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Psoriasis is an inflammatory disease of
progressive and recurrent autoimmune etiopathogenesis. Its features are skin
lesions of varying sizes, with dry scales, silver or gray may appear on any
surface of the body, especially in areas of greatest stress or skin
resurfacing. Conventional treatments are phototherapy, topical drugs and
systemic use. However such treatments are long and can cause toxic effects,
thus impairing their long-term use or associated with another treatment. A
better understanding of the pathophysiology of psoriasis enabled the
development of targeted treatments for specific targets in psoriatic plaque
from immunobiological. However, despite these new drugs showed a satisfactory
response in the treatment of pathophysiology, are still unknown adverse
effects. Help evaluate the effectiveness increases in rates of treatment and identify
adverse effects is pharmacist's role in the preparation, monitoring and
dispensation of pharmacotherapy for psoriasis. The immune process of psoriasis
is associated with many skin alterations. Among them, they can cite the high
INFγ levels that deviate dendritic cells IL-12 production in IL-23 that are
responsible for maintaining the lesion. Another possibility is the action of
Th17 lymphocytes that produce TNF-α and IL-17, associated with the Th22
lymphocytes produce IL-22 inhibits the differentiation of keratinocytes. There
is no differentiation occurs hyperproliferation of keratinocytes causing a
disorderly release of cytokines. Thus immunobiological drugs are targeted to
TNF-α and interleukins (IL-17, IL-22 and IL-23) reduced the immune response to psoriatic
plaque, controlling the hyperproliferation of keratinocytes. Another advantage
is the low toxicity due to the drug that allows the association to other
treatments. The combination of biopharmaceuticals with traditional therapies
can provide optimal therapeutic alternatives, being a specific method,
non-toxic and economically viable.
Keywords: Psoriasis, Biopharmaceuticals,
Psoriatic plaque, Pharmacotherapy for psoriasis
INTRODUCTION
Psoriasis and leprosy were classified
together until the late eighteenth century. In the early nineteenth century,
Robert Willian carefully and accurately characterized psoriasis and its
clinical diseases and Hebra in 1840 definitively separated psoriasis from
leprosy. From several epidemiological, immunological and genetic clinical
studies carried out mainly in the last 60 years, there is a great evolution of
the understanding of the disease [1].
Psoriasis until the 1990s concentrated only
on abnormalities in keratinocyte proliferation, believing that this change
would be responsible for the disease. Thus, the first treatments of the
pathology were topical drugs based on corticosteroids by methotrexate that
inhibit keratinocyte hyperproliferation [2].
A major breakthrough in the pharmacotherapy
of psoriasis was after evaluating transplanted patients with psoriasis who were
receiving cyclosporine that is an inhibitor of the immune system and cytokines
that activate the T-lymphocyte. Evident, characterizing an autoimmune disease
[3].
Psoriasis
is an inflammatory disease of progressive and recurrent autoimmune
etiopathogenesis that still has a poorly understood pathophysiology. However,
psoriasis is considered to be a dysfunction of immune system cells and cytokine
network, i.e., clinical lesions are the result of altered normal epidermal cell
growth cycle with concomitant cellular hyperproliferation with inflammatory
processes, in which stands out the dense infiltrate of polymorphonuclear
The spread of psoriatic plaques is rash in
areas of constant stress on the skin, such as elbows, knees, pre-tibial region,
sacral region, nails and scalp. Because psoriasis is not accurately diagnosed,
it can be confused with dandruff, but in joints it can simulate arthritis.
Psoriasis can affect the entire skin in 50 to 80% of cases. Patients with
severe psoriasis may be associated with more severe comorbidities such as
metabolic syndromes, cardiovascular disease, inflammatory bowel diseases such
as Chron's disease, depression, panic syndrome, and the consumption of
substances such as alcohol and tobacco follow up with a multidisciplinary team
[2].
It is also known that it is a
non-communicable skin disease, occurring more frequently between 15 and 30
years, in both sexes, affecting about 1 to 3% of the world population with
great impact on patients' quality of life [5].
The most common form of the disease is
psoriasis vulgaris, which is characterized by lesions of varying sizes, with
dry, silver or gray scales that can appear on any surface of the body,
classified into three categories: mild, moderate and severe, which is
responsible for 85-90% of cases. If left untreated, psoriasis can develop into
psoriatic arthritis, which is the form present in 6 to 40% of patients with
pathophysiology, which involves nails, axial skeleton, peripheral joints,
sacroiliac and enthesis which if left untreated evolve to injury and permanent
joint deformity. The less common forms are reverse psoriasis, pustular,
erythrodermic, palmoplantar and guttate [6].
Psoriasis is a disease with great social
impact on the patient's life. A study showed that in Portugal more than 250,000
people are affected by this disease, which causes physical and mental
discomfort, thus causing psychosocial comorbidities. Psychic impairment leads
some patients to alcohol and tobacco consumption, compromising the immune
system, accentuating the disease picture with the appearance of more psoriatic
plaques [2].
The pathophysiology of psoriasis is related
there are psychic changes. Because it is an autoimmune disease, it affects the
body as a whole, that is, any change in its psychic state may be associated
with high percentages of spread of lesions [7].
Currently, patients with severe and moderate
psoriasis treat with topical or corticoid-based drugs and conventional systemic
therapies such as methotrexate, acitretin and cyclosporine, which limit their
continued use because of their toxicity [8].
In recent years, based on new research on the
pathophysiology of psoriasis, new treatments have been developed to target
specific psoriatic plaques. The immunobiologicals used in the treatment of
psoriasis correspond to antibodies, cytokines (IL-12/IL-23) and fusion proteins,
which is a human tumor necrosis factor p75 receptor protein produced by
recombinant DNA technology in an expression system. Mammalian these drugs act
by modulating the immune response reducing damage caused by autoimmunity [9].
Although these new drugs have a satisfactory
response in the treatment of pathophysiology, their adverse effects are still
unknown. Helping to evaluate increases in treatment effectiveness indices and
identifying adverse effects is the pharmacist's role in the design, follow-up
and dispensation of pharmacotherapy for psoriasis.
METHODS
This study is a bibliographic review in which
were searched in scientific articles topics on the subject in databases such as
Google Scholar, Scielo Brazil, Periodicals Capes and Brazilian Digital Library
of Theses and Dissertations.
The study was conducted using publications
from any country in the world, without language restriction, obtained in full
from 2000 onwards. The descriptors used in the research were: “psoriasis”;
“Immunobiological”; “Psoriasis pharmacotherapy” and “psoriasis monoclonal
antibodies”.
Immune response
Psoriasis is a multifactorial chronic disease
that presents an immune-mediated inflammatory response. It is suggested that it
is influenced by genetic, environmental (emotional stress, medication, trauma,
infections, weather) and behavioral factors. Although its pathophysiology is
not yet defined, it is believed that the disease is triggered by inflammatory
phenomena mediated by T-lymphocytes [2].
To understand the immune dysfunction of the
pathology, it is relevant to understand skin changes, especially the physiology
of keratinocytes, relating the action of dendritic cells, macrophages,
neutrophils, mast cells, endothelial cells and T lymphocytes [10].
Currently, the pathophysiology of psoriasis
is described by an immune process that begins after a series of stimuli related
to environmental factors, such as emotional stress and/or medications that can
trigger the inflammatory process against keratinocytes.
It is suggested that the initial stimulation
for keratinocyte hyperproliferation starts from a dysfunction of the immune
system with increased production of proinflammatory cytokines that activate
dendritic cells. Dendritic cells present antigen to circulating naive T
lymphocytes. Adhesion molecules (ICAM-1) initiate the process of a mediated
immune response, leading to the release of interleukins IL-12, IL-23, IL15,
cytokines TNFα (tumor necrosis factor-alpha), INFα (interferon-gamma) resulting
in targeting of immune system cells to the site of inflammation. T-lymphocyte
activation promotes differentiation into Th-1 or Th-17 subtypes with cytokine
production and release of mediators involved in the inflammatory pathway
IL-12/Th1 (IL-2, INF-γ and TNF-α), IL-23/Th17 (IL-6, TNF-α, IL-17, and IL-22)
[6].
The-17 cells stimulate IL-17 production,
which in turn induces the production of chemokines that play an important role
in the pathophysiology of recruitment of neutrophils, CD8+ T lymphocytes and
dendritic cells mediating early tissue inflammation, causing psoriatic injury
[2].
The immune process of psoriasis is associated
with many epidermal changes. These include interferon-gamma (INFγ), which in
dendritic cells that divert the production of IL-12 to IL-23 that is
responsible for the maintenance of the lesion. Another possibility is the
action of Th17 lymphocytes that produce TNFα and IL-17, which associated with
Th22 lymphocytes produce IL-22 inhibiting keratinocyte differentiation. If
there is no differentiation there is a hyperproliferation of keratinocytes
causing a disordered release of cytokines, inducing an inflammatory process in
the dermis that characterizes the psoriatic plaque (Figure 1) [11].
Pasi
Psoriasis area and severity index (Pasi) is used to assess disease
severity and can range from 0 to 72. An index greater than 18 means severe
disease. The Pasi 75 reference means a 75% reduction in the pretreatment index
and is used to evaluate therapeutic success. Relapse of the disease is
considered when there is a 50% increase in this index after a period of
improvement. Pasi, however, does not consider the impact of the disease on
quality of life, which in daily clinical practice is important when choosing
treatment [13].
Conventional
therapies
Psoriasis is a chronic inflammatory disease,
and the choice of treatment must take into account age, gender, occupation,
existing diseases and other health problems. There are several treatment
options for pathology, with various mechanisms of action, which may interfere
in different parts of the immune system and others only in the proliferation of
keratinocytes. Treatments can be topical use, phototherapies, systemic drugs
and immunobiological [14].
Corticosteroids: Topical corticosteroid for mild
pathology has rapid and effective effects on disease onset because it is
anti-inflammatory, immunosuppressive (reduces activation or efficacy of the
immune system) and anti-mitogenic (inhibiting proliferation) action. Despite
its therapeutic advantages, its interruption causes a greater appearance of
psoriasis rash, usually more severe than the pre-existing one and often
presents tachyphylaxis (losing its effect in prolonged use) [4].
Methotrexate: Methotrexate acts by interfering
with cell replication (cytotoxic) indicated in the treatment of psoriatic
arthritis, psoriasis or erythrodermic forms. Its mechanism of action is through
the dihydrofolic acid-reducing enzyme that synthesizes tetrahydrofolate
inhibiting the formation of purines and, consequently, the synthesis of RNA to
DNA. Thus having a good result in psoriasis by its action that is DNA
replication, as in the case of keratinocytes in psoriasis eruptions, and also
having an action to decrease immunological (immunosuppressive) activity [15].
Methotrexate can be given orally and I.V,
although it requires strict control because of its adverse effects that require
constant laboratory tests, as it has important hepatotoxic potential. Thus it has
to make a careful evaluation to each individual [15].
Cyclosporine: Cyclosporine is a major inhibitor
of the immune system is mainly used to prevent organ rejection. Cyclosporin
acts by inhibiting cytokine production and release, including IL-2 and also by
inhibiting cytokine release by activated T cells. Cyclosporine should not be
given in pregnancy and its nephrotoxicity can trigger high blood pressure and
heart problems. Because of its immunosuppressive action, there is a higher risk
of infections and the development of malignancies. It also requires frequent
examinations, careful evaluation and monitoring because of its hepatotoxic
potential [4].
Acitretin: Acitretin is a second-generation
drug used to treat patients with cutaneous T-cell lymphoma and belongs to the
class of vitamin A-derived retinoids. As a synthetic aromatic retinoic acid
analog, its function would be to bind to nuclear receptors by altering
expression. Of a series of genes, but its mechanism of action is still
undefined in psoriasis, which leads to the belief that it has an
immunomodulatory and anti-inflammatory effect, acting on the growth and
differentiation of epidermal cells [15].
In the epidermis, retinoids may induce
expression of differentiation markers and exhibit inhibitory effects on
keratinocyte proliferation. It is used in cases of generalized plaque
psoriasis. In resistant cases may be associated with phototherapy. The most
common side effects are photosensitivity, paronychia, chelitis, xerosis, pure,
epistaxis, conjunctivitis, periungual granulomas and alopecia. The adverse
effect of the medication is restricted to its use in women of childbearing age
due to teratogenicity. The medication is available in 10 and 25 mg capsules and
the recommended dose is 0.5 to 1.0 mg/kg/day (Table 1) [15].
Non-pharmacological
associated treatment – Phototherapy
Phototherapy is used to treat various
dermatoses with UVA and UVB irradiation. In psoriasis, phototherapy can be used
with other drugs to decrease treatment and doses used by drugs such as
corticosteroids, methotrexate and acitretin. Phototherapy is used for its anti-proliferative,
anti-inflammatory and immunosuppressive activity. This treatment leads to a
decrease in cells on the antigen-presenting surface and consequently decreases
the activation of T lymphocytes. Phototherapy can be used alone or in
combination with other topical and/or systemic medications, thus seeking to
decrease the doses of both drugs radiation, reducing both side effects and
maintaining therapy. Side effects include nausea, headache, dizziness, herpes
simplex, etc. Symptoms in which patients should be aware that there may be a slight
increase in photoaging, cataract and risk of skin cancer among other symptoms
[17].
Conventional systemic medicines have a
satisfactory response to the treatment of moderate to severe psoriasis but
cause numerous adverse effects such as hepatoxicity and teratogenicity. Also,
treatment is discontinued due to dose and/or period.
With a better understanding of the
pathophysiology of the disease, it was possible to develop new drugs. Through
immunobiological drugs that act specifically to mitigate immunopathogenic
changes. Immunobiologicals are developed through the use of recombinant
biotechnology and are called biological agents that have revolutionized the
treatment of moderate to severe psoriasis. However, in addition to the observed
efficacy, one of the great advantages over existing drugs is the safety profile
with no toxicity in target organs [6].
In this reality emerged the immunobiological
agents. Currently, in BRAZIL, there are four ANVISA approved biological drugs
for the treatment of psoriasis: Adalimumab, Infliximab, Etanerceptte and
Ustekinumab, which are used in cases of moderate to severe psoriasis [13].
These new classes of treatments consist of
recombinant molecules developed from living organism gene sequences. They are
fusion proteins and monoclonal antibodies that specifically target the activity
of inflammatory T cells or cytokines by inhibiting or modulating specific
immune system agents. Biological drugs can save other organs and minimize side
effects. However, biological therapy has been associated with lower toxicity
than previously used systemic treatments [2].
Among the
biological therapy tools, monoclonal antibodies (mAb - Monoclonal Antibodies)
stand out, giving rise to the sulphix MAB (MABE) in drug nomenclature. The
mAb's production method generates different definitions:
Human Monoclonal Antibodies are genetically
engineered and have the characteristic of not being immunogenic since the amino
acid sequence in their content is identical to that of human antibodies.
Humanized Monoclonal Antibodies are murine
monoclonal antibodies that are fused to humanized antibodies to acquire Fc
portion of the human antibody and are substituted on the Fab portion by
specific amino acid sequences aimed at decreasing their immunogenicity.
Chimeric Monoclonal Antibodies are hybrid
immunoglobulins using the constant region from a human antibody and the
variable region from a mouse antibody.
Another biological molecule used for
pharmacological action is fusion proteins, which by definition are cell surface
receptors bound by the constant portion (Fc) of a monoclonal antibody (fused
proteins), which seek to mimic components responsible for cellular signaling in
the inflammatory cascade [18].
Regarding the safety of treatment with
biological agents, patients have to go through a thorough and adequate
laboratory investigation to ascertain their history. Immunobiologicals are
known to facilitate the onset of opportunistic infections and reactivation of
latent infections and may also alter the course of occult neoplasia. Thus
offering a necessary safety in the administration of these immunosuppressive
drugs to patients [13].
Regarding the immunobiological drug due to
its high cost and limited availability in the Unified Health System (SUS), only
a few patients receive direct release and many patients need to resort to legal
means to receive treatment which can often delay the treatment [13].
TNF-α inhibitors
Tumor necrosis factor (TNF-α) is a naturally
occurring cytokine, compromised in normal immune system inflammatory responses
[4].
TNF-α inhibitors bind to the
TNF-α cytokine produced by macrophages, monocytes, neutrophils, T cells, CAA
and keratinocytes preventing their binding to the receptor and hence its
proinflammatory action. The most common adverse effect during the
administration of these drugs is injection site reactions such as erythema,
pruritus, pain, edema and in rare cases anaphylactic shock. These drugs should
be used with extreme caution in patients with heart failure due to several
reports indicating the occurrence or worsening of congestive heart failure in
patients using this medication [19].
Etanercept
(Enbrel®): Etanercept is a TNF-α receptor fusion protein linked
to the human immunoglobulin (IgG1) p75 Fc fraction. The drug is a competitive
inhibitor of TNF-α which prevents interaction between this cytosine and its
cell surface receptors. Etanercept also modulates the activity of other
inflammatory cytokines and does not induce complement-mediated cell lysis in vitro [20].
Adalimumab
(Humira®): Adalimumab is a recombinant humanized monoclonal
antibody that specifically binds TNF for its high affinity and high
specificity, nullifying its biological function by blocking its communication
with cell surface TNF (p55 and p75) surface receptors [4].
In existing studies with
Adalimumab, it was reported that 70% to 80% of patients with the condition had
improvement at 16 weeks, showing a big difference from methotrexate which
achieved only 35% improvement in the same period [4].
Infliximab
(Remicade®): Infliximab is a murine human IgGI chimeric monoclonal
antibody obtained by artificial DNA sequence technology that results from the
combination of different DNA sequences. This drug binds with high affinity to
soluble and transmembrane forms of TNF. Thus with a high affinity, forming a
stable cluster that prevents the binding of tumor necrosis factor-alpha,
thereby decreasing the expression of proinflammatory cytokines [21].
Interleukin inhibitors
Interleukins IL-12 and IL-23
are produced by activated dendritic cells. Interleukins IL-12 stimulates the
differentiation of naive T cells into Th1, which produce TNF, INF and IL-2.
Interleukins IL-23 promotes activation and differentiation of Th-17 cells,
which secrete interleukins IL-17, IL12 and TNF, protagonist interleukins in the
pathogenesis of psoriasis [18].
Ustekinumab
(Stelara®): Ustekinumab is a monoclonal antibody that acts against
IL-12 and IL 23 p40 subunits, cytokines related to the transformation of naive
T cells into Th1 and Th17 cells. The role of the IL-12 and IL-2 mediated
pathway in the mechanism of various inflammatory diseases, especially
psoriasis, has been well recognized (Figure
2 and Table 2) [18].
Immunobiologicals represent a new modality of therapy for psoriasis. But
due to the chronicity of the disease and the high cost of immunobiological and
their unknown adverse effects, associations with conventional drugs such as
methotrexate, acitretin, cyclosporine, and phototherapy are suggested. In this
condition, the effects of each drug are potentiated and may use lower doses and
consequently with less toxic effects. Another advantage in the association of
immunobiological with traditional drugs is the reduction in the cost of
treatment (Table 3) [22].
CONSIDERATIONS
Pharmacotherapy
with immunobiological has advantages over the treatment of systemic drugs
(traditional treatment), due to the specificity and the absence of
pharmacological toxicity. Combining immunobiological with traditional therapies
can provide optimized therapeutic alternatives for patients who respond
inappropriately to a single pharmacy strategy. Additionally, therapeutic
efficacy may be increased by supplementation with another associated systemic
drug [23].
Traditional
therapies for psoriasis are often unable to meet desired treatment goals,
mainly due to high doses and long-term use causing toxicity. Combination
pharmacotherapy offers psoriatic patients a specific method with low
pharmacological and toxicological risks [24].
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Table 1 -
Table 2
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Table 3
