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Skin Conditions And The Pharmaceutical Industry
PSORIASIS – disease mechanisms and current
therapy
Of the three disorders discussed in this booklet,
psoriasis has seen the most rapid increase in our
understanding and advances towards new medicines.
Disease mechanisms in psoriasis: Psoriasis is characterised
by an abnormally rapid rate of cell division
in the skin and the proliferation of small blood
vessels. It also has many of the features of an autoimmune
disease – that is, a disease in which our immune
system turns on the body’s own tissue and attacks
it. The accumulation of clusters of white immune
cells (lymphocytes) in the dermis is typical of such
conditions.
But how does this cause disease? Perhaps the
best way to visualise these interactions is
to draw an analogy with a mechanical clock. The
outer surface (or dial) belies the complexity
of what is going on inside. Take off the cover
and at once you are confronted with a mass
of springs, axles, cog wheels and balance wheels.
Every part has to be in the correct position
and functioning in order to tell the time.
To prevent a clock telling the time, you could do
many things – remove the hands while leaving
the mechanism running, or block the mechanism by
jamming up any one of the many components.
The surface of psoriatic skin is like the dial – simply
the end result of a very complex chain of events.
Look inside, and you find a bewildering mixture of
cells and chemicals all playing a role in perpetuating
the disease. Many of these will be communicating
with each other either by direct contact through
receptors on their surface – in the way that
the cog wheels of a clock interact – or by
the release of chemical signals called cytokines.
There are many cytokines with names such as tumour
necrosis factor, interleukins, interferons, and growth
factors. These can trigger cell multiplication, abnormal
development and inflammation. To understand psoriasis,
scientists have had to separate out each of these
components and find out what they are doing. It then
becomes possible to devise medicines that will ‘jam
up’ the works and turn off the disease process.
Many of the recent experimental medicines and where
they act are shown in the figure overleaf, but the
purpose of this diagram is to convey the great complexity
of psoriasis, rather than present exact scientific
accuracy.
Current medicines for psoriasis: It is important
to note that psoriasis is a very variable
condition in terms of the severity, the
body area affected and the appearance of the lesions.
For that reason, this account can do no
more than give a general indication of some of
the treatments available. In any case,
treatment should be tailored to the needs of the
individual taking account of the disease profile
as well as their age and social background.
It is usual to commence treatment by prescribing
topical agents – treatments applied directly to the
area concerned.
• Early topical treatments: Coal tar products
have been used for 100 years or more and seem to
work by stopping the synthesis of DNA in cells and
thus cell division. The treatment is messy and smells,
and today it only has a small place in psoriasis.
Coal tar preparations are also available as creams
and ointments for outpatient use once the acute phase
is over.
Dithranol (anthralin) has also been in
use since the early years of the twentieth
century and also seems to work by blocking
cell division. A full regime is tedious
to follow, because dithranol is irritant
to normal skin, so areas around treated
lesions have to be protected by a bland
ointment. It also stains nearly everything
it contacts a purple-brown colour.
It cannot be used on the face or genital
areas. A short-contact regime (30 minutes
each day) is more acceptable for home
use in patients with stable plaque
psoriasis and can greatly reduce the severity and
improve the appearance of lesions.
HOW MEDICINES ARE LICENSED
- Initial
research on new compounds is carried
out in the laboratory,
- using a wide variety of techniques.
- Promising
compounds are then studied in animals,
to investigate effects that currently cannot
be predicted from computer and test tube
studies.
- A sequence of phases of clinical assessment
in humans follows strict guidelines:
• Phase 1: a small number of healthy volunteers
is given the compound.
These trials will determine some aspects
of how it works in humans and help to
establish the dose required.
• Phase 2: a small number of patients with the
condition are given the medicine
to assess both that it works and that
it does not produce unacceptable
side effects.
• Phase 3: many more patients, perhaps several
thousand, take the medicine
under appropriate supervision for an
appropriate period. It is tested in
comparison with an established compound
and/or a placebo. These studies
are used to establish the efficacy of
the new medicine. If the results prove satisfactory
in terms of quality, efficacy and safety,
the data gathered are presented to the
medicines evaluation authorities. If the evidence satisfies
the authorities, a marketing authorisation
is issued.
• Phase 4: the newly-licensed medicine is studied
in large numbers of patients in general
practice to assess its clinical effectiveness.
- SAMM (Safety Assessment of Marketed Medicines) studies
are sometimes initiated
after the medicine has been made available
for doctors to prescribe and to help
identify any unforeseen side-effects. These
may involve many thousands of patients.
- GP databases are also used to identify medicine safety issues
and to explore the potential for new and better
uses of medicines once the product is available
for prescription.
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•Topical corticosteroids: Topical
steroids are often the first line of treatment in
psoriasis. They are easy to use, clean and non-irritant.
However, they do have some side effects and can cause
skin thinning with prolonged use. There are many
steroid-based products on the market ranging in potency
from ‘mild’,
to ‘very potent’. Some are combinations
with antimicrobial agents for use on infected lesions.
They come in many forms such as creams, gels, foams,
lotions, ointments, and solutions. The choice of
product will be made by the doctor and will depend
on the severity of the lesions and their location
(e.g., scalp, face,
skin folds).
Many people may find their lesions are controlled
with a mild or moderate steroid such as hydrocortisone,
while others may require the use of a very
potent steroid such as clobetasol (GlaxoSmithKline).
Sometimes low concentrations of a steroid may be
injected directly into lesions if they are well defined
and isolated. Occasionally, steroids cause worsening
of psoriasis, especially if applied excessively or
on stopping treatment, and their use should be monitored
carefully.
There is almost no use of steroids as systemic
treatments in psoriasis, except in emergency
acute situations when they may be combined
with methotrexate. When used in this mode,
the patient must be weaned from the compound
slowly or life-threatening flare-up can occur.
• Topical medicines related to Vitamin D: Vitamin
D has to be converted into a related molecule called
an active metabolite before it is active in the
human body. Once converted, however, it has many actions,
including the regulation of keratinocyte growth
and maturation, and immune stimulation. Unfortunately,
the use of the active metabolite itself in psoriasis
is limited, because it also causes an increased
level of calcium in the body with potentially serious
effects. In order to avoid these unwanted effects,
chemists have made more than 1,500 similar compounds
to try to find one which retains the useful actions
but lacks the ability to cause calcium accumulation.
Several with improved properties have been identified,
but can still only be used externally as creams for
topical application.
One of these, calcipotriol (Leo) is available
alone and combined with a steroid for the treatment
of stable plaque psoriasis. A second is tacalcitol,
(Crookes), while the most recent addition
is calcitriol (Galderma) for mild to moderate
plaque psoriasis. All of these agents are effective,
but there are small differences in their irritancy.
It is also possible to use them together with
another topical or systemic medicine or UV
therapy, with generally improved response rates.
For example, calcitriol alternated with a topical
steroid morning to evening gave better results. Similarly,
calcipotriol used either with systemic cyclosporin
or systemic retinoids was superior than the
products used alone, while calcitriol can potentiate
the action of UV light. In each case, the vitamin
D derivative was able to reduce the amount
of steroid, retinoid, immunosuppressive or UV light
needed, thus reducing the risk
of toxicity.
• Topical retinoids: Until recently, all the retinoids
had to be given systemically, but in 1997 the first
topical vitamin A derivative (tazarotene, Allergan)
reached the UK market. This new medicine is available
as a gel for once daily application and has proved
especially favourable for elbow and knee lesions that
are usually difficult to treat. Like dithranol, it
can irritate normal skin but, provided it is applied
only to lesions and allowed to dry, then surrounding
skin does not need protecting or the plaques covering.
The technique of application and the amounts to be
used need to be discussed on an individual basis and
will depend on the sensitivity of the individual’s
skin. Trials have also shown that further improvements
can be obtained if tazarotene and a topical steroid
are used daily but at different times, or on alternating
days. A similar enhancement of effect has also
been shown with tazarotene (once a day) and one
of the Vitamin D medicines (twice a day), and tazarotene
can reduce the dose of ultraviolet light needed
in UVB treatment by 30 to 50 per cent.
• Oral retinoids and immunosuppressives: Etretinate
was first shown to be active against
psoriasis in 1975, but was phased out when it was
shown that it was converted in the body to another
active compound, acitretin (Roche). Used alone, acitretin
can improve severe psoriasis in 75 per cent of patients,
30 per cent achieving complete clearance. However,
it is generally most effective when combined with
topical steroids, dithranol, or psoralen-UVA (PUVA)
treatment – in the latter,
reducing the number of treatments necessary.
It has a special role in plantar and pustular forms
of psoriasis, where it is the treatment
of first choice.
Three immunosuppressive medicines are
used in severe, refractory psoriasis:
methotrexate (Pfizer), cyclosporin
(Novartis) and hydroxyurea. All three
have to be used with caution due
to their
potential toxicity. Methotrexate
has a place in severe, resistant psoriasis,
cyclosporin and hydroxyurea in severe
plaque psoriasis. Cyclosporin seems
to act by preventing T-cell
activation and the production of
interleukin-2 (IL-2) – another gear wheel in
the mechanism of psoriasis. It is used mainly to
get severely ill patients into remission,
after which treatment is switched
to better tolerated medicines.
• Systemic monoclonals and fusion
proteins (biologicals): Alefacept
(Biogen Idec) is the pioneer of a new class of
immunomodulatory medicines and represents a major
breakthrough in medical and immunological
terms. A fusion product of two
human proteins, it was approved
in the USA for moderate-to-severe
plaque psoriasis in patients
suitable for systemic therapy
or phototherapy in January 2003.
It appears to work in two ways.
Firstly, it blocks CD2 receptors
on overactive T-cells. This leads
to a rebalancing of T-cell numbers
away from those that are messengers
of the disease process, thus
confirming the importance of
T-cells in psoriasis. Secondly,
it induces the programmed death
of immature keratinocytes. Both
these actions appear to contribute
to the activity and clinical
improvements observed.
In 2002, another biological, etanercept (Wyeth),
was approved for psoriatic arthritis, an indication
for which it is also available in the UK. This is
also a fusion product of two human proteins. Following
favourable clinical trials, the US company applied
for authorisation for moderate-to-severe plaque psoriasis.
Etanercept works differently to alefacept because
it is a soluble TNF receptor binding to excess TNF,
thus neutralising its activity. When produced in
excess or in the wrong place, as in psoriasis, TNF
can be highly destructive. Any compound that interferes
with the action of TNF has to be used with caution,
because this cytokine has a protective action in
the body against tumours and some types of infection
such as TB. However, no increase in the incidence
of malignancies has been seen in patients treated
with etanercept to date. Etanercept also neutralises
TNF-b, but the clinical role of this action is not
clear.
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