TOwards Precision TREATment for advanced osteoarthritis: the TopTreat cohort

Osteoarthritis (OA) is a chronic degenerative disease of one or more joints
involving the cartilage and its surrounding tissues (1). It can develop in any
synovial joint, but the knees, hips and hands are the most commonly affected
sites (2,3). It is the most frequent form of arthritis and a leading cause of
pain and disability worldwide, resulting in a high clinical and societal
burden. Globally, knee and hip OA were ranked as the 11th most common cause of
disability among 291 conditions studied (4). Besides this, OA is associated
with comorbidities, including type 2 diabetes mellitus, obesity, metabolic
syndrome, cardiovascular diseases, and widespread pain, although putatively as
epiphenomenon or consequence, rather than cause of these diseases (5,6).

In the Netherlands alone, almost 1.5 million people suffer daily from
the consequences of this disease (7). Towards 2040, it is estimated that the
number of OA patients will rise to 2.5 million (8). This means that OA will
become the most common chronic disease by then. OA also has a significant
impact on healthcare costs. The direct medical costs of OA in the Netherlands
were estimated at 1.2 billion euros in 2017 (9). This corresponds to 18% of the
costs for musculoskeletal diseases and 1% of the total healthcare costs. The
economic burden, however, is not confined to direct medical costs alone. It
also includes indirect costs, which consist of costs due to reduced
productivity, absenteeism, and compensation of household work by others (10).
These indirect costs accounted for approximately 83% of the total economic
burden of OA (11). Both the direct as well as the indirect costs will only
continue to rise in the future. Considering the increasing individual and
societal burden of OA, individualized patient care based on their specific
needs should be the focus of management (2).

Currently, management of OA can be characterized by a stepped-care
approach, suggesting that more complex, intensive or invasive treatment options
are only tried after failure of relatively simple modalities (12). However, the
options are limited and the outcomes of existing interventions are suboptimal.
An important explanation for this is the outstanding variation in clinical and
structural manifestations between patients. To increase cost-effectiveness, a
multidisciplinary approach tailored to the needs of individual patients has
been proposed. Appropriate patient stratification will enable clinicians to
target treatment to the needs of individual patients or characteristics and to
differentiate patients who are likely to improve with safer and cheaper
interventions, such as exercise and diet, from those who may need additional
interventions (likely more complex and expensive, such as pharmaceutical
intervention and/or surgery) or a higher level of care (13). This is
particularly crucial in secondary care where complex and costly treatment
options such as joint replacement are being considered. Recent retrospective
research found a high prevalence of patients who had premature total knee
replacement as well as patients for whom total knee replacement was potentially
appropriate but did not undergo surgery (14). These findings underline the need
for better alignment of care.

Over the last twenty years, research has mainly focused on disease progression
using cohorts, in which patients are studied prospectively and longitudinally
(table 1) (17-33). Only a few focused on the established stage of the disease
and 1 (of which the findings were not representative for general OA) on OA at
multiple sites. This is important because the burden of disease in terms of
quality of life and medical costs is concentrated on patients with more
advanced stages of OA and joint-pain comorbidities. From these cohorts, we have
learnt that more than half of the patients with knee OA referred to secondary
care experience further clinical worsening in the short term and that 18% to
50% of the patients are eligible for knee replacement surgery (34,35). Also,
for hand OA, both radiological and clinical deterioration was demonstrated
after 2 years of follow-up (36). These declines are associated with physical
impairments (increased pain, reduced muscle strength), comorbidity and
overweight, psychological and social factors (poor mental health,
self-efficacy, social support, anxiety, depression, low vitality, fatigue),
health behaviors (lack of activity), and sociodemographic factors (higher age,
female sex, ethnicity, social class, being retired) at baseline (37).

Despite all these efforts together with the conduct of several clinical
studies, no disease modifying osteoarthritis drugs (DMOADs) have been approved
yet (15). This can partly be attributed to the heterogeneity of this disease.
To address this issue, phenotyping of patients has gained attention in recent
years. In literature, this approach distinguishes mechanistic, prognostic, and
treatment response or prescriptive phenotypes. Mechanistic phenotypes are
defined by their molecular mechanism or endotype. Studies so far have
identified a few potential endotypes related to, amongst others, gene
signatures, inflammation, and pain mechanisms (38-40). Prognostic phenotypes
differentiate between subgroups at risk of reaching the outcome of interest
within a given timeframe. Examples of subgroups within this phenotype are based
on clinical trajectory progression, pain intensity, and mechanical factors
(41,42). Prescriptive phenotypes identify subgroups that are more likely to
respond to a given (combination of) intervention(s). Distinctions can be made
for example based on gender, trajectories of pain response and function, or
comorbidities (43,44). However, outcomes have not resulted in implications for
the OA research field and/or clinical care. A reason for this might be that
there are only a few studies that combined multiple characteristics relevant
for phenotyping.

Therefore, we will set up a cohort in which we aim to identify
subgroups from a multidisciplinary perspective. This will be done in 2 parts.
The first part, on which this protocol is focused, aims to identify subgroups
of patients based on patient and disease related characteristics, and to
identify subgroups of patients based on disease progression. Additionally,
associations between baseline characteristics and disease progression will be
examined. In the second part, on which additional applications will be
submitted for ethical approval, we intend to perform add-on studies requiring
additional collection of data or bodily material and to conduct several
proof-of-concept randomized controlled trials. This allows us to collect
in-depth information in a limited number of patients and/or to identify
subgroups of patients that are more likely to respond with a given
intervention. The cohort will focus on the segment of the patient journey when
knee or hand OA becomes a chronic persistent disease and patients experience a
high clinical burden. We define a high clinical burden as having complaints in
at least two joint groups and when pain impacts daily functioning. In contrast
to previous cohorts, this cohort is the first to comprehensively study this
segment of the patient journey taking relevant elements of a multidisciplinary
perspective into account and to study potential treatments for OA
simultaneously. The acquired knowledge will improve existing clinical decision
support tools in providing individualized advice or services to help alleviate
possible issues, resulting in significant benefits to both the healthcare
system and individuals.

This observational cohort study aims
1. To identify subgroups of patients with hand and/or knee OA based on patient
and disease related characteristics
2. To identify subgroups of patients with hand and/or knee OA based on disease
progression
3. To gain insight in factors underlying disease progression from a
multidisciplinary perspective
4. To identify statistically significant and clinically relevant changes in
real-world mobility in people with lower extremity OA
5. To facilitate the conduct of multiple proof-of-concept randomised controlled
trials
6. To assess the health economic impacts of hand and/or knee OA

The study concerns an observational cohort study in which patients will be
followed over 3 years. At baseline, participants will be invited to undergo a
series of tests to comprehensively study a number of clinical, metabolic,
inflammatory, mobility, psychological, social, and behavioral markers. Every
three months patients will be asked to complete short set of questions, and
every 6 months online questionnaires on symptoms, daily functioning and health
care consumption . After 36 months or prior to joint replacement surgery(if
applicable) participants are invited at the Sint Maartenskliniek to assess
mobility and to take X-rays of the knees and hands if not available within the
past 6 months.
In addition, 125 consecutive consenting participants from the cohort, with
lower extremity OA (e.g. knee, hip or ankle) will be asked to wear a smartwatch
to monitor their individual mobility patterns longitudinally, for the duration
of the study. We will use this data to identify relevant changes in their
mobility, to be distinguished from natural fluctuations or variability of such
measures. In addition, we will ask participants to walk for 2 minutes each week
by sending a notification through the smartwatch or connected smartphone.

Upon inclusion in the cohort, additional consent will be sought from
the participants to approach them for in-depth and/or follow-up measurements
such as biological or biochemical factors derived from body material, or
additional assessments in if knee replacement is indicated. In addition, after
a minimum of 1 year the cohort offers an infrastructure to carry out (small)
proof-of-concept trials of (new) advanced interventions that fit specific
characteristics of participants. This is also known as the Trials WithIn
CohortS (TWICS) design (https://www.twics.global/) and may include both
pharmacological treatment options as well as and non-pharmacological treatment
options. At the initiation of a trial within the cohort, informed consent (IC)
to be randomly assigned to either the control or experimental group is then
sought in those eligible for the trial.

Burden: 1 reimbursed visit to the Sint Maartenskliniek to gather baseline
characteristics (clinical examination, questionnaires, x-rays of the knees and
hands if not available within the past 6 months, blood sampling (16 mL),
mobility analyses) (duration: half-day). Online questionnaires every 3 months
for a total of 3 years (duration varying from 1 - 20 minutes). 1 reimbursed
visit to the Sint Maartenskliniek after 36 months to assess mobility and to
take x-rays of the knees and hands if not available within the past 6 months
(duration: 60 minutes). A subgroup will continuously wear a smartwatch to
capture walking activity.
Benefit: finding subgroups might enable us to tailor OA care. We assume that
this in turn will positively influence the quality-adjusted life years of
patients.
Group relatedness: our research will increase the knowledge of knee and hand OA
and can offer a step in the right direction to impact the burden of OA.