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Skin Conditions And The Pharmaceutical Industry
Eczema – disease
mechanisms and current
therapy
Disease mechanisms in eczema: We have already seen
how the common forms of eczema may arise through
external or internal mechanisms. The former (often
called contact eczema or contact dermatitis) has
been intensively studied for over 80 years. It occurs
as a reaction to an external irritant or allergen,
especially if the skin has been damaged by soaps,
detergents or just excess water.
In skin biopsies of contact dermatitis, blood vessels
in the dermis are seen to be enlarged, the tissue
is spongy due to excess fluid, and clusters of
inflammatory cells are present. It is known that
these release chemicals that stimulate the nerve
endings and cause itch. Fluid ‘blebs’ from the dermis move
up into the epidermis, thus weakening the structure
and causing it to swell, separate, develop a flaky
appearance, weep and crust. Epidermal cells themselves
begin to divide more rapidly. If such changes persist
for a long period, the condition can become chronic
with thickening, cracking and scaling.
But how and why do these changes occur? We now
know that contact dermatitis is not just a skin
complaint, but involves the whole immune system
- lymph nodes and a multitude of white cells
based in the blood and tissues.
It is now clear that the disease develops in
several stages (see page 22), namely:
- an irritant or allergen enters damaged skin
and encounters Langerhans cells, which
are found scattered within the epidermis.
- these take up the antigen and then migrate
back to lymph nodes where they pass on the ‘message’ to
T-lymphocytes (CD4+ and CD8+ cells).
- these T-cells then multiply, circulate round
the body and then begin to accumulate
at the site of the reaction.
- if the antigen is still present, the T-cells
are activated and respond by
releasing a variety of inflammatory molecules including
the interleukins IL-1a, IL-8, IL-10, and
IL-13, as well as growth factors, interferon-gamma
(IFN- γ), and tumour necrosis factor-alpha (TNF-α).
- these factors recruit yet more cells or cause
direct tissue damage.
Interleukins IL-2, IL-4 and IL-15 have
been implicated in the activation
stage and proliferation of the T-lymphocytes.
This ‘soup’ of mediators
results in fluid leakage from small blood vessels
in the skin (hence swelling and blistering), inflammation,
redness and pain. Unless this cycle can be broken,
the eruptions can become chronic.
A similar, though not identical,
scheme can explain the response
to metals or irritants. Irritants
may cause a structural change to
living skin cells or, as in the
case of some metals, can bind tightly
to keratin. The modified cells
are ‘seen’ by
the body’s immune system as foreign – not
unlike the situation with an allergen – and
an immune response is mounted. Unfortunately in this
case, the immune system has memory T-cells, so if
the irritant is encountered again, there will be
a flare-up with the risk of development of a chronic
state. Hence the importance of eliminating the cause
if it can be identified.
Atopic eczema is still something
of an enigma, because the picture
seen in the skin is very similar
to contact dermatitis, but without
obvious exposure to antigens or
irritants. Evidence has accumulated,
however, that many everyday materials
or events can act as a trigger.
Examples are moisture (saliva and
milk), overheating, house dust,
mites, wool or scratchy fabric,
skin scales from pets, cigarette
smoke, traces of detergent on washed
clothes, and soap. Occasionally,
food allergy may be the root cause
and the eczema of some individuals
may be worsened by cows’ milk,
egg white, tomatoes, oranges and lemons, chocolate
and nuts. No doubt the immune system is involved
here also. This is demonstrated by the efficacy of
steroids which have immunomodulating action and also
the recent introduction of non-steroidal immunomodulators
such as tacrolimus and pimecrolimus.
Current medicines for eczema: There
is a general similarity in the
treatment of the commonest types
of eczema, which is likely to consist
of one or more of the following:
• Emollients – Creams, lotions, ointments
or gels which help keep the skin moist and supple and
reduce inflammation. These should be used as often
as possible in washing, bathing and showering, or be
applied directly if the eczema is sore. Help in selecting
the right preparation can be obtained from the National
Eczema Society. For example, an ointment will be better
for dry and thickened skin, while a lotion will spread
more easily in the hair. A soap substitute should be
used, as this is much less drying.
Such preparations are often underestimated
as their regular use is often enough
to keep mild to moderate eczema
under control. A study in 1999
showed an 89 per cent reduction
in the severity of atopic eczema
in children when emollients were
used correctly.
• Topical corticosteroids – There
are many of these available, with weak, moderate
or potent action. The choice will depend on the site
of the eczema, whether the condition is acute or
chronic, and on its severity at any particular time.
They have a role in both contact eczema and atopic
eczema. The aim will be to bring the skin reaction
under control as soon as possible. Once this is achieved,
the use of emollients will be preferred.
• Antibacterials and antibiotics – Sometimes
(e.g. seborrhoeic eczema where pityrosporum yeast may
be involved, or in secondary infections) steroids may
be combined with antibacterials or anti-fungal medicines.
Antibiotics often prescribed are flucloxacillin, fusidic
acid (Leo) and erythromycin. Fusidic acid is available
alone and in combination with a steroid in various
forms (creams, ointments, solutions) to suit particular
body sites and needs. For yeast infection, ketoconazole
is often used as either a cream or shampoo.
• Agents to combat pruritus (itch) – Breaking
the itch-scratch cycle is very important in eczema.
Physical measures like cutting finger nails and bandaging
can be used, but sometimes topical creams such as crotamiton
(Novartis) or systemic antihistamines may be necessary.
The treatment of some less common
forms of eczema (seborrhoeic, discoid,
varicose, asteototic, etc) often
draws upon specific nursing or
management techniques. The above
medicines may be used in some situations
or specific remedies such as potassium
permanganate, tar bandages and
emollients may be applied. These
are beyond the scope of this booklet,
but leaflets are available from
the National Eczema Society.
• Immunomodulating medicines – Recently,
two new non-steroidal immunomodulating medicines have
become available for eczema, tacrolimus (Fujisawa)
and pimecrolimus (Novartis). These represent the first
truly new medicines to be introduced for many decades.
The first, tacrolimus, has been
used for a few years as an oral
and intravenous medicine to prevent
tissue transplant rejection. Studies
showed that it was able to block
the effects of T-cell activation
and reduce the production of cytokines.
It was also active when applied
to the skin. It was made available
in the USA in 2000 for atopic dermatitis
in people for whom other treatments
had failed or were inappropriate.
In 2002, studies were presented
that showed that tacrolimus ointment
is equal or similar in its effect
to topical steroids. It is not
a cure, but provides another option
for people with moderate-to-severe
disease. Improvements of 90 per
cent were normal with extended
treatment.
Pimecrolimus was made available
in March 2003. It was developed
specifically for the skin and can
be used in mild to moderate atopic
eczema. It is suitable for children
over two years old and in adults
and is especially useful in sensitive
skin areas such as the face and
neck. It also works by preventing
the activation of T-cells, thus
reducing the release of inflammatory
cytokines that cause inflammation,
redness and itch.
In view of the novelty of tacrolimus
and pimecrolimus, the NHS has been
cautious in its recommendation
of these medicines. Experience
with them is still limited, they
are very costly compared to steroids,
and their long-term toxicity is
not known. The government’s
National Institute for Clinical Excellence (NICE)
is expected to publish a review in September 2004.
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