- The main hypothesis of this study is that JIA patients at risk of a flare due to subclinical inflammatory activity may be identified by analysis of the phagocyte activity marker S100A12 and hsCRP. The goal is a stratification of the therapeutic…
ID
Source
Brief title
Condition
- Joint disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The outcome measures are basically the same used in the MTX withdrawal trial
already published [1]. Documentation is performed in intervals of 3 months in a
prospective manner, starting with time point 0 month = first documentation of
remission on medication. (alternatively 3 or 6 months). The documentation is
planned using the PRINTO core set criteria, as well as draft criteria for
definition of remission.
1) Patient data: Patient data will be collected as in CRFs
2) Patient history: Diagnosis, duration of disease, date of inclusion into the
study, maximum of affected joints, maximal combined medication, time point of
the discontinuation of DMARD/biological, time point of relapse (if applicable),
date of examination
3) Joints: Joint with swelling, joints with limited motion, and joint pain.
Joint with active arthritis is a joint with swelling not due to bony
enlargement or, if no swelling is present, limitation of motion accompanied
either by pain on motion and/or tenderness (16)
4) Core set criteria: 1) MD global assessment (VAS scale 0-10cm); 2) patient or
parental assessment (VAS scale 0-10 cm); 3) functional ability (CHAQ; grade 0-3
for 8 criteria; optionally CHAQ pain at defined time points); 4) number of
joints with active arthritis; 5) number of joints with limited range of motion;
6) erythrocyte sedimentation rate (ESR)
5) Criteria for clinical remission: 1) No joints with active arthritis; 2) No
fever, rash, serositis, splenomegaly, or generalized lymphadenopathy
attributable to JIA; 3) No active uveitis; 4) No elevation in ESR or/and CRP
attributable to JIA (if both are tested, both should be normal); 5) Physician*s
global assessment of disease activity indicates no disease activity (i.e. less
than VAS scale 1 cm)
Clinical remission On Medication: The criteria for the first documentation of
remission on medication must be met for a minimum of six continuous months and
maximum one year, in order for the patient to be considered to be in a state of
clinical remission on medication.
Clinical remission Off medication: The criteria for clinical remission must be
met for a minimum of 12 continuous months while off all anti-arthritis and
anti-uveitis medication in order for the patient to be considered to be in a
state of clinical remission off medication.
6) Definition of flare: Occurrence of any sign of active arthritis and/or
active systemic symptoms
7) Laboratory parameters: Documentation of the erythrocyte sedimentation rate
and/or standard CRP (whenever determined). In addition serum (2 ml freshly
centrifuged) will be obtained and shipped to the study center. Results of the
analysis will be provided to the center within 14 days to enable stratification
of the patient (i.e. withdrawal or continuation of therapy)
Secondary outcome
Serious adverse events, withdrawal from the study (if applicable)
Background summary
Juvenile idiopathic arthritis (JIA) is among the most relevant chronic
disabling diseases of childhood. It is a rare but potentially disabling
condition, which is today treatable. However, it often takes a remitting
disease course, needs immunosuppression for years, and the longterm outcome is
not easy to predict. Therefore, physicians have to balance the risk of doing
too little (e.g., withdrawing medication and provoking flares) vs. the risk of
doing too much (e.g., continuing medication despite a stable remission and
thereby accepting the risk of adverse effects). In the case of JIA,
methotrexate (MTX) is the most widely used diseasemodifying drug. Novel
therapies include biologics, e.g. TNF-Blockers such as etanercept or
adalimumab. Remission can be induced in most patients continuing medication
(also referred to as *remission on medication*) using combined
anti-inflammatory treatment, and up to 50% of such patients reach a continuous
status of remission after discontinuing medication (also referred to as
*remission off medication*). However, about half of the patients have flares
after withdrawing or tapering therapy. Clinical scores and routine laboratory
markers currently in use cannot detect residual inflammation that influences
the risk of flares when stopping treatment; hence, clinicians would benefit
from improved molecular biomarkers of inflammation. Reliable molecular markers
should allow stratification of patients: Those with high risk of relapse (due
to subclinical disease activity) should remain on therapy (or even
intensified), while in those with low risk therapy could be withdrawn.
Previous studies confirmed that JIA patients have flare rates of about 50%
after withdrawal of MTX, independent from the duration of MTX therapy after
remission is achieved. We have performed the first randomized, controlled trial
to assess therapy withdrawal in JIA. Our
controlled trial on MTX withdrawal revealed that the flare risk may be
significantly reduced if either therapy is continued (flare risk on medication
25%) or therapy was only withdrawn in patients with low S100A12/high
sensitivity C-reactive protein (hsCRP) levels (flare risk off medication 27% in
these patients). Three previous studies addressed the question of
therapy-withdrawal in JIA and the ability of a biomarker to identify patients
with risk of disease flares. In Muenster they have shown that the
Myeloid-related proteins (MRP8 (S100A8) and MRP14 (S100A9), which are secreted
by activated phagocytes and form a heterocomplex (MRP8/14 or 'calprotectin')
can be used as a predictive marker for the risk of flares. In JIA, MRP8/14 has
been shown to be a marker of subclinical disease activity not detectable by
clinical investigation or laboratory tests. While erythrocyte sedimentation
rate and C-reactive protein levels are not sensitive enough to assess residual
inflammatory joint disease, MRP8/14 is a marker of local disease activity, and
analysis of MRP8/14 levels detects subclinical inflammation that would exclude
immunological remission. MRP8/14 is a member of the family of *danger signals*
and an endogenous activator of toll-like receptor 4, which is involved in
innate immune mechanisms. It is specifically secreted from activated phagocytes
at local sites of inflammation. The protein complex is very stable, which is
important in clinical practice. Flares after withdrawal of therapy are related
to local disease processes not completely resolved, even though clinical
impression and acute phase reactants suggest remission. In Muenster they have
demonstrated that phagocyte-specific S100 proteins including MRP8/14 detect
subclinical inflammation influencing the risk for flares. In the clinical
setting it seems to be a clear benefit for the patient to use MRP8/14 as a
biomarker of synovial inflammation, as levels below 700 ng/ml make subclinical
disease activity at the time the test is performed unlikely (negative
predictive value, 98%). In further analyses, the more granulocyte-specific
protein S100A12, especially in combination with hsCRP has been demonstrated to
be an even more valuable predictive marker [9]. As this combination, with a
cut-off for S100A12 at 175 ng/ml and for hsCRP at 0.3 mg/dl, has been proven to
be better than MRP8/14 analyses alone, we propose a stratification of therapy
withdrawal decisions based upon a combined S100A12/hsCRP measurement.
Study objective
- The main hypothesis of this study is that JIA patients at risk of a flare due
to subclinical inflammatory activity may be identified by analysis of the
phagocyte activity marker S100A12 and hsCRP. The goal is a stratification of
the therapeutic approach: Maintenance therapy for patients with elevated levels
of the biomarkers, stop of therapy if both biomarkers are low.
- The second major hypothesis of this study is that a risk-stratified decision
on withdrawal of therapy is superior to treatment stop time point based solely
upon the clinicians* perspective (regarding the prevention of flares).
- An additional hypothesis is that the current definition of remission may be
refined, adding *immunological remission* as a status that will be robust
enough to last after discontinuing medication.
Study design
After inclusion into this study patients will be treated in a dynamic
stratification protocol to ensure a standardized therapeutic approach to all
JIA patients who have reached a status of disease remission on therapy.
- Therapy maintaining remission will be continued in patients who have ongoing
subclinical disease activity based upon molecular markers S100A12/hsCRP
(minimal residual disease activity).
- Therapy will be stopped as soon as the molecular marker S100A12/hsCRP
indicates that there is no subclinical disease activity.
1) WATCH-AND-WAIT PHASE
Visit W1 = Time point 0 months. First confirmation of remission on medication
(6 months + 6 weeks of inactive disease) on the basis of signs of disease
activity (no joints with active arthritis; no fever, rash, serositis,
splenomegaly, or generalized lymphadenopathy attributable to JIA; no active
uveitis; no elevation in ESR or/and CRP attributable to JIA; physician*s global
assessment of disease activity indicates no disease activity). At this point,
ONLY monotherapy with or a combination of non-steroidal anti-inflammatory drugs
(NSAIDs) plus DMARDs and/or biologics at a stable dose is allowed. Treatment is
continued with stable dosage after this time point. One NSAID is allowed.
S100A12/hsCRP analysis is performed and documented.
Visit W2 = Time point 3 months. Documentation of the clinical course after 3
months in remission. Confirmation of remission on medication. Alternatively
inclusion of new patients after 3 months in remission (9 months +/- 6 weeks of
documented inactive disease based on the criteria as mentioned above).
2) INTERVENTION PHASE
After 6 months the further approach will be based upon the biomarker result.
Therapy will be continued as long as S100A12 is above 175 ng/ml and/or hsCRP is
above 0.3 mg/dl. As soon as both biomarkers are below these cut-offs, therapy
will be withdrawn. The biomarker analyses will be performed every 3 months up
to 18 months after inclusion (intervention phase). Accordingly, there are 5
time-points when the decision to continue or immediately stop therapy will be
reconsidered. In patients who stop therapy, a follow-up of 12 months after
withdrawal will apply. If S100A12/hsCRP stays above the threshold over the
whole study, therapy will be continued for 18 months in total. Afterwards, the
decision to continue or stop will be left to the physician with further
follow-up of 12 months.
Visit I1 is the last alternative time-point of inclusion of new patients after
6 months in remission (12 months +/- 6 weeks of documented inactive disease
based on the criteria as mentioned above).
Visits I1-5 = Time points 6, 9, 12, 15, and 18 months. Visits will be performed
every 3 months. Confirmation of remission; serum is obtained and instantly
shipped to Muenster. S100A12/hsCRP analysis is performed and reported to the
center within 14 days for further intervention. Therapy will be continued as
long as S100A12 is above 175 ng/ml and/or hsCRP is above 0.3 mg/dl. As soon as
the biomarker is below this cut-off, therapy will be withdrawn. The decision
will be reported to the patient by the responsible physician. The biomarker
analyses will be performed every 3 months up to 18 months after inclusion
(intervention phase). Accordingly, there are 5 time-points when the decision to
continue or immediately stop therapy will be reconsidered. If patients stop
therapy at any of the time point in the intervention phase, they enter the
follow-up phase.
3) FOLLOW-UP PHASE
Visits F1-4 = Time points minimally 9, 12, 15, and 18 months (if stopped at
earliest possible time point = visit I1); maximally 21, 24, 27, and 30 months
(in patients who do not stop during the intervention phase). In those who stop
therapy, a follow-up of 12 months after withdrawal will apply, i.e. the last
visit will be the visit at 12 months after stopping therapy. If S100A12/hsCRP
stay above the threshold over the whole intervention phase, therapy will be
continued during the whole intervention phase. Afterwards, they will enter the
follow-up phase after 18 months. The decision to continue or stop will be left
to the physician with further follow-up of 12 months. As a minimum requirement,
the outcome 12 months after withdrawal needs to be recorded.
Intervention
Withdrawal of therapy if at least 6 months clinical remission on medication AND
S100A12 <175 ng/ml AND hsCRP< 0.3 mg/dl
Study burden and risks
Regarding burden: the patients simply get their 3-monthly clinic visit with the
standard questionnaire, physical and blood tests. Per visit, only one tube (2
ml serum) additional bloodsample is needed for this study.
In terms of risk: It has already been shown for methotrexate that using this
bloodtest might reduce the risk of a relapse to 27% instead of the 50% that it
is today. The risk of side effects for the individual by using an
anti-rheumatic drug (that they use for a long time) up to one year longer is
minimal.
The standard treatment is currently that the physician stops medication without
knowing whether there is subclinical activity and does not know the blood
levels of hsCRP and S100A12 with the result that the withdrawal has the same
value as a coin toss: in half of the patients a recurrence of arthritis
appears. We believe it would be better to take this decision with knowledge of
hsCRP and S100A12 before discontinuing therapy.
Schlossplatz 2
Muenster 48149
DE
Schlossplatz 2
Muenster 48149
DE
Listed location countries
Age
Inclusion criteria
Patients with polyarticular course of any JIA subcategory (including extended oligoarthritis
and polyarticular course of systemic JIA without systemic features) will be included at first
confirmation of remission on medication, i.e. after clinically documented inactive disease (no
joints with active arthritis; no fever, rash, serositis, splenomegaly, or generalized
lymphadenopathy attributable to JIA; no active uveitis; no elevation in ESR or/and CRP
attributable to JIA; physician*s global assessment of disease activity indicates no disease
activity) for at least 6 months. Alternatively patients can be enrolled until 12 months (+/- 6
weeks) to ensure access to the study after 6 months of inactive disease. At the time
remission is documented, patients may be ONLY on non-steroidal anti-inflammatory drugs
(NSAIDs) plus DMARDs and/or biologics at a stable dose. Only approved medication is
allowed during the study. Steroids must have been withdrawn at least 1 month before
remission is documented. Intraarticular joint injections should not have been performed 6
months before remission is documented. At inclusion into this study patients will be
considered being in clinically documented remission on medication.
Exclusion criteria
Patients with persistent oligoarthritis subtype or systemic JIA having systemic features
(within 1 year prior to inclusion) are excluded.
In addition, patients may not have received treatment with steroids in the month before remission is first documented or treatment with intraarticular joint injections etc. in the 6 months before remission is first documented.
Patient with a history of uveitis or macrophage activation syndrome are excluded.
Patients may also not be included if withdrawal of any biological drug has ever been unsuccessful in the past.
Patients who are not followed for pharmacovigilance in our anonymized Pharmachild-database.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-003956-18-NL |
| Other | ISRTCN 69963079 |
| CCMO | NL45211.041.13 |