The Role of Conditioning for Pharmacotherapeutic Treatments in Rheumatoid Arthritis.

Expectancies about health can induce physiological (autonomic, neuroendocrine,
and immune) responses that may directly and positively influence health and
treatment outcomes. Expectancies can be influenced by conditioning, which is
implicit expectancies based on repeated pairing of two previously unrelated
stimuli, leading the one to elicit a similar response when administered alone.
This automatic, i.e. conditioning expectancy learning mechanism has been shown
to elicit psychological and physiological effects in both healthy and (less
often studied) clinical populations. Potentially, this expectancy learning
mechanism could be applied to enhance pharmacotherapeutic treatment effects in
patients with chronic diseases, with subsequent improvements in psychological
and physiological (e.g., immune) functioning. For instance, medication regimens
making use of conditioning via principles of variable reinforcement have shown
to lead to similar therapeutic effects as full pharmacological treatment, while
significantly reducing adverse side effects. However, this has not yet been
investigated in patients with rheumatoid arthritis (RA). The ability to
influence pharmacotherapeutic effects by means of conditioning could offer new
therapeutic possibilities in the treatment of chronic diseases that require
long-term pharmacological treatment, such as inflammatory conditions.

This study aims to enhance pharmacotherapeutic effects in patients with
recent-onset RA by means of conditioning (via a variable reinforcement
schedule).

A multicenter randomized, clinical trial will be conducted in patients with
recent-onset RA, closely following the current pharmacological treatment
recommendations.
The study is divided into four periods of four months, with both groups
receiving the same cumulative amount of active medication during each period:
1. Month 1-4: After initial screening, patients who are eligible for stable
standard pharmacological treatment will start on MTX and prednisone.
2. Month 5-8: Only patients who completed the baseline period without
significant protocol violations as assessed by the rheumatologist and achieved
clinical remission (based on the rheumatologist's opinion, in principle on the
DAS < 1.6) will continue to the second phase of the study and will be
randomized to one of two groups. The different groups will follow different
treatment schedules:
2.1 Control group: standardized treatment dosage (240 mg MTX in total).
2.2 Conditioning group: variable treatment dosage (240 mg MTX in total).
3. Month 9-12: During the third period, MTX will be tapered and discontinued if
patients are still in clinical remission (based in the rheumatologist's
opinion, in principle on the DAS < 1.6), with dosages either decreasing
linearly (Control group) or variably (Conditioning group).
4. Month 16: End-of-study visit.

The intervention consists of pharmacological conditioning (variable treatment
dosage).

As the study closely follows standard treatment protocol for recent-onset RA,
most assessments will be conducted during regular patient visits to the
hospital (at initial screening and after each 4-month period), with each
appointment lasting approximately half an hour to one hour, thus a total time
investment of approximately three hours in 16 months. Blood samples will be
collected as part of standard care whenever possible. Additional blood samples
will be collected in order to determine cytokine values. Questionnaires that
will take approximately one hour to complete (totaling about 10 hours over a
period of 16 months), can be filled out at home. The study may lead to enhanced
treatment effects in the patients within theConditioning group and may lead to
new therapeutic possibilities for patients with RA and other chronic diseases
requiring long-term pharmacological treatment.