Induction of Cure in Early Arthritis. A single blind randomized clinical trial.

Based on previous research, rheumatologists in daily clinical now will start
treatment in patients with (suspected) rheumatoid arthritis as early as
possible, aiming at achieving rapid remission, and often will then start
tapering medication, potentially to nil. This approach has resulted in
significant improvements in the disease outcomes of patients with early RA. As
disease activity is rapidly and effectively suppressed, functional ability is
improved to almost normal and radiologic damage progression is prevented. In a
large proportion of RA patients it is now possible to taper, and sometimes
stop, medication.
In the Leiden EAC (early arthritis clinic) we have shown that there appears to
be a window of opportunity, where initiation of effective treatment may prevent
chronicity and induce sustained drug free remission. [2].

To date, rheumatologists are poised to recognize and treat UA patients as early
as possible, starting with methotrexate (MTX), a conventional synthetic Disease
Modifying Anti-Rheumatic Drug (csDMARD), in line with EULAR/ACR recommendation
1 on the treatment of early arthritis [3].
However, although the benefits of early treatment initiation for patients with
RA are clear, for patients with UA this is less so. Some may need only
temporary symptom relief with analgesics, non-steroid anti-inflammatory drugs
(NSAIDs) and/or a single injection with corticosteroids, as in up to 30% of UA
patients the symptoms go into spontaneous remission.[4]
Yet the majority of UA patients continue to have chronic arthritis, about half
of those progressing to classifiable RA. There have been few studies that
tested whether in UA early DMARD treatment results in induction of remission,
or even earlier symptom relief. In cohort studies. Methotrexate, dose adjusted
aiming at low disease activity (Disease Activity Score, DAS <=2.4) was tested
against placebo in the PROMPT study in 110 patients with undifferentiated
arthritis (UA), clinically (anti-citrullinated peptide antibodies, ACPA, were
at that time not routinely available) suspected to have early RA. The results
showed that in patients with ACPA, MTX prevented progression to RA, but when
MTX was stopped after 12 months, most patients still progressed. In UA patients
without ACPA, MTX did not outperform placebo. [5]
If early DMARD treatment is better than a wait and see policy, is MTX the best
option for treatment of UA? Despite having the reputation of being the *corner
stone* of RA treatment, MTX as initial monotherapy is only successful in
inducing early remission in a minority of patients with classifiable RA. [6-8]
Especially when aiming at rapid efficacy, a downside of MTX is that it is
slow-acting. International recommendations therefore advise to (temporary)
co-treat early RA patients with corticosteroids. And despite being generally
safe, MTX is associated with nausea, malaise and increased liver enzymes in
many patients. [9-11]
A recently developed multi-target antirheumatic drug, JAK-inhibitor
baricitinib, has been shown to be more and more rapidly effective than MTX in
patients with early RA [12]. It may be also more effective than MTX in
induction of rapid remission in patients with UA. If this would be so, it has
to be answered whether patients can then immediately stop baricitinib, or
whether it is better to continue for 6 more months to prevent relapses and
insure cure.

Primary Objectives:
* to establish
- which is the best treatment, MTX or baricitinib, to ensure rapid symptom
relief of recent onset UA, based on clinical and patient reported outcomes from
baseline to 3 months.

Secondary Objective:
* to establish
- which is the best strategy to ensure early remission (within 3 months) of
recent onset undifferentiated arthritis (UA): early treatment with MTX or
baricitinib or delayed treatment in case spontaneous remission does not occur
within 3 months.
- which is the best strategy to achieve cure (or sustained drug free remission)
of recent onset UA: early treatment with MTX or baricitinib
-which is the best treatment to prevent (or delay) progression of early
unclassified arthritis to rheumatoid arthritis
-which is the best treatment in terms of patients* (in)tolerance of medication
and reported side effects (including depressive feelings) and drug toxicity
over time
-which is the best treatment to ensure optimal functional ability over time
-which is the best treatment in terms of patients* satisfaction with treatment,
to be assessed after 3 months on NSAIDs, MTX or baricitinib

- Exploratory goals:
* to identify potential patient and/or disease characteristics which are
associated with clinical response and disease outcomes in the 3 treatment
strategy arms.
* to identify potential factors in illness perception and/or patient coping
strategies which are associated with functional outcomes and quality of life
(HAQ and SF-36) irrespective of disease activity.

This will be a single blind (using independent disease activity assessors)
randomized multicenter clinical trial.

Study group expertise
Our study group is uniquely prepared to conduct and complete the proposed
study. In the Netherlands there is an established practice to refer patients
with (suspected) arthritis as rapidly as possible to the rheumatologist. In our
rheumatology outpatient clinics we have reserved *slots* for such patients to
avoid referral delays. Since 1997 we systematically follow these patients up in
the Leiden Early Arthritis Clinic (EAC). Since 1993 we collaborate with
rheumatologists in hospitals in the Southwest of the Netherlands in the
Foundation for Applied Rheumatology Research. Together, we have done several
large multicenter studies in patients with early RA and/or UA to improve
treatment strategies for these patients: the BeSt study, PROMPT study and
IMPROVED study. Combined these studies have resulted in over 90 publications in
major rheumatology journals. Following up on data from the Leiden *clinically
suspect arthralgia* (CSA) cohort, we are currently doing an ongoing multicenter
randomized clinical trial to test methotrexate against placebo to see whether
(and in which) patients with CSA development of clinical arthritis can be
prevented. Thus we have shown to be in the forefront of developing treatment
improvements for patients with arthritis and we have the infrastructure,
knowledge and experience to conduct the currently proposed trial.

Nature and extent of the burden and risks associated with participation,
benefit and group relatedness
Patients will be asked to return for study visits every three months, to
undergo physical examinations and laboratory tests (ca 6 ml per blood draw),
fill in multiple questionnaires, have radiographs of hands and feet taken every
6 months, and follow the treatment protocol as determined by randomization. All
treatments in this study are registered medications, routinely used for
treatment of early unclassified arthritis, with the exception of baricitinib,
which is currently approved and used for the treatment of rheumatoid arthritis,
but is not used for early unclassified arthritis. This will be provided as
study medication in the current trial.
Benefits of participation are related to the benefits of intensive monitoring
and close access to care while in the study, and the potential access to
treatment with baricitinib, which in trials in rheumatoid arthritis patients
has proven to be more and more rapidly effective than methotrexate and safe.

Intervention
After giving informed consent, patients will be randomized to three treatment
arms:
-arm 1: treat symptomatically with NSAID or COXIB and a single dose of
intramuscular or local intra-articular corticosteroids and wait for spontaneous
remission.
-arm 2: methotrexate (or sulfasalazine as alternative) increased to max.
tolerated dose in 4 weeks, and a single dose of intramuscular or local
intra-articular corticosteroids. NSAID or COXIB allowed.
-arm 3: baricitinib and a single dose of intramuscular or local intra-articular
corticosteroids. NSAID or COXIB allowed.

Total study duration per patient: 12 months

Patients will be asked to return for study visits every three months, to
undergo physical examinations and laboratory tests (ca 6 ml per blood draw),
fill in multiple questionnaires, have radiographs of hands and feet taken every
6 months, and follow the treatment protocol as determined by randomization. All
treatments in this study are registered medications, routinely used for
treatment of early unclassified arthritis, with the exception of baricitinib,
which is currently approved and used for the treatment of rheumatoid arthritis,
but is not used for early unclassified arthritis. This will be provided as
study medication in the current trial.

Benefits of participation are related to the benefits of intensive monitoring
and close access to care while in the study, and the potential access to
treatment with baricitinib, which in trials in rheumatoid arthritis patients
has proven to be more and more rapidly effective than methotrexate and safe.