Training immune functions through pharmacotherapeutic conditioning in
juvenile idiopathic arthritis

A growing body of studies show that treatment outcomes can be influenced by
expectations and learned associations, also known as the placebo effect, in
both medical and psychological practice. Recently, these placebo effects have
been utilized in the context of drug therapy in order to optimize treatment
outcomes by using the principle of pharmacotherapeutic conditioning.
Pharmacotherapeutic conditioning is based on classical conditioning, where
repeated drug administration leads to a learned association. After the
association has been made, a learned response can now be induced by a placebo,
similar to Pavlov*s famous conditioning experiment where dogs start salivating
upon hearing a bell which indicates food. Medication regimens making use of
pharmacotherapeutic conditioning via principles of variable reinforcement
(varying doses of medication) have shown to lead to good therapeutic effects,
while significantly reducing adverse side effects. Methotrexate (MTX) is a
widely prescribed drug for rheumatic diseases in both children and adults, but
is frequently hampered by its severe side effects. Especially in children
diagnosed with juvenile idiopathic arthritis (JIA) who are treated with MTX as
the drug of first choice, side effects are common and new approaches to reduce
these burdensome side effects are urgently needed. This study specifically aims
to reduce these side effects by administrating MTX through a variable
reinforcement schedule.

This study*s objective is to reduce MTX related side effects with
pharmacotherapeutic conditioning, by using variable reinforcement principles in
patients with JIA. Pharmacotherapeutic conditioning enables to alternate
standard MTX dosing with lower MTX doses, by utilizing learning effects
(conditioning). By this, children with JIA will be less affected by MTX related
side effects, without compromising for its therapeutic efficacy. A reduction in
side effects will be assessed by intolerance percentages as defined by a cutoff
score of * 6 on the Methotrexate Intolerance Severity Score (MISS)
questionnaire.

A multicenter, clinical, randomized controlled trial will be conducted in
patients diagnosed with JIA, closely following current pharmacological
treatment recommendations. The study design is divided into 3 periods: 1. A
baseline period (6 months) where MTX stable doses are administered according to
standard dosing (12,5 - 15 mg/m²/wk). 2. Intervention period (9 months):
patients who have followed protocolized treatment and have shown a good MTX
response (based on JADAS <3 or based on the paediatric rheumatologist*s
opinion, will be randomized to control or intervention group. Both groups will
follow different MTX treatment schedules. Group 1 * Control group: Standard
MTX dosing schedules as a continuation of baseline period. Group 2 *
Conditioning group: Variable reinforcement schedule, where standard MTX dosing
is intermittent with subtherapeutic dosing (2,5 - 5 mg/m²/wk, depending on body
surface area). Duration of the intervention period is based on a recent
revision of clinical (Dutch) guidelines for MTX treatment for JIA. 3. Month 18:
End-of-study visit: Treatment effects will be followed up and (early) flare-ups
will be monitored.

The intervention consists of pharmacotherapeutic conditioning (variable
treatment schedule).

This study closely follows standard treatment for JIA, and assessments will
therefore be conducted during regular patient visits to the hospital (at
initial screening and subsequently visits every three months up till 18 months)
whenever possible, with each appointment lasting approximately half an hour
(time invested to complete questionnaires will be 10 to 20 minutes). Blooddraws
will take place during regular clinical blooddraws, and do not necessitate for
additional puncture, as blooddraws are part of standard of care.