: International Consensus Confer-
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response and DLQI improvement, respectively, at week
7. Saurat JH, Stingl G, Dubertret L, et al. Efficacy and safety results from
12n.72 Taking into account that the best cost-efficacy ratios the randomized controlled comparative study of adalimumab vs.
are obtained with nonstandard doses, these conclusions methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br
should be carefully evaluated. The different results also J Dermatol 2008;158:558-66.
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