Profile of certolizumab and its potential in the treatment of psoriatic arthritis

Article (PDF Available)inDrug Design, Development and Therapy 7(default):339-48 · April 2013with39 Reads
DOI: 10.2147/DDDT.S31658 · Source: PubMed
Abstract
Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy associated with psoriasis (PsO). PsA could be considered an enthesal disease because of the link between mechanical stress (entheses) and immunologically active tissue (synovium). Evidence of efficacy of anti-tumor necrosis factor alpha (TNF-α) is supported by reduction of histological vascularity and immune cell infiltrates in synovial tissue after treatment. Certolizumab pegol (CZP) is a polyethylene glycolylated (PEGylated) Fab' fragment of a humanized monoclonal antibody that binds and neutralizes human TNF-α. The PEG moiety of the Fab fragment, markedly increases the half-life of CZP and confers to the drug a unique structure that differs from the other anti-TNF-α agents tested for the treatment of Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritis, nonradiographic spondyloarthritis, PsO, and PsA. In contrast to other anti-TNF-α agents, CZP did not mediate increased levels of apoptosis, suggesting that these mechanisms are not essential for the anti-TNF-α efficacy in Crohn's disease. As CZP, infliximab, and adalimumab, but not etanercept, almost completely inhibited lipopolysaccharide-induced interleukin-1 beta release from monocytes, this cytokine-production inhibition may be relevant for drug efficacy. Due to these characteristics, it has been demonstrated in clinical studies that CZP effectively improves signs and symptoms of arthritis and physical function and skin manifestations of PsO, with a safety profile similar to rheumatoid arthritis. This drug can be considered as a valid treatment in patients affected by PsA. The efficacy and tolerability profiles suggest CZP as a suitable antipsoriatic drug in the treatment of PsA.

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Drug Design, Development and Therapy 2013:7 339–348
Drug Design, Development and erapy
Prole of certolizumab and its potential
in the treatment of psoriatic arthritis
Maria Sole Chimenti
1
Rosita Saraceno
2
Andrea Chiricozzi
2,3
Alessandro Giunta
2
Sergio Chimenti
2
Roberto Perricone
1
1
Unit of Rheumatology, Allergology,
and Clinical Immunology,
2
Unit
of Dermatology, University of Rome
Tor Vergata, Rome, Italy;
3
Laboratory
for Investigative Dermatology,
Rockefeller University, New York,
NY, USA
Correspondence: Maria Sole Chimenti
Unit of Rheumatology, Department
of Internal Medicine, University of Rome
Tor Vergata, 1 Via Montpellier,
Rome 00163, Italy
Tel +39 06 2090 0587
Fax +39 06 2090 0358
Email maria.sole.chimenti@uniroma2.it
Abstract: Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy associated with
psoriasis (PsO). PsA could be considered an enthesal disease because of the link between
mechanical stress (entheses) and immunologically active tissue (synovium). Evidence of efficacy
of anti-tumor necrosis factor alpha (TNF-α) is supported by reduction of histological vascularity
and immune cell infiltrates in synovial tissue after treatment. Certolizumab pegol (CZP) is a
polyethylene glycolylated (PEGylated) Fab fragment of a humanized monoclonal antibody that
binds and neutralizes human TNF-α. The PEG moiety of the Fab fragment, markedly increases
the half-life of CZP and confers to the drug a unique structure that differs from the other anti-
TNF-α agents tested for the treatment of Crohn’s disease, rheumatoid arthritis, ankylosing
spondylitis, axial spondyloarthritis, nonradiographic spondyloarthritis, PsO, and PsA. In contrast
to other anti-TNF-α agents, CZP did not mediate increased levels of apoptosis, suggesting that
these mechanisms are not essential for the anti-TNF-α efficacy in Crohn’s disease. As CZP,
infliximab, and adalimumab, but not etanercept, almost completely inhibited lipopolysaccharide-
induced interleukin-1 beta release from monocytes, this cytokine-production inhibition may
be relevant for drug efficacy. Due to these characteristics, it has been demonstrated in clinical
studies that CZP effectively improves signs and symptoms of arthritis and physical function
and skin manifestations of PsO, with a safety profile similar to rheumatoid arthritis. This drug
can be considered as a valid treatment in patients affected by PsA. The efficacy and tolerability
profiles suggest CZP as a suitable antipsoriatic drug in the treatment of PsA.
Keywords: psoriatic arthritis, certolizumab pegol, biological therapies, anti-TNF
Introduction
Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy commonly associated
with psoriasis (PsO). Several epidemiologic studies have examined the association
between PsO and inflammatory arthritis. In studies performed in outpatients suffering
from PsO, arthritis prevalence varied from 6% to 39%.
1
Joint disease is characterized
by systemic inflammation and extensive synovitis, resulting in erosions of articular
cartilage leading to joint destruction. Progressive damage begins early in the course
of the disease as a consequence of the active inflammation, and results in radiological
damage in up to 47% of patients at a median interval of 2 years, causing irreversible
disability.
2
PsA belongs to the spondyloarthritis (SpA) group and affects primarily the
peripheral joints, the spine, and the entheses. The pathogenesis of PsA is linked to innate
immune response that generates high concentrations of inflammatory cytokines, such
as tumor necrosis factor alpha (TNF-α), which promotes effector function of a variety
of tissue cells and thereby sustains the chronic inflammation leading to synovitis in
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PsA.
3
Overexpression of TNF-α is believed to play a key role
in the pathogenic mechanisms linking PsO and arthritis.
4
This
cytokine has been implicated in a number of inflammatory
diseases, including PsA, by inducing the production of other
inflammatory cytokines such as interleukin (IL)-1 and IL-6,
chemokines like IL-8, and degradative enzymes, including
several matrix metalloproteinases.
5
Moreover, it mediates a
number of biological processes that can result in joint damage
characterized by stimulation of bone resorption and inhibition
of bone formation and of synthesis of proteoglycans. TNF-α
may also contribute to vascular proliferation, which is
probably one of the key and earlier observable changes in
psoriasis and PsA.
6
Therapies neutralizing pivotal cytokines
might not only limit joint damage and skin inflammation
but also reduce the incidence of adverse metabolic and
cardiovascular events in affected patients.
7
Several trials
have shown excellent clinical results with anti-TNF-α agents,
etanercept,
8
infliximab,
9
adalimumab,
10
and golimumab.
11
These agents have been proven to be effective in different
aspects of the disease, including skin lesions, joint pain
and swelling, enthesitis, and dactylitis, resulting in a
significant improvement both in mobility and in radiographic
progression and quality of life (QoL) parameters.
12
Recently,
certolizumab pegol (CZP) has been tested and evaluated
for several inflammatory diseases, and for its safety and
efficacy profiles. This drug can also be considered for
the treatment of PsA. In this review, we investigated the
pathogenetic roles of TNFα in inflammatory arthritis as
PsA, and the mechanisms of action of CZP. In particular,
the evidence of efficacy of CZP in PsA will be explored.
Pathogenesis of PsA: link
with TNF-α
Although the biological function of TNF-α is not completely
clear in both normal and pathological conditions, elevated
levels of TNF-α have been found in patients experiencing
inflammatory diseases, and clinical data on the efficacy of
TNF-α-blocking agents suggest that it plays a key role in
the pathogenesis of various inflammatory disorders such as
Crohn’s disease (CD), rheumatoid arthritis (RA), and SpA,
as well as PsO and PsA.
13
PsA pathogenesis is incompletely
understood, and a pathophysiological role of the synovium
has been recently suggested. Some authors consider PsA as
an enthesal disease linking mechanical stress (entheses) to
immunologically active tissue (synovium).
4
A dermatological
perspective brings an alternative view of autoimmunity
that could partly explain the role of innate immunity. The
skin may likely secrete proinflammatory mediators, such
as TNF-α, to the affected proximal or distant joints, and
the interruption of this pathological communication may
represent a therapeutic target
14
(Figure 1). TNF-α produced
by macrophage infiltration in synovial tissue may constitute
the basis of synovium hypersensitization to endogenous
ligands of the innate immune system.
15
Synovial tissue
analysis has been used in order to distinguish PsA from other
inflammatory arthritis, particularly in terms of pathological
aspects and response to synthetic or biological disease-
modifying antirheumatic drugs (DMARDs).
16
Recent
findings suggest an important feature of PsA synovium:
the presence of lymphoid aggregates of variable size and
organization, previously considered highly specific of RA
while recently observed in other inflammatory arthritis as
PsA. Two major cytokines are involved in the pathogenesis
of lymphoid aggregates: TNF-α and lymphotoxin beta.
They play a potential role in the development of the high
endothelial venule phenotype and in the expression of homing
chemokines. Moreover, increased levels of these cytokines
have been demonstrated in PsA synovial fluid.
17
It has been
suggested that these structures linked to inflammatory
cytokines may play a role in multiple processes, including
antigen presentation, T-cell costimulation, and synthesis of
soluble mediators.
18
For this reason, TNF-α-targeting agents
represent a valuable therapeutic approach in treating such
disorders as PsA. There are five marketed agents targeting
TNF-α that possibly have a complex mechanism of action
beyond the plain TNF-α neutralization. They differ in
structure, pharmacokinetic, and in vitro properties, all of
which may have relevant therapeutic implications.
Treatment of PsA: evidence
of anti-TNF-α efcacy
Few studies have focused on the correlation between
clinical composite scores and changes in PsA synovium.
Treatment with DMARDs can modify synovial cell
populations and infiltrates, correlating with the clinical
improvement observed in treated patients.
19
One of the
first studies establishing the efficacy of anti-TNF-α
in modifying synovial tissue in PsA showed reduced
vascularity and suppression of immune cells after treatment
with infliximab.
20
In particular, the authors of this study
evaluated the effects of anti-TNF-α treatment on histologic
abnormalities of the synovium in patients with SpA in
order to confirm a potential benefit on peripheral synovitis
and to investigate the mechanism of action of anti-TNF-α
agents. Histologic and immunohistochemical data showed
a significant decrease in vascular cell adhesion molecule 1
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expression on the synovial endothelium, a reduction in
neutrophil and macrophage infiltration of the synovial
sublining layer, and diminished presence of macrophage-
like synoviocytes. The aforementioned properties suggest
that primarily anti-TNF-α agents act in deactivating the
endothelium, with a decrease in vascularity, which in
turn reduces migration and homing of inflammatory cells
into the synovial tissue. Additionally, the thickness of the
synovial lining was normalized after only 12 weeks of
treatment. This effect is possibly mediated by a reduction
in TNF-α-induced proliferation and/or restoration of Fas-
mediated apoptotic cell death of synovial fibroblasts.
20
Moreover, the number of CD55-positive synovial lining
fibroblasts was significantly reduced at week 12. The most
striking immunohistopathological changes included a
reduction in lining layer thickness and in downregulation of
hypervascularity and in endothelial activation, resulting in a
decrease of the inflammatory cell infiltrate with differential
effects on T and B cells.
21
Kruithof et al demonstrated a
significant reduction in CD3-positive cells in a cohort
of PsA patients treated with adalimumab. Interestingly,
a significant reduction in the number of CD3-positive cells
was observed after only 4 weeks of treatment.
22
Systemic
modifications of the inflammatory process during anti-
TNF-α treatment concern mediators of inflammation.
In fact, the evaluation of complement-system fragments
in patients with PsA treated with anti-TNF-α agents
showed a significant decrease in plasma C3 and C4 levels,
independently from the anti-TNF-α used. Patients with good
response showed a more pronounced reduction in serum
TNFα, IL-1, IL-6
FLS
TNFα
INFγ
CD80/86-CD28
RANK/RANKL
C3 and C4
C5a, MAC
CD59
MCP-1,
IL-8,
MMPs
Immune cell
recruitment
VEGF
INFα
IL-12/IL-23
SelfDNA
Immune cell
recruitment
Figure 1 Enthesal and Joint pathology in Psoriatic Arthritis. The origin of Inammation in the enthesal complex in PsA is multifactorial. When stimulated by stress, infections
and trauma (Koebner phenomenon), in a genetic background, broblast-like synoviocytes express selfDNA or/ and secrete inammatory cytokines and MMPs. They produce
complement system factors as C3 and C4 and express less CD59 during inammation, who is an inhibitor of complement system activation. The activation of the complement
system lead to the release of C5a and production of MAC with the lysis of cells and recruitment of immune cells. FLS secrete MCP-1 and IL-8 necessary for recruitment
and activation of MΦ. Polyclonal activation of CD4+Tcells and Th17 is the consequence of the immunological synapse with DC linked to the binding with CD80/86 and
CD28. When activate CD4+ Tcells produce: RANKL with activation of OC with the consequence of bone erosions and VEGF with the activation of endothelial cells and
the formation of HEV
Abbreviations: PsA (Psoriatic Arthritis); FLS (broblast-like synoviocytes); TNF (Tumor Necrosis Factor); MMP (Matrix metalloproteinases); MCP-1 (monocyte chemotactic
protein-1); OC (Osteoclast); MΦ, (monocytes/macrophages); RANK/RANKL (Receptor activator of nuclear factor kappa-B/ ligand); MAC (membrane attack complex); VEGF
(vascular endothelial growth factor); Th17 (T helper 17); DC (dendritic cell); CD (cluster differentiation).
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complement C3 levels as well as low baseline C3 levels.
These findings underline that a reduction in complement
native components may be considered as an improvement
of a preexisting proinflammatory status reverted by anti-
TNF-α drugs. It could be postulated that persistently
elevated C3 levels may represent a negative predictive
factor influencing the outcome of anti-TNF-α therapy in
RA and PsA. As a consequence, the detection of blood
C3 levels may provide an additional tool in monitoring
disease activity during treatment with anti-TNF-α in
PsA patients.
23
Recently, the Group for Research and
Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)
reported recommendations for PsA treatment.
12
An
excellent therapeutic improvement has been obtained by
the introduction of biologic treatments designed to modify
and regulate pivotal and specific mechanisms involved in
PsO and PsA immunopathogenesis. To date, anti-TNF-α
has been suggested to have a more favorable side-effect
profile than synthetic DMARDs.
24
Prole of certolizumab
Structural function
CZP (Cimzia; UCB, Brussels, Belgium) is a PEGylated
(polyethylene glycol) Fragment antigen binding (Fab)
of a humanized monoclonal antibody that binds and
neutralizes human TNF-α. The structure of CZP differs
significantly from the other agents that have undergone
clinical evaluation. In vivo, the pharmacokinetic properties
of Fab are limited. However, attachment of a 40 kDa PEG
moiety to the Fab fragment markedly increases the half-life
of CZP to a value comparable with that of a whole-antibody
product, conferring to the drug a fast and lasting effect on
the inhibition of joint damage and inflammation. The Fab
fragment was engineered with a single free-cysteine residue
in the hinge region, which enables site-specific attachment
of PEG without affecting the ability of the Fab fragment
to bind and neutralize TNF-α.
26,27
The unique structure
of CZP differs from that of other anti-TNF-α agents that
have been tested for the treatment of CD, RA, ankylosing
spondylitis (AS), axial SpA, nonradiographic SpA, PsO,
and PsA. In fact, clinical efficacy of the drug reported in
clinical trials highlighted the rapid improvement of CZP
in signs and symptoms of inflammatory arthritis.
Mechanisms of action of CZP
Concerning the mechanism of action of this drug, it is not clear
why CZP does not induce apoptosis of cells bearing TNF-
α, conversely to other anti-TNF-α agents. Hypothetically,
in contrast to the other TNF-α-targeting drugs, CZP may
bind to a different epitope compared to the other agents,
which leads to a different intracellular signaling pattern.
Increased apoptosis has been reported in tissue sections from
affected bowel after 24 hours and 6 and 28 days of infliximab
treatment.
28
It is possible that the anti-inflammatory effect
of infliximab indirectly induces apoptosis of activated cells.
In this context, a series of comparative in vitro studies were
conducted in order to explore the mechanism of action of CZP
in CD. The mechanisms, including induction of apoptosis,
antibody-dependent cell-mediated cytotoxicity (ADCC),
and complement-dependent cytotoxicity (CDC), may not
be required for clinical efficacy of an anti-TNF-α agent in
CD, however, inhibition of bacterially stimulated cytokine
production from macrophages may be needed for the function
of an anti-TNF-α agent to produce efficacy. In fact, in contrast
to the other anti-TNF-α agents tested, CZP did not mediate
increased levels of apoptosis in any of the in vitro assays
used, suggesting that these mechanisms are not essential for
the efficacy of anti-TNF-α agents in CD. As CZP, infliximab,
and adalimumab, but not etanercept, almost completely
inhibited lipopolysaccharide-induced IL-1-β release from
monocytes, this mechanism of inhibition of cytokine
production may be important for efficacy of anti-TNF-α
agents.
29
Recently, Ueda et al investigated the cytotoxic
effects of the anti-TNF-α agents CZP and golimumab.
30
Upon evaluation of their ability in binding to transmembrane
TNF-α (tmTNF-α), and in inducing ADCC and CDC, both
agents were proven effective in neutralizing tmTNF-α. In
contrast to CZP, golimumab was also able to induce ADCC
and CDC, similarly to infliximab and adalimumab. While
CZP directly provoked nonapoptotic cell death in tmTNF-
α-expressing cells, golimumab generated a weaker apoptotic
effect compared to infliximab and adalimumab. Accounting
for these properties, the cytotoxic effects of anti-TNF-α
agents on TNF-α-expressing cells underline their efficacy
in treating granulomatous diseases.
30
The direct cytotoxic
effect of CZP on TNF-α-producing cells may contribute to
the clinical effectiveness in the treatment of CD, whereas
golimumab may be less effective for the treatment of
granulomatous diseases.
28,30
Intracellular signal transduction of CZP
Another important concern about the mechanism of action of
CZP is the evidence of the intracellular signal transduction
triggered by the drug. All available anti-TNF-α biologics
have in common the capability to effectively neutralize
TNF-α as a major pharmacological mechanism of action.
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However, there are distinctions with respect to the effect of
engagement with tmTNF-α. In all cases, anti-TNF-α biologics
can act as antagonists by blocking interaction between
tmTNF-α and TNFR1/2 (Tumor necrosis factor receptor 1/2)
expressed on a responsive cell. A recent study reported similar
ability of CZP, adalimumab, and infliximab in neutralizing
mTNF-a-mediated (membrane Tumor necrosis factor-α
mediated) signaling, whereas etanercept appeared to be about
twofold less potent.
31
However, in certain instances, an anti-
TNF-α may also act as an agonist through the phenomenon
known as “reverse signaling, in which the engagement of
tmTNF-α leads to phosphorylation of specific serine residues
in the cytoplasmic tail of tmTNF-α and a signal is transduced
in the cell expressing tmTNF-α.
32,33
Furthermore, regulated
intramembrane proteolysis of tmTNF-α by signal peptide
peptidase-like proteases is reported to release a TNF-α
intracellular domain mediating reverse signaling in dendritic
cells. The full significance of reverse signaling is unknown.
One consequence of reverse signaling through tmTNF-α in
activated human T cells by both etanercept and infliximab is the
induction of E-selectin.
34,35
However, by binding only a single
TNF-α homotrimer, etanercept does not cross-link tmTNF-α
(in the absence of rheumatoid factor), contrary to bivalent mAbs
(monoclonal antibodies) such as infliximab. In this regard, it
is interesting to highlight that infliximab, but not etanercept,
suppresses T-cell proliferation by inducing G
0
/G
1
cell-cycle
arrest. Although the rheumatoid factor positively interferes in
cross-linking etanercept to tmTNF-α, the suppression of cell
proliferation is weakly observed, approximately half the level
occurring with infliximab.
36
Another possible consequence
of reverse signaling induced by biologic anti-TNF-α relates
to intracellular events and potential competition for shared
signaling pathway molecules, in particular those induced
by endotoxin-mediated TLR (Toll-like receptor) signaling,
given the observation that in vitro reverse signaling through
tmTNF-α induces endotoxin resistance and suppression
of cytokines, including TNF-α, IL-1β, IL-10, and IL-12.
37
Regarding cytokines, as mentioned above, various in vitro
studies report that infliximab and/or adalimumab markedly
suppress lipopolysaccharide-induced production of cytokines,
including TNF-α, IL-1β, IL-10, and IL-12, as well as CZP
whereas this does not occur with etanercept.
28,38
First data on the efcacy of CZP
An interesting study performed by Nesbitt et al compared the
biological effects of CZP to other anti-TNF-α agents.
28
The
different spectrum of biologic effects mediated by TNF-α has
hampered efforts to define the mechanisms of action of these
agents. Although CZP can bind to human polymorphonuclear
cells no increase in cell death or release of myeloperoxidase
was observed, possibly because of a difference in the way
in which it signals through membrane mTNF. In contrast,
the other three anti-TNF-α agents all induced both cell
death and release of myeloperoxidase. In contrast with these
biological differences between the drugs, no clinical studies
were performed to compare the clinical efficacy between
the five anti-TNF-α agents available. Actually, positive
clinical outcomes from the PRECISE study on CZP in CD
provided an opportunity to reassess available data from
infliximab, adalimumab, and etanercept clinical trials.
39,40
CZP, infliximab, and adalimumab appear to be similar in
terms of induction, maintenance of response, and remission,
as reported in the PRECiSE
40
, ACCENT I (A Crohn’s Disease
Clinical Trial Evaluating Infliximab in a New Long-term
Treatment Regimen) and CHARM (Crohn's Trial of the Fully
Human Antibody Adalimumab for Remission Maintenance)
trials.
41,42
Use of certolizumab in
inammatory arthritis: is there
a rationale in psoriatic disease?
Distribution of CZP in inamed tissues
The main feature of CZP is the distribution of the drug in
inflamed tissues due to the effect of PEGylation. This aspect
has been investigated using a noninvasive biofluorescence
labeling methodology in murine arthritis.
43
CZP, adalimumab,
and infliximab distributed more effectively into inflamed
tissue rather than noninflamed tissue. The penetration of CZP
into arthritic paws was greater compared with adalimumab
and infliximab, as was the duration of drug exposure in the
inflamed tissue. These important features, characterizing
CZP activity, may be attributed to the PEGylation and the
smaller molecular weight. Exposure to a drug at the site of
inflammation may be relevant in terms of efficacy for the
treatment of inflammatory disorders such as inflammatory
arthritis, namely RA and PsA. In this context, Palframan et al
developed an in vivo methodology, enabled to measure
antibody-type reagents in normal and inflamed tissue
by detecting the distribution of TNF-α, using a novel
noninvasive biofluorescence method.
44
This technique
indicated the ratio of penetration of CZP into inflamed
arthritic paws compared with normal tissue was greater than
that observed with adalimumab and infliximab. Furthermore,
the duration of exposure in the inflamed versus normal tissue
was more prolonged for CZP than for both adalimumab and
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infliximab, and the accumulation of CZP in diseased tissue
was more responsive to the severity of inflammation when
compared with adalimumab and infliximab. These distinct
structural features may affect efficacy, tolerability, rapidity,
and/or sustainability of effect of CZP.
45
In support of these
findings, CZP was tested in inflammatory noninfectious
diseases.
Clinical efcacy of CZP in active RA
Clinical efficacy of CZP in inflammatory arthritis – RA,
46
PsA,
47
and SpA
48
was evaluated in several clinical trials
(Table 1). However, the first clinical evidence comes from
the use of CZP in the treatment of CD.
39
Actually, in Europe,
CZP in combination with methotrexate (MTX) is indicated
for the treatment of moderate to severe active RA in adult
patients when the response to DMARDs including MTX
has been inadequate. CZP can be given as monotherapy in
case of intolerance to MTX or when continued treatment
with MTX is contraindicated.
49
The drug has been shown to
reduce the rate of progression of joint damage, as measured
by X-ray, and to improve physical function when given in
combination with MTX.
50
Moreover, CZP was associated
with a rapid, consistent clinical response in a diverse
group of RA patients, including those with prior TNF-
α-inhibitor exposure in the Dose Flex dose-comparison
trial.
51
Dose Flex was a 34-week, phase IIIb, open-label,
run-in, double-blind, placebo (PBO)-controlled randomized
study in patients with active RA on stable-dose MTX. Of
333 patients who entered the run-in, 53.5% had prior TNF-
α-inhibitor use. CZP demonstrated similar efficacy in RA
patients with or without prior exposure to TNF-α inhibitors
over 34 weeks of treatment. When CZP was withdrawn
at week 16 in American College of Rheumatology 20
(ACR20) responders, a greater maintenance of response
in patients who had not previously been exposed to TNF-α
inhibitors was observed. Moreover, a long-term safety
study of 400 mg CZP for the treatment of RA was made
with a period of observation of over 5 years.
51
Patients in
the FAST4 WARD trial
52
were monitored for safety. The
retention rates were reported up to week 280 (5.4 years) and
safety results up to week 364. Adverse events (AEs) and
serious AEs, as well as the number of serious infections,
were similar between CZP and PBO; these ndings were in
the range of those reported for anti-TNF-α. Therefore the
use of CZP 400 mg combination or monotherapy has been
confirmed to have an acceptable long-term safety profile
in line with what would be expected from an anti-TNF-α
agent.
52,53
Clinical efcacy of CZP
and quality of life in SpA
Following the excellent results observed in patients affected
by RA, as well as in patients affected by CD treated with CZP,
the drug was tested in randomized clinical trials
48,54
in SpA
patients. Axial SpA (axSpA) is a form of SpA that includes
both AS and nonradiographic axial SpA (nr-axSpA), as
defined by the Assessment of Spondyloarthritis International
Society criteria.
55
Both subgroups of patients have been
shown to have a similar burden on QoL. In particular, the
effect of CZP on signs and symptoms of AS and nr-axSpA
was evaluated in a 24-week, double-blind, randomized, PBO-
controlled phase III trial;
54
325 patients were randomized.
Baseline characteristics were similar between groups.
54
Improvements in the CZP-treated groups were observed
in pain, fatigue, Bath Ankylosing Spondylitis Functional
Index, and AS-QoL from the first measurement at week 1
through to week 24 compared to PBO. Patients in the CZP-
treated arm had greater improvements in all the parameters
studied compared to PBO. Improvements were also seen in
the Medical Outcomes Study, the Short Form (36) Health
Survey Mental Component Summary, and domains. CZP
effectively improved patient-relevant outcomes in the broad
population of axSpA patients classified using the Assessment
of Spondyloarthritis International Society criteria.
55
One of
the main characteristics of SpA is the bone marrow edema
of sacroiliac joints (SIJs) and spine, leading to chronic back
pain. axSpA
54
was the first report of the effect of CZP on
inflammation of spine and SIJs in axSpA patients, including
both AS and nr-axSpA patient populations, using magnetic
resonance imaging (MRI). Moreover, improvements in
Spondyloarthritis Research Consortium of Canada MRI,
SIJ scores, and ankylosing spondylitis spine MRI score
for activity, Berlin modifications, were observed in both
CZP-dose arms compared to PBO overall and in both
AS and nr-axSpA populations. Greater reductions in
SIJ inflammation were observed for patient subgroups
with ,5 years’ symptom duration, age , 45 years, and in
males. In this clinical trial, CZP was effective in reducing
inflammation in the SIJs and spine, as assessed by MRI
in patients with axSpA, and in both AS and nr-axSpa
populations.
54
The application of CZP in PsO
Concerning PsO, CZP at an initial dose of 400 mg fol-
lowed by 200 or 400 mg every 2 weeks was evaluated in
a randomized, PBO-controlled, double-blind study.
56
The
drug results were significantly more effective than PBO in
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the treatment of patients with moderate to severe plaque
psoriasis. Coprimary end points were $75% improvement
from baseline in the Psoriasis Area and Severity Index
(PASI 75) and a Physician’s Global Assessment (PGA) of
clear–almost clear at week 12. A 75% decrease in PASI score
was observed as early as the initial observation at week 2 in
some CZP-treated patients. Therefore, CZP was well toler-
ated in patients with moderate to severe PsO, with a low
incidence of injection-site pain or treatment discontinuation
due to AEs.
51
A retreatment extension study was conducted
in 71 CZP PASI 75 responders who relapsed during a 12-
to 24-week observation period without treatment. PASI
75 was achieved by 75%, 83%, and 47% of patients in the
CZP 200 mg, CZP 400 mg, and PBO groups, respectively
(P , 0.001 for both treatment arms vs PBO). A PGA score
of clear–almost clear was achieved by 53%, 72%, and 2%,
respectively (P , 0.001 for both treatment arms vs PBO).
In the retreatment study, median PASI scores were similar
at week 12 in the first treatment and retreatment periods
for both CZP groups. Serious AEs occurred in 3%, 5%,
and 2% of CZP 200 mg, CZP 400 mg, and PBO patients,
respectively. Treatment with CZP significantly improved
psoriasis at week 12. Similar efficacy was observed at week
12 in patients receiving retreatment for loss of response after
drug withdrawal.
56
Efcacy of CZP in PsA: rational
use in psoriatic arthritis
Clinical and experimental findings suggest that CZP has
a unique property of distribution in inamed tissues.
Moreover, in a recent paper of Shu et al, CZP was effective
in inhibiting human dermal microvascular endothelial
cell expression of angiogenic adhesion molecules and
decreased human dermal microvascular endothelial cell
angiogenic chemokine secretion.
57
At the same time, CZP
downregulated TNF-α-induced myeloid cell adhesion to
endothelial cells and blocked leukocyte–endothelial cell
adhesive interactions in RA synovial tissue, suggesting
a novel role for CZP in blocking monocyte adhesion to
inflamed synovial vasculature.
57
In this regard, PsA can be
considered as a systemic disease that involves not only skin
and joints but also such other organs as enthesis, vascular
endothelium, and adipocyte tissue. PsA synovial tissue is
typically characterized by the presence of high endothelial
venules associated with immune cell infiltrates.
16
Concerning only joint and enthesis involvement, Mease
et al experienced for the first time the clinical efficacy and
safety of CZP in PsA (RAPID-PsA).
47
Patients with active
PsA who had failed $ 1 DMARD and could have failed
# 1 anti-TNF-α were randomized PBO or CZP 400mg at
week 0, 2 and 4 followed by either 200 mg CZP or 400 mg
CZP. Patients receiving PBO who failed to achieve $10%
decrease in tender-joint count and swollen-joint count
at both weeks 14 and 16 were rescued and randomized
at week 16 to receive CZP 200 mg or CZP 400 mg.
The clinical primary end point was ACR20 response at
week 12. A total of 409 patients were randomized with
similar baseline demographic characteristics, and 20% of
patients had previously failed an anti-TNF-α treatment.
ACR20 response at week 12 was significantly higher
in both CZP arms vs PBO. The majority of the overall
response rate observed at week 24 was achieved by week
12. Response with CZP was rapid, with a greater ACR20
response as early as week 1 (7.4% for PBO vs 21.0% for
CZP 200 mg [P = 0.001] and vs 23.0% for CZP 400 mg
[P , 0.001]). At weeks 12 and 24, both CZP arms showed
significantly greater improvements than PBO in ACR50
and in ACR70. Greater improvements were also observed
for both CZP arms in PASI 75, as well as in the Health
Assessment Questionnaire Disability Index at week 24.
AEs occurred at the rates of 68% vs 62% and serious
AEs at 4% vs 7% in PBO vs CZP, respectively. The safety
profile was similar to that observed with CZP in RA.
47
The authors concluded that CZP effectively improved the
signs and symptoms of arthritis, physical function, and skin
manifestations of PsO in patients with PsA, with a safety
profile similar to RA.
53
Other clinical values, like enthesitis
and nail psoriasis, were considered in the ongoing 158-
week RAPID-PsA trial (double-blind and PBO controlled
to week 24, dose-blind to week 48, and then open-label to
week 158). In patients with enthesitis (64.3%), the Leeds
Enthesis Index change from baseline at week 24 was -2.0
with CZP 200 mg (P , 0.001) and -1.8 with CZP 400 mg
(P , 0.003) vs -1.1 PBO. For patients with baseline nail
disease (73.3%), Nail Psoriasis Severity Index change from
baseline at week 24 was -1.6 with CZP 200 mg and -2.0
with CZP 400 mg vs -1.1 PBO. No differences in Leeds
Dactylitis Index change from baseline were observed in
patients with baseline dactylitis.
58
Efcacy of CZP in radiographic
progression in PsA
Furthermore, the efficacy of CZP was also evaluated in
radiographic progression in PsA patients. Gladman and
colleagues performed a 24-week patient-reported outcome,
phase III, double-blind, randomized, PBO-controlled study.
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Prole of certolizumab in the treatment of psoriatic arthritis
Drug Design, Development and Therapy 2013:7
Effect of CZP on the multiple facets of PsA included an
analysis of changes from baseline of modified Total Sharp
Score. CZP was efficacious in inhibiting radiographic
progression compared to PBO. Conventional radiographic
imputation methods showed that CZP effectively inhibited
radiographic progression in PsA patients. Significantly
fewer patients had progression with either CZP dose
compared to PBO. CZP was shown to be effective also in
improvements in productivity at paid work and within the
household, and increased participation in daily activities in
patients with PsA.
56
Compared to the other anti-TNF agents,
CZP is characterized by a different mechanism of action,
possibly due to both structure and signal transduction.
These features could be related to exact epitopes to which
the anti-TNF agents bound the anti-TNF.
Conclusion
Psoriatic arthritis should be rather considered as a systemic
disease but the major clinical characteristics are involvement
of joints, enthesis and skin.
1
Pathogenetic and clinical
evidence suggests the role of a complex interplay between
chronic inflammatory processes and bone remodeling.
14
Clinical guidelines and consensus statements on anti-TNF-α
treatment are under constant revision, as data from long-
term studies are becoming continuously available. CZP is
effective and safe for the treatment of such inflammatory
diseases as CD38, RA46, AS, SpA48 and PsO56 and has
been evaluated for the treatment of PsA47, with various
interesting results. Moreover, the properties of the drug have
several advantages for a rapid remission of the diseases.
Subcutaneous administration confers good compliance in
treated patients for procedures and time of administration.
Furthermore, considering PsA as a systemic disease, with
major involvement of both skin and joints, clinical trials
demonstrated that CZP is efficacious in PsO, PsA, and
SpA, as well as in radiographic progression.
54,59
Moreover,
CZP treatment should be taken into consideration not only
in patients unresponsive to synthetic DMARDs but also in
those patients who have failed to respond to previous anti-
TNF-α treatments, as has been demonstrated in several
clinical trials.
51,52
Acknowledgments
We would like to thank the rheumatology and dermatology
unit health professionals of the University of Rome Tor
Vergata. We gratefully acknowledge Dr Simone Emanuele
Auteri, UCB Pharma, for scientific support in manuscript
preparation.
Disclosure
The authors report no conflicts of interest in this work.
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Table 1 Clinical indications of certolizumab pegol
Present indications Futures indications
Europe (EMA) RA CD, PsO, PsA and SpA
Swiss RA, CD PsO, PsA and SpA
Russia RA, CD PsO, PsA and SpA
USA
Canada
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RA, CD
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Chile, Mexico
Argentina
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Australia RA CD, PsO, PsA and SpA
Asia RA CD, PsO, PsA and SpA
Japan RA
Notes: Cetolizumab pegol was approved for the treatment of rheumatoid arthritis
in the EU, US and Canada in 2009, and for the treatment of Crohn's Disease in
Switzerland in 2007 and in the USA in 2008. Certolizumab pegol is entering into an
increasingly competitive marketplace, especially in rheumatoid arthritis, but clinical
data demonstrate benets across a range of other inammatory disease.
Abbreviations: EMA, European Medicines Agency; RA, Rheumatoid Arthritis); CD,
Crohn's disease; PsO, Psoriasis; PsA, Psoriatic Arthritis; SpA Spondyloarthritis.
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    • "Certolizumab pegol is a polyethylene glycolylated Fab′ fragment of a humanised monoclonal antibody, the polyethylene glycol moiety markedly increasing the halflife of the drug. In contrast to other TNFi agents, certolizumab pegol did not mediate increased levels of apoptosis, suggesting that these mechanisms are not essential for the TNFi effect [42]. "
    [Show abstract] [Hide abstract] ABSTRACT: Psoriatic arthritis (PsA) is the second most common inflammatory arthropathy, after rheumatoid arthritis diagnosis, in early arthritis clinics. Most patients have established psoriasis, often for years, prior to the onset of joint pain and swelling; in addition, associated features of nail disease, dactylitis, enthesitis, spondylitis or uveitis may be present. Psoriasis may not be immediately apparent, as small or patchy lesions may occur in the scalp or perineum. PsA presents as a symmetrical polyarthritis, similar to rheumatoid arthritis, or an asymmetrical oligoarthritis with a predilection for the distal interphalangeal joints. Spinal involvement is similar, although not identical, to ankylosing spondylitis. Joint damage occurs early; up to 50% of PsA patients have an 11% annual erosion rate in the first 2 years of disease duration, suggesting it is not a benign condition. There have been significant advances in our understanding of PsA pathogenesis in recent years, in the areas of genetics and molecular biology, implicating both the innate and the adaptive immune systems. This has lead to the introduction of evidence-based targeted therapy, primarily with tumour necrosis factor inhibitor (TNFi) agents. Therapy with disease-modifying anti-rheumatic drugs, such as methotrexate and leflunomide, remains the first-choice therapeutic intervention, even though there are few randomised controlled trials with these agents. In contrast, a number of successful studies of TNFi agents demonstrate excellent efficacy, in combination with methotrexate, and several novel agents are currently in development for the treatment of PsA.
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  • [Show abstract] [Hide abstract] ABSTRACT: Tumour necrosis factor (TNF) plays an important role in the pathogenesis of immune-mediated inflammatory diseases (IMIDs). TNF inhibition results in down-regulation of abnormal and progressive inflammatory processes, resulting in rapid and sustained clinical remission, improved quality of life and prevention of target organ damage. Adalimumab is the first fully human monoclonal antibody directed against TNF. In this article, we review the role and cost effectiveness of adalimumab in the treatment of IMIDs in adults and children. The efficacy and tolerability of adalimumab has been demonstrated in patients with a wide range of inflammatory conditions, leading to regulatory approval in rheumatoid arthritis (RA), psoriatic arthritis (PsA), plaque psoriasis, inflammatory bowel diseases (Crohn's disease, ulcerative colitis, paediatric Crohn's disease, and intestinal Behçet's disease), ankylosing spondylitis (AS), axial spondyloarthritis (SpA) and juvenile idiopathic arthritis. The major tolerability issues with adalimumab are class effects, such as injection site reactions and increased risk of infection and lymphoma. As with all anti-TNF agents, adalimumab is immunogenic, although less than infliximab, and some patients receiving long-term adalimumab will develop anti-drug antibodies, causing a loss of response. Comparisons of its clinical utility and cost effectiveness have shown it to be a valid treatment choice in a wide range of patients. Recent data from Italian economic studies show the cost effectiveness of adalimumab to be below the threshold value for health care interventions for most indications. In addition, analysis of indirect costs shows that adalimumab significantly reduces social costs associated with RA, PsA, AS, Crohn's disease and psoriasis. The fact that adalimumab has the widest range of approved indications, many often presenting together in the same patient due to the common pathogenesis, may further improve the utility of adalimumab. Current clinical evidence shows adalimumab to be a valuable resource in the management of IMIDs. Further research, designed to identify patients who may benefit most from this drug, will better highlight the role and cost-effectiveness of this versatile TNF inhibitor.
    Full-text · Article · Nov 2013
  • [Show abstract] [Hide abstract] ABSTRACT: It has been proven that tumor necrosis factor (TNF) plays an important role in the pathophysiology of psoriatic arthritis (PsA). TNF inhibitors have been demonstrated to improve the skin and joint manifestations of psoriasis. New possibilities of treatment of the disease have appeared due to availability of biological drugs which are TNF inhibitors. Among the first TNF inhibitors that have been used to treat PsA were etanercept, adalimumab, infliksymab. Due to primary and secondary ineffectiveness of the therapy occurring in large numbers of PsA patients investigations are going on in order to develop new, more effective, safer and more convenient methods to treat PsA. Such a new therapeutic possibility is offered by the new generation TNF inhibitor with a molecular structure different from other TNF inhibitors - certolizumab pegol (CZP). In this article the results of clinical studies concerning the application of CZP in PsA treatment are presented.
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