Post-Traumatic Arthritis: Pathogenesis, Diagnosis and Management

362 Pages·2015·13.87 MB·English

by  Steven A. Olson

Steven A. Olson · Farshid Guilak
Editors
Post-Traumatic
Arthritis
Pathogenesis, Diagnosis
and Management
123
Post-Traumatic Arthritis

Steven A. Olson (cid:129) F arshid Guilak
Editors
Post-Traumatic Arthritis
Pathogenesis, Diagnosis
and Management
Editors
Steven A. Olson, MD Farshid Guilak, PhD
Professor Laszlo Ormandy Professor
Department of Orthopedic Surgery Department of Orthopedic Surgery
Duke University Medical Center Duke University Medical Center
Durham , NC , USA Durham , NC , USA
ISBN 978-1-4899-7605-5 ISBN 978-1-4899-7606-2 (eBook)
DOI 10.1007/978-1-4899-7606-2
Library of Congress Control Number: 2015939800
Springer New York Heidelberg Dordrecht London
© Springer Science+Business Media New York 2015
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To Diane and Thomas—Without your love and support,
I could not do what I do
To Mom and Dad—Thank you for allowing me to pursue my
interest in medicine
To My Mentors—Bill Allen, Mike Chapman,
and Joel Matta—your dedication to excellence inspires
me in all I do
To Farsh Guilak—Who is a gifted researcher, an unselfi sh
mentor, and a true friend
Thank you,
Steven A. Olson, MD
To Lori, Dina, and Justin, the loves of my life.
To my dear parents, Hooshang and Nahid, whose love,
support, and inspiration are unparalleled.
To the best lab group in the world, who make every day fun,
challenging, and exciting.
To Steve Olson, an incredible surgeon, scientist, and friend.
Thank you,
Farshid Guilak, PhD

Foreword
If cancer is the emperor of all maladies, osteoarthritis might be considered to
be the peasants and serfs that inhabit the countryside. The American Cancer
Society (ACS) estimates that about 15 million people are living today in the
USA who have, or have had, some form of cancer. Among this group nearly
half are over the age of 70 and the majority were diagnosed over 5 years ago.
The ACS also estimates that the total of all healthcare costs in the USA attrib-
utable to cancer in 2011 was $88.7 billion. To confront this emperor, the NIH
invests over $5 billion yearly in cancer research. Resulting advances in genet-
ics have transformed our understanding of this disease and opened a new era
in its treatment. In the last 10 years, about 300 new cancer drugs have been
approved for the treatment of cancer and another 800 drug candidates are
presently being tested in 3,137 active trials.
Clearly, the emperor is receiving royal attention and respect—serfs and
peasants not so much. The Arthritis Foundation estimates that over 27 mil-
lion people in the USA suffer from osteoarthritis. Healthcare costs attribut-
able to this disease in the USA were estimated to be $185.4 billion in 2009.
In terms of drug treatments, more has been lost than gained over the last 10
years as toxicities of available infl ammatory and analgesic agents have been
recognized. No new disease modifying drugs have been introduced and few
if any are in development. This slow progress is mirrored by comparatively
low funding levels for a disease that is recognized as the leading cause of
disability in the USA. In 2015 the projected NIH budget for arthritis research
is $240 million, much of which is allocated to infl ammatory diseases such as
rheumatoid arthritis and lupus. The problem with the search for better thera-
peutics for OA is not so much a lack of drug targets or lead compounds as is
the challenge of testing potential therapeutic agents in humans. It is diffi cult
to identify patients with very early OA who are likely to progress to joint
damage, typically the disease evolves slowly necessitating lengthy observa-
tion periods, and fi nally it has been recognized that the plain joint X-ray is
largely impractical as an end point for human clinical trials. As a conse-
quence, most therapeutic trials have been conducted in patients with rela-
tively advanced disease, when chances for benefi t are likely lowest, the costs
of trials have been high, and signals of effi cacy have been meager at best.
Clearly a better approach to drug development for OA is needed. Fortunately
vii
viii Foreword
the NIH has recognized that a major hurdle is identifi cation of better
measures of disease outcome in OA and has launched the Osteoarthritis
Initiative, a component of which is seeking new biomarkers that predict risk
of progression of OA.
C linically, joint space narrowing, osteophyte formation, and sclerosis of
subchondral bone defi ne OA. This radiologic picture represents the fi nal out-
come of diverse processes that alter the tissues of joints including genetic
factors, mechanical forces, neurological alterations, metabolic disturbances,
oxidative stress, infl ammation, and cellular senescence. Most if not all of
these processes are likely to be engaged to variable degrees in any individual
with OA. Finding ways to optimize the care of patients with OA requires full
understanding of each of these processes and how they interact to affect the
musculoskeletal system. For example an ACL tear in a healthy adolescent is
likely to be dominated almost exclusively by the mechanical alterations while
the same injury in an older obese smoker with diabetes may superimpose this
injury upon joint tissues that are already altered by metabolic and oxidative
stress. As implied by results in the MOON study (reviewed in Chap. 2 0 ),
evolution of OA in these two individuals proceeds at different rates and along
different paths and is likely to require different treatment strategies. A clas-
sifi cation scheme for OA based on the relative contribution of these different
processes could potentially streamline clinical care and drug development for
all patients who have or are in the process of evolving OA.
Post-Traumatic Arthritis: Pathogenesis, Diagnosis, and Management fi lls
admirably a major need for a comprehensive and up-to-date assessment of
the arthritis that follows joint injury. The authors use the terms post-traumatic
arthritis and post-traumatic osteoarthritis interchangeably. Perhaps to put a
fi ne distinction upon terminology, post-traumatic arthritis might apply when
an overwhelming injury damages the joint tissues beyond recovery whereas
post-traumatic osteoarthritis might apply when joint trauma sets in motion
pathophysiological processes that over time render the joint dysfunctional.
For example the long-term outcome of a fracture that tears cartilage apart so
that healing is not possible might be categorized as post-traumatic arthritis
whereas an ACL injury that initiates pathophysiological processes that lead
to dysfunction in joint tissues that were not part of the initial injury might be
categorized as post-traumatic osteoarthritis. This distinction becomes impor-
tant because different interventions are likely to be required in these separate
conditions. In this work, Guilak and Olson have worked with a distinguished
group of authors to assemble the entire body of knowledge of how mechani-
cal stress can promote joint dysfunction and how these processes can be stud-
ied to gain an even more refi ned picture in future studies. The work ranges
across basic in vitro studies to animal models to human trials and includes
analysis at both structural and biochemical levels.
T his work will be of interest to basic investigators who are interested in
gaining a better understanding of the tissues of joints and how they interact in
health and disease, to clinical investigators who are seeking to translate basic
Foreword ix
biological insights into an understanding of the disease mechanisms of OA in
humans, to drug developers who are seeking strategies to improve tissue heal-
ing after overwhelming injury and new interventions that can halt OA pro-
gression, to clinical trialists as they contemplate testing of new therapeutic
agents for OA, and to clinicians as they seek to optimize care for patients with
OA. In summary this compilation of knowledge fi lls a major need that is
expressed in rheumatology, Orthopedic surgery, bioengineering, physical
therapy, and healthcare policy. I congratulate the editors and all of the authors
for this enormously important contribution.
Bronx, NY, USA John A. Hardin, MD