Differential effect of adalumimab versus etanercept on apoptosis in the psoriatic skin

Differential effect of adalumimab versus etanercept on apoptosis in the
psoriatic skin

Psoriatic arthritis (PsA) is an auto inflammatory disease characterized by
inflammation of both skin and joints. The most common form of psoriasis is
plaque psoriasis. Although psoriasis is characterized by thickening of the
epidermis, the immune system has a prominent role in the development of the
disease. Psoriatic skin is characterized by hyperproliferation of keratinocytes
which is regulated by cell proliferation, cell influx and programmed cell death
/ apoptosis(1). T-cells and macrophages are also present in the inflamed skin.
Keratinocytes, dendritic cells, T-cells as well as macrophages in skin all can
produce TNF-α. TNF-α is found at particular high concentrations in the skin
lesions and plasma of patients with psoriasis(2-4).
TNF-α is a multifunctional cytokine belonging to the TNF-superfamily of ligands
and receptors. TNF-α can induce a proliferative response characterized by cell
growth and differentiation, but can also induce programmed cell death and
apoptosis or cellular necroses. Which effect dominates depends on celltype, the
TNF receptor involved (receptor 1 and/or 2), and the subsequently activated
intracellular signaltransductionroutes(5).
In vitro studies showed that TNF-α stimulates keratinocyt proliferation.
Binding of TNF-α with it*s receptor leads to further keratinocyt proliferation
and induction of syntheses of pro-inflammatory cytokines like IL-6 en IL-8
and induces the up regulation of adhesionmolecules, with subsequent T-cell
migration to the skin. For this migration the T-cell needs interation
respectively between; CLA (cutaneous lymphocyte antigen) and E-selectine,
chemokines and their chemokine receptor, and LFA-1 (leukocyte function
associated antigen-1) and intercellular adhesionmolecule-1 (ICAM-1) on the
dermal postcapillary venules (1).

Besides this important role for TNF-α in cellular activation and induction of
adhesion molecules, TNF-α also is an important inducer of apoptosis(6).
Apoptosis or programmed cell death is a natural process which is essential for
the homeostasis of the human body. During apoptosis all kind of intracellular
changes take place characterized by blebbing of the cell membrane and changes
in the colour and shape of the nucleus. Apoptosis of the cell is followed by a
fast receptor mediated phagocytosis of tissue macrophages.
Inhibition of this process leads to an increase in the number and longevity of
keratinocytes as seen in psoriatic arthritis. In the psoriatic skin an
aberrant expression has been found of molecules involved in the apoptotic
process. The present markers suggest a suppression of the apoptotic
process(7;8). Bcl-2 and associated proteins such as Bax en Bcl-xl, modulate the
apoptotic process (6) . Bcl-2 is anti-apoptotic and Bax is pro-apoptotic. In
the psoriatic skin an increase has been found of the anti-apoptotic (9)It has
been shown that inhibition of TNF-α has an excellent effect on skin lesions in
PsA. Patients with severe psoriasis of the skin are almost fully
cured(10-12).The exact mechanisms involved are at present unclear. One study
showed that, the degree of apoptosis in the skin of patients with PsA before
and after treatment with infliximab (TNF-α blocking antibody) did not change.
As expected there was almost no apoptosis before treatment, and also, which was
unexpected 48 hours after treatment(13). This in sharp contrast with studies
done in Crohn*s disease in which large amounts of apoptotic T-lymphocytes can
be found 24 hours after treatment with infliximab(9). One of the explanations
for the differences found, between the two studies, could be that the skin
biopsies in the first study were taken 48 hours after start of treatment. This
could be to late to study apoptosis. In a recent study done in rheumatoid
arthritis (RA) both infliximab as well as etanercept (soluble TNF receptor
fusion protein) induced apoptosis of macrophages but, not of T-cells(14).
Apoptosis was seen in cultured monocytes 24 hours after treatment and in
synovial biopsies taken from involved joints up to 8 weeks after treatment.
This in contrast to the findings in Crohn*s disease in which infliximab induces
no apoptosis of monocytes / macrophages only of T-cells(15;16). Several reports
indicated that adalumimab (a fully human monoclonal directed against TNF-α) is
superior to etanercept with respect to the skin lesions as seen in PsA(17;18).
The exact pathogenesis involved has not been studied so far.

We hypothesized that one of the key mechanisms explaining the differences in
effect between adalumimab and etanercept on psoriatic skin is that adalumimab,
by being a monoclonal antibody like infliximab, is a better inducer of
apoptosis resulting in a better effect on skin lesions in PsA.

Patients having active PsA with skin lesions despite treatment with etanercept
and methotrexate, and no contraindications for TNF blockers, are eligible for
the present study. PASI scores and DAS scores will be performed before and
after therapy at 4 different time points.
Patients will be followed for three months, during the study, and continue on
TNF blocking therapy when indicated after the study is finished.
Skin biopsies will be taken before and shortly after (2 biopsies) the start of
adalumimab and processed for immune histochemistry. The biopsies will be
stained with markers for different cell types (T-cells, macrophages,
keratinocytes and dendritic cells) and markers for apoptosis (caspase 3) .
Cellular infiltrates and apoptotic cells will be scored on a numeric scale.

Nature and extent of the burden and risks associated with participation,
benefit and group relatedness.

The burden for the patient exists of three skin biopsies, extra control visits
and the extra blood samples during regular blood sampling. There will be no
direct benefit for the patient during the study. We hope that gaining insight
in the mechanisms involved in psoriatic arthritis skin disease will help
defining new effective treatment strategies.