Rheumatoid arthritis (RA) is a chronic illness in
which the immune system, which protects us from
viral and bacterial invaders, turns on our own body
and viciously attacks the membranes that line our
joints. The consequences can be excruciating: pain,
swelling, stiffness, and decreased mobility. Over
time, the joints can become permanently contorted,
as in this X-ray image.
X-ray image of the hands of a patient with rheumatoid arthritis. Note that the joints at the base of the fingers are eroded — and some, like the index finger on both hands, are actually dislocated.
Copyright (2012) American College of Rheumatology.
There are several RA medications on the market, but
a new one called tofacitinib, a pill which the FDA
approved late last year [2] works by targeting a
protein called Janus kinase 3, which was discovered
by John O’Shea and colleagues at the National
Institute of Arthritis and Musculoskeletal and Skin
Diseases (NIAMS) 20 years ago [3]. It takes a really
long time to go from a basic discovery to a drug—in
most cases nearly 15 years. This drug has been even
longer in the making! Shortly after discovering
Janus kinase 3 in 1993, NIAMS researchers also
revealed its role in inflammation, leading to a
public-private collaboration with Pfizer that has
now culminated in the approval of tofacitinib.
These Janus kinases (JAKs) are critical messengers
in the cell. They receive signals from immune
proteins and growth hormones, among others, and
convey that message to another group of proteins
called STATs (signal transducers and activators),
which then alter the activity of particular genes.
This JAK-STAT messenger system is absolutely
essential for regulating cell growth and
development, metabolism, blood cell formation,
immune system function, and many other activities
critical for normal health and development.
Mutations in a particular JAK or STAT can make these
proteins too active, or not active enough,
disrupting the messenger system and causing diseases
ranging from cancer to dwarfism to autoimmune
conditions, including rheumatoid arthritis. Other
mutations in the JAKs and STATs make some people
more vulnerable to viruses and bacteria, or block
the development of their white blood cells.
Tofacitinib is particularly noteworthy because it is
the first FDA approved drug for treatment of an
autoimmune disease that works by inhibiting a JAK
protein.
There’s a terrific review article on the role of
JAKs and STATs in the January 10th issue of the New
England Journal of Medicine [4] that describes the
four JAK proteins, and the seven STAT proteins, and
their roles in health and disease. For example, a
mutation in JAK3 that makes the protein less active
causes an immune deficiency condition similar to
that suffered by the Bubble Boy, David Vetter, 30
years ago. On the other side of the coin, mutations
in other JAKs that make these proteins hyperactive
can trigger T-cell and B-cell acute leukemia or
types of lymphomas. Hindering the activity of STAT1
leaves a person vulnerable to bacteria and viruses.
You get the idea. Each of these proteins has a
specific job, so if you are developing a drug you
want to target only the misbehaving protein—you
don’t want to disrupt the functions of all members
of that protein family as well.
Tofacitinib inhibits three of the four JAKs,
ratcheting down the overactive immune response that
drives RA. It changes the way the immune system
works, potentially raising the risk of some cancers.
However, the most common side effects have been
upper respiratory infections, headaches, and
diarrhea.
Ultimately researchers will likely discover drugs
that specifically target each one of these JAK and
STAT proteins, so that we can minimize drug side
effects and treat the broad array of diseases that
occur when the JAK-STAT pathway is disrupted. But
for now, having the first magic bullet to target
this pathway in autoimmune disease and help the
legions of people with RA is a great step forward.
For more information
http://directorsblog.nih.gov/
(MDN)
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