IMPROVED: Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease;A randomized clinical trial in patients with recent-onset arthritis to compare the efficacy of DMARD combination therapy including prednisone with combination therapy including adalimumab, a TNF-blocking agent.

During the last decades a dramatic change has taken place in the way rheumatoid
arthritis (RA) patients are treated. Disease modifying antirheumatic drugs
(DMARDs) are prescribed earlier in the disease course and often in combinations
with or without prednisone or a tumor necrosis factor (TNF)-blocking agent.
Frequent assessments, for instance using the Disease Activity Score (DAS), can
be used to adjust the medication in order to achieve optimal suppression of the
disease process, regardless of the therapeutic strategy used. For patients with
recently established RA, these changes have resulted in earlier suppression of
disease activity, earlier improvement in functional ability and less
radiological joint damage, without more side effects. Moreover, with these
novel insights in treatment strategies clinical remission appears to be a goal
within the reach of many patients.
In order to start treatment as early as possible, it has been argued to start
treatment even before the diagnosis of RA is made. Undifferentiated arthritis
(UA), defined as an inflammatory arthritis in which no definitive diagnosis can
be made, has been shown to progress to RA within 1 year in 6 to 55 % of cases,
dependent on the UA criteria used, with similar clinical and radiological
outcome as patients that presented with RA. Recently, the PROMPT-study showed
that treatment of UA patients with MTX monotherapy for one year postponed the
progression to RA and retarded radiographic progression during treatment. After
discontinuation of MTX, however, disease activity increased and patients still
progressed to RA, defined by fulfilling the criteria of the American College of
Rheumatology (ACR). It appears that if a window of opportunity exists in UA, in
which by temporary treatment the course of the disease can be fundamentally
altered, MTX monotherapy is not the treatment to rely on. Since combination
therapy is the superior therapy in established RA, initial combination therapy
aiming at clinical remission may also be the best choice for patients with
recent-onset UA.
Current knowledge suggests that combination therapies including prednisone or a
TNF-blocking agent with MTX as the anchor drug are most effective in
suppressing disease activity, reducing radiological damage and functional
disability and can even induce clinical remission in recent-onset RA. Even
short-term use of combination therapy can lead to long-term benefits. However,
there is still no systematic approach to the treatment of patients with
recent-onset arthritis. A head-to-head comparison of DMARD combination therapy
including prednisone and DMARD combination therapy including a TNF-blocking
agent could provide insight into which treatment is superior in efficacy and
cost-effectiveness with the most acceptable toxicity profile.
Therefore, we designed a randomized clinical trial to compare two combination
therapies, including prednisone or a TNF-blocking agent, in recent-onset
arthritis (UA and RA) patients aiming at clinical remission: the
IMPROVED-study: Induction therapy with Methotrexate and Prednisone in
Rheumatoid Or Very Early arthritic Disease. After the same initial treatment
with MTX and a tapered high dose of prednisone, the two different treatment
strategies will allow a comparison of efficacy, safety and cost effectiveness
of early treatment with a combination of MTX, SSZ, HCQ and low dose prednisone
(MSHP), versus treatment with a combination of MTX with the TNF-blocking agent
adalimumab.

The objectives of this study are:
* To determine the percentage of patients with recent-onset RA and UA who
achieve and maintain clinical remission on treatment with a combination of
methotrexate 25 mg/week and extended prednisone pulse (tapered high dose) after
4 months.
* To determine whether, if clinical remission is not achieved,
methotrexate+prednisone combination therapy should be extended with
sulphasalazine and hydroxychloroquine or switched to methotrexate+adalimumab
combination therapy.

This protocol describes a multicentre, randomized, single-blinded one-year
follow-up clinical trial comparing two combination therapies in patients with
recent-onset arthritis (UA and RA) aiming at clinical remission.

In an initial open parallel prospective desing all patients will receive an
initial combination therapy with MTX and tapered high dose prednisone. Patients
who do not achieve clinical remission after 4 months, defined as a disease
activity score (DAS) of <1.6, will subsequently be randomized into two
treatment arms.

1. Extended medication, adding hydroxychloroquine and sulphasalazine while
methotrexate and low dose prednisone are continued.

2. Switching to adalimumab and discontinuation of prednisone, while
methotrexate is continued.

1) The initial combination therapy includes methotrexate building up to 25
mg/day and prednisone pulse therapy starting with 60 mg/day and tapering to 7,5
mg/day in 7 weeks. Subsequently, methotrexate will be continued in a dose of 25
mg/day and prednisone in a dose of 7,5 mg/day for 4 months.


2) After 4 months, patients who did not achieve remission according to a DAS <
1.6 will be randomized into two different treatment groups:

A) Extended combination therapy with:
methotrexate 25 mg/day
prednisone 7,5 mg/day
sulfasalazine 2000 mg/day
hydroxychloroquine 400 mg/day

B) Switching therapy to:
methotrexaat 25 mg/dag
adalimumab injection subcutaneously 40 mg every other week

The burden for the patients associated with participation include systematic
physical joint examination, questionnaires, blood samples and X-rays of hands
and feet every four months for 1 year. At start and after 1 year a DEXA scan
and extra blood samples. At start screening for tuberculosis and hepatitis B,
consisting of lung X-ray, skin test and serology.

Possible risks to the patient are mainly associated with the toxicity of the
drugs used in both treatment arms:
- increased risk for tuberculosis or reactivation of hepatitis B infection
- increased risk for virus, bacteria and other infections
- skin injection reaction with erythema, itching
- allergic reactions including headache, nausea, dizziness, palpitations and
breathing problems
- possible increased risk for lymphoma
- central nervous system symtoms like tintling, muscle ache or stiffness

More general adverse events:
- gastrointestinal: nausea, vomiting, stomache ache
- huid: rash, stomatitis
- bloed: decrease in leucocytes
- liver function disturbances
- kidney function disturbances
- visus disturbances
- hypertension and hyperglycemia

Combination therapies as the ones used in this study, did not show more
toxicity than the single drugs in prior studies, with a comparable or higher
efficacy. Moreover, next to a direct expected beneficial effect for the
patients included,
this study will provide important scientific information for the amelioration
of treatment strategies for patients with recent-onset rheumatoid arthritis in
the future.