Validation of four quantitative radiological techniques to image cartilage quality in patients with knee osteoarthritis scheduled to undergo total knee replacement.

Osteoarthritis (OA) is a very frequent degenerative joint disease causing
substantial morbidity. It has been demonstrated that compared to other chronic
disorders, OA contributes most to impaired physical quality of life in the
general population, and leads to considerably higher costs to society than
other musculoskeletal diseases such as rheumatoid arthritis and osteoporosis.
These costs are largely attributable to joint replacement surgery in patients
aged 65 years or older, which is nowadays the only definitive treatment
strategy in end stage OA. Due to the ageing population, this OA associated
socio-economic burden will only increase in future. It has been estimated that
the number of OA patients in the Netherlands will have increased by almost 50%
in 2040.
Because of this growing impact of OA to our society, current research
in the field of OA is mainly focused on the pathogenesis, prevention and the
development of disease modifying osteoarthritic drugs. Radiological imaging is
of utmost importance to gain more insight into the pathogenesis of OA, as well
as to monitor prevention and treatment strategies both in the setting of
research and in clinical care. Radiography has been extensively been used to
detect and follow OA development over time. There are, however, major
limitations of radiography applied for OA. Radiography cannot depict cartilage
directly, which is an important tissue affected by OA. Instead, radiography
only depicts joint space narrowing due to gross cartilage loss in moderate to
advanced stage OA and is incapable of detecting OA progression sensitively
within a reasonable time interval. Because of this, radiography should not be
used as an outcome measure in OA research anymore. Therefore, magnetic
resonance imaging (MRI) has been regarded as the most accurate radiological
tool for imaging of OA related cartilage change nowadays. Until now, however,
radiological evaluation of OA with MRI has usually been based on rather
subjective assessment of morphologic cartilage damage.
For accurate monitoring of treatment strategies or detecting and
following OA in an early stage, the current morphology based MRI techniques are
insufficient: they lack quantitative (numerical) outcome measures of cartilage
quality. Because of the lack of these quantitative outcome measures in OA
research, many pharmaceutical companies have abandoned the OA research field,
since no good outcome measures for efficacy studies of potential treatments
were available which could also show an effect within a reasonable period of
time.
To overcome the need of quantitative outcome measures to detect subtle
changes and to evaluate early stages of OA before morphologic alterations
occur, novel radiological techniques have been introduced in the past decade.
These new techniques enable a sensitive and objective quantitative outcome
measure of cartilage quality in terms of the glycosaminoglycan (sGAG) and/or
collagen content of cartilage, which are known to be lost from the cartilage
during the early stages of the disease. Currently, the most widely used
quantitative technique in clinical research is delayed gadolinium enhanced
magnetic resonance imaging of cartilage (dGEMRIC), which uses the inversed
relation between a contrast agent and the sGAG content of cartilage. Recently,
It has been shown that Computed Tomography arthrography (CTa) may also be used
as a technique to quantitatively measure cartilage quality similar to dGEMRIC.
In addition to dGEMRIC and CTa, other promising techniques which have been
introduced are T1rho and T2 mapping. These techniques also measure cartilage
quality using MRI, but without the use of a contrast agent. The latter is a
potential benefit of these techniques compared to dGEMRIC and CTa.
Although these quantitative MRI and CT based techniques have been
reported as sensitive and accurate to detect abnormal cartilage quality in
certain patient groups and healthy volunteers, no systematic comparison of the
outcomes these different techniques in vivo against established reference
standards for cartilage quality in-vitro have been performed.
In the present study, quantitative imaging of cartilage quality using
MRI and CT will be evaluated in patients scheduled to undergo total knee
replacement surgery, but with a discrepancy in OA stage between both
compartments of the tibiofemoral joint (one compartment severe and one
compartment mild to moderate OA). By doing so, we have can validate the
different techniques in different stages of OA within the same study. Outcomes
of the imaging techniques in-vivo will be compared with in-vitro reference
standards for cartilage quality (contrast-enhanced µCT (EPIC-µCT), histology
(biochemical staining quantification) and biochemical sGAG and collagen assays
on specimens of the knee cartilage obtained during total knee replacement
surgery. This multi-parametric approach will enable us to thoroughly validate
novel quantitative imaging techniques for cartilage, which has not been
performed before.

We hypothesize that all different novel quantitative radiological imaging
techniques under investigation in this project are a measure for cartilage
quality in terms of the sGAG content, collagen content, or a combination of
both.

The primary objectives of the present study are:
1. To assess to which extent in vivo dGEMRIC does measure cartilage quality in
terms of the sGAG and/or collagen content of cartilage as determined by the
reference standards for sGAG and collagen content.
2. To assess to which extent in vivo T1rho does measure cartilage quality in
terms of the sGAG and/or collagen content of cartilage as determined by the
reference standards for sGAG and collagen content.
3. To assess to which extent in vivo T2 mapping does measure cartilage quality
in terms of the sGAG and/or collagen content of cartilage as determined by the
reference standards for sGAG and collagen content.
4. To assess to which extent in vivo CTa does measure cartilage quality in
terms of the sGAG and/or collagen content of cartilage as determined by the
reference standards for sGAG and collagen content.

Although the pathogenesis of OA and associated pain has not been fully
clarified, it has been suggested and we hypothesize that altered blood
perfusion in the subchondral bone may play an important role by affecting the
structure of articular cartilage and by inducing specific patterns of OA pain
possibly through blood vessel and nerve proliferation.
Quantification of subchondral bone perfusion is possible with dynamic
contrast enhanced (DCE)-MRI. Although DCE-MRI has not been widely applied in OA
research, patients included in this study get an intravenous injection with
contrast agent for acquisition of dGEMRIC anyway. This contrast agent also can
be used to acquire a DCE-MRI and therefore, without extra burden for the
participants, we will also acquire a DCE-MRI prior to dGEMRIC in this research
project.

The secondary objective of the present study is:
To assess if different symptom phenotypes of OA are associated with findings on
the novel quantitative radiological imaging studies mentioned above by
comparing their outcomes with the outcomes of clinical examination and the
outcomes of two questionnaires validated for OA (the Western Ontario and
McMasters Universities Osteoarthritis Index (WOMAC) and the Intermittent and
Constant OsteoArthritis Pain (ICOAP).

The present study has a cross-sectional observational design. Participating
patients will undergo a MRI scan and a CTa scan, both in a separate session.
The investigations will take place before surgery during which a total knee
replacement is performed.

The measurements needed for the data collection of the present study consist of
a blood test to determine the kidney function, two questionnaires (the Western
Ontario and McMasters Universities Osteoarthritis Index and the Intermittent
and Constant OsteoArthritis Pain, a MRI scan (combination of dGEMRIC, T1rho and
T2 mapping in one session) of the knee and a CTa of the knee (separate
session). The burden for the patients consists of an extra visit to the
hospital to undergo CTa (approximately one hour total time) and an intravenous
(MRI) and intra articular (CT) injection with contrast agent before undergoing
the MRI and CT examination.