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Biologic agents for the treatment of alopecia areata
It is generally accepted that alopecia areata is
mediated by activated T cells. The process of lymphocyte activation
requires two signals
between T cells and antigen- presenting cells (APCs). The first
signal involves the presentation of a specific antigen by the
MHC (HLA) molecule on the surface of the APC and its recognition
by its specific T cell receptor on the surface of the T cell. After
T cell recognition of the antigen, a second co-stimulatory signal
must be delivered
by the APC to lead to full T cell activation. This co-stimulation
involves several interactions and these co-stimulatory molecules
are the targets of many biologic drugs now used to block T
cell activation. As a consequence of cell activation cytokines,
chemical
signals that cells use to communicate with each other, are
also produced. Some cytokines promote inflammation and these cytokines
are the targets for other biological drugs.
Essentially, APC cells "eat" any sick, viral infected
cells, debris, bacteria etc., they come across. they
digest it and then
present fragments of the antigen on their surface to lymphocyte
cells. These antigenic fragments must be presented in a certain
way. The fragments are placed in a cup-like structure called an
MHC class II protein. CD4 lymphocyte cells have receptors that
recognize the combination of antigen and MHC protein.
However, when the CD4 cell receptor binds to the antigen/MHC
protein structure it requires a secondary signal to actually activate
the cell into a responsive state. It's like when you try to delete
a computer file and as a safety measure the operating system asks
you "are you absolutely sure you want to delete this?" and you
have to tell it YES!! a second time. That secondary signal comes
from the CD4 cell binding to another protein structure on the
APC at the same time it binds to the antigen/MHC. If the CD4 cell
recognizes the antigen/MHC complex and the second structure then
its all systems go.
Many biologic drugs interfere with this process and stop antigen presentation. Biologic agents are proteins that possess pharmacologic activity
and can be extracted from tissues or synthesized through recombinant
DNA techniques. Recombinant DNA methods are powerful, revolutionary
techniques that allow the isolation of single genes with a particular
function from a pool of thousands of genes and the modification
of these isolated genes or their regulatory regions for reintroduction
into cells. With the insertion of these modified genes into cells
(usually special bacteria cells) and their subsequent culture,
the genes are expressed and the product the gene codes for is
manufactured by the cells. The product can then be collected and
purified ready for use as a drug treatment.
Biologic molecules either mimic the action of normal body proteins
or they interact with circulating proteins. Biologics are larger
than “small-molecule” drugs and are most often administered
by or intravenous injections and less frequently by intramuscular
or sub-cutaneous injection.
The mechanism of action of these biological agents includes four
basic strategies:
- Reduction of pathogenic T cells.
- Inhibition of cell activation.
- Immune deviation.
- Blocking the activity of inflammatory cytokines.
There are three distinct types of molecules that have been developed
for use as biological drugs:
- Recombinant human proteins are exact replicas of normal human
proteins that have been developed through DNA combinations.
They exert specific effects in physiological doses.
- Monoclonal
antibodies are chemically and immunologically homogenous proteins
that specifically bind to proteins.
- Fusion proteins are molecules
that combine sections of different proteins. The fusion protein
has binding specificity to
for a particular ligand (an ion, a molecule, or a molecular group that
binds to another chemical entity to form a larger complex)
and is soluble in plasma.
Knowledge of the pathogenesis and new treatment modalities of
alopecia have been substantially expanding during the last two
decades. There is sizeable evidence to support that alopecia areata
is an autoimmune disease, and new therapeutic modalities by way
of biological immuno-modulators promise extremely good results,
are relatively safe, and are easy to produce. These treatment
modalities will hopefully come to take an important place in the
future of
alopecia areata therapy.
Current
biologic agents in use
Four biologic agents that have so far been developed for therapeutic
management of rheumatoid arthritis, psoriasis, psoriatic arthritis,
and Crohn’s disease are in use today. As such, none of these
drugs have been developed for alopecia areata. However, because
some treatment modalities that have been successful in treating
psoriasis have also been effective in treating alopecia areata,
clinical trials of the use of biological drugs in alopecia areata
may help define a universally acceptable form of treatment for
patchy hair loss. These four agents are:
Etanercept (Enbrel) is a human fusion protein that inhibits the
inflammatory cytokine TNF- a. In medicine, tumor necrosis factor
(TNF) a is an important cytokine involved in systemic inflammation
and the acute phase response. Etanercept is an FDA approved drug
for the treatment of rheumatoid arthritis and psoriatic arthritis
and is administered twice weekly as a subcutaneous injection.
Clinical trials with Etanercept in psoriasis have shown favorable
responses, although safety with respect to its long-term use needs
to be determined.
Infliximab (Remicade) also inhibits the inflammatory cytokine
TNF- a. It is a chimerical (mouse/human) antibody protein. Specifically,
Infliximab is used for treating the inflammation of Crohn's disease,
rheumatoid arthritis, and psoriatic arthritis. By blocking the
action of TNF- a, Infliximab reduces the signs and symptoms of
inflammation. Controlled clinical trials in psoriasis have shown
promise of Infliximab’s rapid efficacy. It is given to the
patient by intravenous infusion over 90 minutes.
The long-term safety of TNF- a inhibition is being monitored
in North America and Europe. Rare instances of tuberculosis activation,
multiple sclerosis, positive antinuclear antibodies, lymphoma,
and pancytopenia (a pronounced reduction in all the formed elements
of blood) have been reported. However, most patients with such
side effects were on concomitant immunosuppressive therapy for
rheumatoid arthritis or Crohn’s disease, and no relationship
has been established linking these events and the use of TNF-
a inhibitors.
Efalizumab (Raptiva) is a humanized monoclonal antibody that
has several effects with potential therapeutic benefit in alopecia
areata. It binds CD11a, a component of LFA-1 that binds to ICAM-1
on APCs, and thus it interrupts the co-stimulatory signals explained
earlier. It also blocks T cell adhesion to endothelial cells and
T cell migration (trafficking) into inflamed tissues. In phase
II clinical trials of the drug in psoriasis patients, 62% of patients
showed 50% improvement as measured by the Psoriasis Activity and
Severity Index (PASI), and 30% showed 75% improvement. Other than
mild flu-like symptoms that soon subsided, there were no significant
side effects reported in these clinical studies. The drug is given
as weekly subcutaneous injections.
Alefacept (Amevive) is a fusion protein that induces apoptosis
in T cells expressing high levels of CD2. It also blocks the LFA-3/CD2
interaction necessary for the activation and proliferation of
T-cells by binding to CD2 on T-cells. The drug is FDA approved
for the treatment of psoriasis. Since the CD4 count is reduced
due to apoptosis, monitoring of the CD4+ T cell count is a mandatory
safety requirement with use of Alefacept in therapy.
In phase II trials in psoriasis, this agent has shown efficacy
with an excellent safety profile. Reports have demonstrated the
potential of Alefacept as an effective therapy for chronic plaque
psoriasis, for it was well tolerated and provided a markedly durable
clinical response, The medication is given once weekly either
intramuscularly or by an intravenous bolus (‘‘push’’).
Alefacept is currently (2006) being testing in a multicenter
study for effectiveness in treating alopecia areata. Results from
this study have not yet been released.
New
biologic drugs under development
The biologic agents above are approved and in use in several
countries for the treatment
of refractory rheumatoid arthritis and psoriasis. However, new
agents inhibiting interleukin-6, interferon gamma, and several
co-stimulatory
pathways are entering clinical phase I and II trials and may also
be available in a few years. New biologic drugs under
development include Abatacept, Anakinra, Rituximab, Humeira, and
Fontolizumab among others. Animal model research suggests that
of biologics under development, CTLA4Ig (Abatacept) andf perhaps
anti-IFNgamma (fontolizumab) may
have the most potential as an effective treatment
for alopecia areata.
If APCs presents self antigen in combination with MHC proteins,
but without producing any costimulatory molecules, it sends a
signal to the CD4 cells to become non-responsive,. When this happens
the cells are tolerized (technically they become "anergic" cells).
The CD4 cell now knows NOT to respond to this antigen because
it is part of self. So having CD4 cells bind to the antigen/MHC
but not getting the secondary co-stimulatory activation signal
is desirable for treating autoimmune diseases.
One way to try and make CD4 cells anergic is to artificially
block one or more of the costimulatory singals. Biologic drugs
have been produced which do just this one of which is called
CTLA4Ig (Abatacept). CTLA4Ig is a fusion
protein
that blocks CD80/86 (B7) co-stimulation binding with
CD28 and is administered by intravenous infusion. Clinical trials
have
been
conductedwith CTLA4Ig
in psoriasis and are in progress in rheumatoid arthritis, giving
substantial hope for broadening the therapeutic application
of
biological agents in medicine. Inject someone with CTLA4Ig and
you should knock out any response to antigenic material without
totally
depleting the rest of the immune system. CTLA4Ig has also been
used exerimentally to stop rejection
of transplanted organs with good success. As such CTLAIg has
been
suggested as a potential treatment for alopecia areata. So far though
it has not been tested on aloepcia areata patients.
In both animal models of alopecia areata and in humans with alopecia
areata there is a signfiicant increase in a proinflammatory cytokine
called interferon gamma (IFNg). IFNg is quite potent and promotes
a high level of lymphocyte activity. It can also block hair growth.
It may be that by blockading IFNg activity that the inflammation
in alopecia areata can be reduced. Anti-interferon gamma biologic
drug fontolizumab has been tested on a few people with alopecia
areata in Russia. So far details have not been published by the
study coordinators did claim a positive result with treatment.
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