TApering strategies in Rheumatoid Arthritis remission induced by anti-TNF&classic DMARDs. Should we taper the classic DMARD or anti-TNF first?

Economic evaluation of tapering medication in Rheumatoid Arthritis (RA) is
important because of the increasing use of expensive biologicals in the
treatment of RA. Previous uncontrolled cohort studies showed that it is
possible to taper anti-TNF or MTX while maintaining remission of disease in
approximately 40% of the rheumatoid arthritis (RA) patients that use the
combination of MTX&anti-TNF. This is not yet common practice which may relate
to the fact that it is unclear which step down (tapering) regime would be
optimal. There are no head-to-head studies available comparing the tapering of
DMARDs, suchs as MTX, with tapering of anti-TNF in DMARDs&anti-TNF using
patients in clinical remission.

Our main aim is to evaluate the effectiveness and cost-effectiveness of two
tapering strategies:(i)DMARD tapering and (ii)anti-TNF tapering in RA patients
with DMARD&anti-TNF(etanercept, adalimumab, certolizumab or golimumab) induced
remission.

A multicenter randomised single-blind controlled trial with a parallel
cost-effectiveness study will be set up to compare the outcomes of the 2
tapering strategies over a 2-yr period

The aim of treatment is to maintain low disease activity as expressed by the
Disease Activity Score (DAS)<=2.4 while tapering the medication. Treatment
strategies will be tightly controlled, with patients being examined every three
months. The tapering strategy will be predefined for the first 12 months, after
which the rheumatologists are free to prescribe they see fit continuing
tight-controlled care aiming for remission. The appended flow diagram shows the
two tapering strategies over time.

1)Tapering DMARD
The DMARD will be tapered in 2 steps. First the baseline DMARD dosage will be
cut in half, followed in the second step by a quarter of the initial nbDMARD
dosage. Thereafter, DMARD will be stopped. During the first year of the study,
anti-TNF will be continued at the initial dosage. In case the classic DMARD was
successfully discontinued in the first year of the study, the anti-TNF will be
tapered during the second year of the study.

2)Tapering anti-TNF
Anti-TNF will be tapered in 2 steps. First the time between 2 gifts is
extended. Enbrel will be given each fortnight, Humira and Cimzia once every 4
weeks and Simponi once every two months. This is followed by half of the
initial dosage, that is 25 mg of Enbrel, 20 mg of Humira, 100 mg of Cimzia or
25 mg of Simponi..Thereafter, anti-TNF will be stopped. During the first year
of the study, the nbDMARDs will be continued at their initial dosages. In case
the anti-TNF was successfully discontinued in the first year of the study, the
classic DMARD will be tapered during the second year of the study.


Discontinuation of tapering
Tapering will be terminated at the time the DAS >2.4 or swollen joint count >
1. If the DAS increases above 2.4 the treatment will be intensified to the last
effective dosage when the patient was still in remission. E.g. if the patient
flares on MTX 12 1/2 mg per week and the previous step was MTX 25 mg per week,
the MTX dosage will be increased to the 25 mg MTX while anti-TNF is continued.
No further attempts will be taken to taper medication in the first year of the
study.

Participating in the TARA trial yields no extra risk for the patient. Patients
taper down their medication under the supervision of their rheumatologist. In
case disease activity increases the last effective dosage will be restarted.

In principle, the risk for having a disease flare for patients tapering down
medication in our study is no greater than that for patients tapering down
medication on a regular basis.

Benefits:
Participating in the study yields no direct benefit for the patient.

Burden:
De patient*s burden consists of:
- Three monthly visits to the research nurse (30-45 minutes/visit, visits will
be combined with the regular check-up visits at the rheumatologist).
- Three monthly completing of questionnaires (20-30 minutes).
- If available at the patient*s hospital: 5 ultrasonographic evaluations of the
joints (ca. 30 minutes/evaluation, will be combined with the regular check-ups
at the rheumatologist).
- Drawing of blood every 3 months (20 ml every visit; at baseline, in case of a
flare and 3 months after a flare max 104 ml every visit)