Three randomized controlled trials with a two-year extension period on the effect of a multidisciplinary lifestyle program (1) for patients with rheumatoid arthritis, (2) for patients with ACPA positive arthralgia and (3) patients with osteoarthritis & metabolic syndrome.

Although life expectancy has increased, people are also suffering from chronic
diseases for longer. Environmental factors play an important role in the
development of these diseases, as only a small part can be explained by genetic
factors. Unhealthy diets, obesity, physical inactivity, stress and smoking are
associated with a higher risk of rheumatoid arthritis (RA), while obesity and
metabolic syndrome (MetS) are associated with a higher risk of and progression
of osteoarthritis. Chronic low grade inflammation is often present in people
with unhealthy diets, lack of exercise and stress and can be an important
factor in the pathogenesis of chronic inflammatory diseases.

The current non-surgical treatment of RA and osteoarthritis consists mainly of
medication, exercise therapy and (for osteoarthritis) sometimes weight loss due
to a low-calorie diet or bariatric surgery. For many chronic diseases,
especially those related to MetS, lifestyle factors have been studied and in
some cases applied as therapy. The combination of different types of therapies
has demonstrated synergy effects. The Ornish Lifestyle Program for
Cardiovascular Diseases, based on full-fledged vegetable nutrition, exercise
and stress management, is a good example of an effective multidisciplinary
approach that is now widely offered and reimbursed by almost all US health
insurers.

A full-fledged vegetable diet has produced promising results for the treatment
of both RA and osteoarthritis, but has not yet been combined with other
lifestyle interventions. Although the application of good medication has helped
patients with RA considerably, 30% of patients do not respond to these drugs
and 69% of RA patients still suffer from pain, fatigue and reduced mobility. In
both RA and osteoarthritis there is a need for more evidence for treatments
focused on nutrition, exercise and mental health and in particular for
multidisciplinary interventions. This need is also relevant, as almost 2
million Dutch people suffer from some form of rheumatism. Healthcare costs
amount to almost ¤2 billion per year. If the costs of absenteeism due to
illness are also included, the total for RA and atrose together amounts to 20
billion euros per year, which is 3% of the Dutch gross domestic product.

Investigating the effect of a 16 week multidisciplinary lifestyle programme,
based on (1) a whole foods plant based diet (WFPD), (2) exercise and (3) stress
management on:
- disease activity (DAS28) for patients with rheumatoid arthritis (RA), in
comparison with usual care,
- the RA-risk score (Amsterdam risk rule score) in patients with ACPA-positive
arthralgia, in comparison with usual care and
- the WOMAC-score for patients with osteoarthritis (OA) and metabolic syndrome
(MetS), in comparison with usual care.

The primary objective of the 2-year extension study is to investigate adherence
to the programme components (diet, exercise and stress management) and to
perform a standardized reduction of medication in case of (near) remission.

The aforementioned objectives (primary objectives of the RCT) for patients with
RA, OA and arthralgia will be included as secondary objectives during the
2-year extension study.

In a 16-week randomized single-blind controlled trial, patients with
1. rheumatoid arthritis (RA) with a low to moderate disease
activity(2.6=2. ACPA positive arthralgia (pilot study, n=16) and
3. OA & MetS (n=80)
will either receive standard care or a multidisciplinary lifestyle
intervention, based on a WFPD, exercise and stress management.

At baseline, halfway and after 16 weeks primary outcomes DAS28, RA-risk score
and WOMAC-score will be measured for RA-, ACPA positive arthralgia- and OA
patients respectively. The control groups will be placed on a waiting list to
receive the intervention after the RCT.

After completion of the RCT, all patients (n=176) who participated in the
lifestyle intervention will be followed in a two-year extension program to
investigate adherence and to perform a standardized reduction of medication in
case of (near) remission.

After screening and baseline measurements (RA patients will also visit a nurse
to determine the DAS28 score), patients are randomized. Those in the
intervention group start with individual intake meetings with a registered
dietician and a physiotherapist at baseline to determine personal objectives
and abilities and limitations regarding physical exercises.

During the 16-week program subjects will meet 10 times in groups of max 15
people. During all meetings (2- 3 hours) subjects will receive theoretical
and/or practical training, based on protocols tested in previous studies on the
following subjects:
1. Whole foods plant based
2. Exercise
3. Stress management

Subjects will be facilitated for their diet by means of fully elaborated week
plans, cooking class and they will receive a small box with supplements and
some specific plant-based products (e.g. condiments like miso and nutritional
yeast as well as *cream* substitutes) to get introduced in a new way of
cooking. Week plans are in line with recommended daily allowances of all
relevant macro- and micro nutrients. Subjects will also receive supplementation
(vitamin B12 and vitamin D according to dietary guidelines for vegan diets).

For exercise, subjects will be introduced to different forms of moderately
intense exercise and are motivated to integrate exercise in daily activities.

For stress management, subjects will receive psycho-education on the effects of
stress on health and stress management, as well as guided practice and home
exercises on relaxation techniques, breathing and visualization exercises and
coaching on sleep.

Medication is preferably not changed during the 16-week investigation period.
Patients with medication for diabetes and/or hypertension are instructed to
contact their general practitioner to discuss lowering of medication when
necessary. Patients are invited to report changes in medication as soon as
possible to the investigators. During the two-year extension period patients in
remission and their rheumatologists will taper medication according to a
standardized scheme.

The control group will receive usual care as delivered by their physician.

Burden:
- All meetings take place at Reade (due to COVID-19 measures now mainly online)
and two visits to the Amsterdam UMC (location Meibergdreef) for the
participants who undergo an MRI.
- Recruitment is targeted at motivated patients who are prepared to participate
in 10 group meetings and 5 to 7 individual visits.
- In addition to the group meetings, participants are inveted to visit for: (1)
baseline: intake interviews and baseline measurements (see below), (2)
measurements after 8 weeks and (3) end measurements. During the extension study
2 more measurements take place and the control group has 2 extra measuring
moments.
- 50 participants (randomly selected) will be asked to undergo an MRI
(Amsterdam UMC), subjects will be asked an extra consent to be invited for the
MRI.
- Intake dietician and physiotherapist: 60-90 minutes, this takes place on the
same day as the baseline measurements.
- Measurements: blood sampling (fasting, per measurement < 50 ml), blood
pressure and heart rate variability (5 minute ECG), DEXA scan, DAS28 (nurse, RA
only), anthropometry, indirect calorimetry, some physical tests (walking test,
get-up-and-go test) and some questionnaires (PROMIS®, which significantly
shortens the number of questions to be answered).
- Participants receive a letter from Reade for their employer/health & safety
service in which Reade proposes to exempt the employee from work for a few
hours per week during the trial (this point was included in consultation with
the 'ambassadors', 11 patients involved in the development of the program,
including an industrial doctor).

Risks:
Given the nature of the intervention, there are few risks, since the trial
concerns healthy behaviour. Subjects are motivated patients who may see the
intervention as an opportunity rather than a burden. The program may be
experienced as difficult or tough. Therefore, dropouts have to be taken into
account, estimated at 20%.