Download Autoimmune and inflammatory disorders

AUTOIMMUNE/PG/AM/CC
15/12/2008
MODULE 1:
16:34
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Autoimmune diseases
PART 1
Autoimmune
and
inflammatory
disorders
Conor Caffrey
MANY of the most common chronic illnesses are autoimmune or
inflammatory disorders. Both autoimmune diseases and inflammatory disorders are characterised by an uncontrolled and
increased immune response, which can be either systemic or
locally specific to one organ.They are differentiated by the fact that
in autoimmune diseases the body elicits a hyperimmune response
specifically to the body’s own antigens. Another difference is that
auto-antibodies are produced in autoimmune diseases.
Diseases as diverse as type 1 diabetes, rheumatoid arthritis
(RA), and lupus are all thought to have some underlying defect
that leads to an unregulated immune response and attack of selfantigens, cells or tissues. Other inflammatory conditions, such as
multiple sclerosis, Crohn’s disease (CD), and ulcerative colitis (UC)
may also have an autoimmune component to their aetiology, but
it has not yet been definitively proven, as either they don’t produce auto-antibodies or no definitive antigen central to the
disease process has been identified.
In the vast majority of cases, although the underlying clinical
consequences are devastating and clearly evident, the trigger of
this group of diseases remains to be elucidated and often either
remains hidden or is difficult to pinpoint. In some cases, such as
when an amoebic infection triggers a later bout of UC type disease,
a specific infectious cause may be a major suspect as a trigger.
The symptoms of autoimmune or inflammatory diseases may
be consistent or they may come and go as the disease relapses
and remits. As with the initial trigger of disease there are plenty of
potential candidates for triggers of relapses, including various
infections, but none have been proven as definitive causes.
Natural immune processes are extremely complex and the critical component is that they have evolved in balance.The immune
system needs to be proactive in its response to infection and foreign antigens that could potentially harm the body. The immune
system also needs to protect the body by attacking cancer cells.
On the other hand, it needs to dampen down attack so that our
own cells and tissues are not damaged when it responds in ‘attack
to kill’ mode. As our body is habitually exposed to vast quantities
of foreign bodies, such as food antigens, bacteria, viruses and
other microbes that may not necessarily harm us, it is important
that the immune system is kept in check and regulated.
We have evolved efficient and complex mechanisms involving
inflammatory mediators called cytokines and special regulatory
cells called T-cells to ensure our immune system is kept in balance. Regulatory pathways are turned on or off in the local
environment by specific critical cytokines.This balance goes awry
and the wrong pathways are switched on and off when damaging inflammatory and autoimmune processes occur.
So in an inflammatory or autoimmune disease the production
and release of cytokines induces certain biochemical pathways,
which may lead to a response that triggers disease. For example,
TNF alpha (TNF-A) is known to be an extremely important
cytokine in a number of diverse inflammatory diseases such as
RA, IBD disease and psoriasis. TNF-A switches on certain regulatory pathways in the normal immune response. Abnormal levels
of TNF-A may switch on abnormal responses leading to inflammation and perhaps autoimmunity in some cases when it acts in
concert with certain other risk factors. Other pro-inflammatory
cytokines, such as IL-17, may be involved. Anti-inflammatory
cytokines such as IL-10 help dampen the immune response in
normal circumstances, so if there is a deficit of this cytokine it may
have a deleterious effect and lead to the imbalance of disease.
Genetic factors
It is not known why individual cytokines are increased or
decreased in autoimmune disorders. For example in RA patients
various genetic factors may lead to a predisposition for higher
TNF-A release in the joint tissues. There may be an inherent predisposition to some sort of inflammatory condition, but some
environmental impact or exposure, most likely some sort of infection, is crucial to the triggering of disease.
Many inflammatory mediated syndromes seem to represent clusters of disease with a wide spectrum of possible symptoms or
severity. This is particularly evident in IBD where CD and UC,
although similar in some aspects of the clinical presentations, may
be very different in terms of the drivers of the inflammatory
processes involved.NOD2 for example is associated with CD but not
UC. But this association is not present in all CD patients and it may
only play a role in a subset of patients. It is likely to be just one of a
number of genetic and environmental factors involved that are not
necessarily essential to the overall process but perhaps potentiate it.
The treatment of autoimmune disorders has been fraught with
the complexity of the symptoms seen in individual patients and
the fact that they relapse and remit. Early in disease symptoms
may be mild or virtually absent. In contrast there may be multiple serious and debilitating symptoms in more severe
intransigent disease so it is hard to know exactly what to treat.
In general,the traditional approach has been to palliate symptoms,
to induce periods of remission and dampen the immune response
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Continuing Education
Biologic treatments
component of inflammatory and autoimmune diseases using
anti-inflammatory agents, such as steroids, NSAIDs and other more
powerful drugs such as cyclophosphamide, methotrexate and AZT.
These agents tend to be non-specific and thus may cause a range
of side-effects and thus raise compliance issues.
Recently more specific therapies have emerged. The development of these drugs was spurred by the finding that there are a
small number of dominant cytokines that are central to the immune
processes of specific inflammatory and autoimmune diseases.In particular, the development of anti-TNF treatments has revolutionised
the approach to treatment.
Currently anti-TNF-alpha drugs are the most effective treatments available for dampening down the unregulated immune
response in a number of conditions with a major inflammatory
component. The effectiveness of these agents has led to the
investigation into the potential therapeutic use of a whole spate
of inflammatory cytokine mediators that are currently undergoing clinical development. These new cytokine therapies may
complement the anti TNFs and be used in combination with other
non specific agents.
New biologics
Anti-TNF alphas belong to a new class of drugs called biologics.
They are in a sense novel medicines in that they are not chemical
drugs synthesised in a laboratory and are derived from living
sources. Treatment with biological medicines, however, is not a
new concept, as vaccines, blood replacement products and insulin
are all well established medicines.
The term ‘new biologics’ is different in that it refers to medicines
generated through biotechnological techniques, such as DNA
manipulation and cell culture. The use of biologics is still in its
infancy, but the available treatments have had a profound impact,
particularly in oncology and in chronic inflammatory conditions
such as RA. Currently there are three different types of new biologic drug treatments that are being used: biosimilars, receptor
proteins, and monoclonal antibodies.
Biosimilars are homologous to natural substances in our body
and used to treat conditions where these substances are missing,
depleted or defective or, perhaps through increasing their concentration, they can positively impact symptoms of disease. Some
insulins used to treat diabetics are biosimilars. Other examples
include the immunomodulator inteferons and interleukins, the
blood production protein Epoetin and growth hormone.
Receptor proteins are special proteins that bind molecules with a
specific function and take them out of action or inhibit them from
functioning. Enbrel and Amevive are examples of these.
Monoclonal antibodies harness innate immune mechanisms
and these biologics have shown great clinical potential already. A
monoclonal is a clone of one type of antibody to a specific body
substance and binding to it stops its function. The big advantage
of monoclonals is that they are highly specific and targeted thus
minimising the side-effects of the more systemic acting drugs.
Cancer
Biologics have major applications in cancer. Interleukins, interferons and colony stimulating factors, such as Epogen, have all
been used to treat a variety of cancers and they often enable
using more aggressive therapies, as they reduce the side-effects
of potent cancer drugs. Monoclonal antibody therapies used in
cancer treatment, include Herceptin for breast cancer, and Rituxan
for Non-Hodgkin’s lymphoma.
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Biologic
Humira
Remicade
Herceptin
Epogen
Enbrel
Orencia
Amevive
Tysabri
Used to treat
RA, ankylosing spondylitis, psoriatic arthritis, CD, psoriasis
RA, ankylosing spondylitis, psoriatic arthritis, CD, psoriasis
Breast cancer
Anaemia associated with chemotherapy, chronic renal failure
RA, ankylosing spondylitis, psoriatic arthritis
RA
Psoriasis
MS
New cancer vaccines have also been developed using recombinant DNA technology. One example is the cervical cancer
vaccine Gardasil which has received a lot of media attention
recently.
The second major application of monoclonals is in diseases
with profound immunological involvement. By downgrading the
inflammatory component of the disease through inhibiting TNFA, patients have improved rapidly and dramatically. Often the
responses have been most significant in those with the most
severe intransigent disease. Rheumatologists were first to harness
the potential of a monoclonal antibody directed against TNF-A,
but now it is used for those with diseases as diverse as IBD and
psoriasis. There are currently three anti-TNF drugs on the market
with slightly different actions and indications.
Many new monoclonal drugs, particularly interleukins, are likely
to be onstream in the next decade or so and it is predicted that
the management of many more diseases will be based on using
these therapies. The big advantage of biologics is that they are
very specific, systemic side-effects are avoided and compliance is
improved, as they tend to have a very narrow spectrum of activity.
Rheumatoid arthritis
There has been a paradigm shift in the rheumatology community to treat RA early and aggressively. New treatment protocols
have been adopted involving the use of biologics as soon as possible after diagnosis. In certain cases it may be able to remove the
patient from the biologic treatment after a period of time and use
immunosuppressant therapies on achieving remission. This
approach may alleviate any concerns over having patients on
these potent drugs for many decades and even for life.There is no
safety data on the risks of these medications long-term and how
they might interact with other long-term medications.
There has been concern about the risk of the occurrence of rare
tumours and an increase in opportunistic infections with the antiTNF biologics.Cases of reactivation of latent TB have been
reported. It is not clear whether these side-effects are a consequence specifically of an immunosuppression threshold being
breached due to biologics being given with other concomitant
immunosuppressants.The rare brain infection, progressive multifocal leucoencephalopathy (PML), associated with the MS drug
Tysabri led to its initial withdrawal from the market but it has
been re-introduced with the proviso that patients are monitored
carefully when on the drug. Patients should be screened for TB
infection before put on biologics.
In the future it may be possible using genomic techniques to
predict who will benefit most from treatment with biologics and
who are likely to be responders. It may also be possible to predict
who are likely to be at increased risk of rare side-effects like the
development of rare cancers or lymphomas or be prone to infection because of excess immunosuppression.
Conor Caffrey is a science writer