Randomised controlled study of dose reduction and withdrawal strategies of adalimumab and etanercept in rheumatoid arthritis: saving costs at what expense?

TNF blocking agents are effective in the treatment of Rheumatoid Arthritis
(RA), with Adalimumab (humira ®) and etanercept (enbrel ®) being the two most
frequently used agents in the Netherlands. These drugs are associated with side
effects, including a dose dependent increase risk for infection. Also, these
agents are much more expensive than traditional anti-rheumatic drugs (DMARD*s),
thus increasing the costs of treatment. Therefore, it seems rational to give
these drugs in the lowest effective dose or even stop the treatment when there
are no longer necessary.
There are data that suggest that dose reduction and withdrawal of TNF blocking
agents is feasible in a subgroup of patients without relevant increase in
disease activity. Using this approach, the same clinical outcome could be
reached with lower risk for side effects and less direct and total cost for
society. However, a number of patients will not be able to reduce dose of
medication. These patients will develop a temporary increase in disease
activity which may give adverse effects for example loss of quality of life and
radiologic damage. Therefore it is usefull to find predivitve factors for
succesfull dose reduction.

This study has 4 primary objectives:

1: To compare the cumulative incidence of patients fulfilling prespecified loss
of response/flare criteria in the intervention group with the usual care group
after 9 months and after 18 months of follow up.

2:To estimate cost effectiveness ratio of a protocollised dose
reduction/withdrawal strategy of adalimumab or etanercept compared to usual
care for the 9 months induction phase and for the 12 months maintenance phase.

3: To predict in the intervention group which baseline factors (including
[change in] serum drug levels and antibody levels and [change in] PET
arthritis) are associated with successful initial (9 months follow up) and
maintained (18 months follow up) dose reduction.

4: To assess the safety of this strategy with respect to proportion of patients
developing radiological damage (change in modified Sharp - van der Heijde18
Score > Minimal Clinical Important Change).

Pragmatic open randomized controlled cost effectiveness strategy trial,
stratified for anti-TNF agent. This study has an induction phase from 0 to 9
months and a maintenance phase from 6 to 18 months.
The induction phase starts at baseline and continues to 9 months follow up.
This phase will gave information about the period in which treating
rheumatologist is advised to actively reduce dose of anti-TNF in 6 months. This
part of the study ends 3 months after withdrawal of anti TNF in the patients
who are able to withdraw. The maintenance phase starts at 6 months follow up,
the time point where some patients can stop anti TNF, and continues to 18
months follow up. This phase will gave information about the period when
patients are on a stable lower dose of or stopped the anti TNF. This
distinction has been made, because it can be foreseen that the cost
effectiveness is very different between these time periods. In the induction
phase, medication costs are still high, patients are seen more often and
quality of life might be compromised by temporary flares. In the maintenance
phase, cost effectiveness may be substantially better for opposite reasons, and
this can probably be extrapolated to subsequent years.

In the intervention group usual care and tight control is provided and the
treating rheumatologist is advised to try to increase interval of adalimumab or
etanercept.
If a patient uses adalimumab the interval will be stepwise increased every
three months from 14 to 21 to 28 days, after that the adalimumab will be
stopped. If a patient uses etanercept, the dosage will be kept the same and the
interval will be stepwise increased every three months from 7 to 10 to 14 days,
after that the etanercept will be stopped. When a persistent flare occurs in
disease activity, the treatment is intensified and interval shortened back to
the last effective interval.

Planned visits every 3 months during the study are usual care and represent no
additional burden. Patients are asked to complete additional questionnaires.
Also a number of times during the study a serum sample will be taken and at 2
time points X-rays of hands and feet are made** wich is also consistent with
standard treatment.
There is a risk a flare of the rheumatoid arthritis will occur. This can
happen in the intervention group as well as in the usual care group. Patients
are encouraged to call if they experience more symptoms in between planned
visits. They can then come to the clinic.

A separate part of the study is the PET scan. This is done in the
intervention group, 1 or 2 times during the study. PET scan is not a standard
examination in the diagnosis of rheumatoid arthritis. The PET scan lasts 2
hours and there is a preparation to it. Patients who are pregnant or
breastfeeding are excluded from this part of the study.
Patients receive seperate information and informed consent form for this part
of the study.