Detailed and consistent clinical and immunological monitoring of patients with Rheumatoid Arthritis who are treated with biological agents.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by
inflammation of joints leading to joint destruction. The onset, course of
inflammation, rate of progression of joint damage is different for each
patient. As thus far no curative therapy is available, the therapeutic
possibilities range from conventional disease modifying anti-rheumatic drugs
(DMARDs), to the more recent biological agents (such as anti-TNFalfa and anti-B
cell therapy). These drugs have been proven to effectively suppress
inflammation whereas "biologicals" might even result in retardation of joint
destruction.
Like the variability in the process of the disease, there is a significant
variability in the response to different "biologicals". Not all patients
respond (to the same extent) to the treatment they get first, second, or in
combination. Patients might thus be subject to potential delay in treatment
efficacy and thereby unnecessary irreversible joint destruction, unnecessary
side effects, and high costs. This in the light of the generally accepted
concept that tight control of these patients early in the disease process,
aimed at remission of disease, provides the best window of opportunity to limit
joint destruction and co-morbidity with major social-economic impact. It is
therefore of major importance to characterise patients with rheumatoid
arthritis in a consistent and detailed way by immunological and clinical
parameters, before, during, and upon change of "biologicals", to identify
subpopulations with specific characteristics, enabling more patient tailored
treatment in the future, preventing delay of treatment efficacy, unnecessary
side effects, and high costs.

With the help of state-of-the-art technologies patients can be characterized in
much more detail than clinical practice allows.
• Gene (mRNA) profiling makes it possible to evaluate a great number of genes
simultaneously, thus avoiding the cost- and time-consuming analysis of single
factors.
• Protein profiling by multicytokine analysis (e.g. Luminex) or specific
targets (such as biomarkers of cartilage and bone turnover) will be performed
on serum, plasma and/or urine samples used to characterize the patients.
Molecules include, but are not restricted to, pro- and anti-inflammatory
cytokines, proteases, and biomarkers of cartilage and bone turnover.
• Phenotypic characterization of sub populations of mononuclear cells will
provide differentiation between patients at the level of immunological
constitution and activity.
• Multiple clinical parameters are gathered and filed in a consistent way.
• Symtom profiling based on Chinese diagnosis can indicate differences in
response to biologicals.

Altogether this study contributes to the emergence of a more customized
treatment for patients with rheumatoid arthritis, preventing unnecessary delay
of treatment efficacy, side effects, and costs.

Proinflammatory cytokines are considered of key importance as initiating and
maintaining factors of fatigue and depressed mood. In rheumatoid arthritis,
the treatment with biologicals reduces disease activity by blocking specific
proinflammatory cytokines. This treatment offers a unique opportunity to
clarify this role of cytokines as a maintaining factor of fatigue and depressed
mood. Two-hundred patients will fill out short diaries daily to assess fatigue
and depressed mood.

The proposed study aims to develop a prediction rule for response to biological
treatment in RA (i.e. effectiveness and adverse events). Guidelines for
treating the disease with biologicals using the (derived) prediction rules will
be defined.
To develop a prediction rule we aim to identify immunological, clinical, and
symptom based characteristics that are predictive of the effectiveness of
different biological agents currently on the market for RA (i.e. anti-TNFa
agents, anti CD20, anti-T-cell activation, and anti-IL6R therapy) and the
characteristics that are predictive of side effects.
The aim of the diary part of the study is to examine whether and to what extent
a decrease of fatigue and depressed mood in rheumatoid arthritis after
treatment with biologicals is a direct effect of cytokine blockade or an
indirect effect of a reduction in disease activity.

Rheumatoid arthritis patients within the SRU (Stichting Reumaonderzoek Utrecht)
study group who start treatment with "biologicals" are asked to participate in
this immunological and clinical monitoring programme. Patient characteristics
and biomaterials are consistently gathered and stored (directly) in electronic
databases and biobanks.
Patient characteristics and biomaterials are gathered consistently and stored
in electronic databases and biobanks.

To evaluate clinical efficacy clinical parameters are evaluated at baseline
(before start with treatment with a new biological), at 3 and 6 months after
start of biological treatment, subsequently yearly and if treatment is stopped
due to inefficacy or side-effects. Questionnaires on "quality of life" and
radiographs of hand and feet are gathered at baseline and yearly. Additionally
patients are asked to fill in a questionnaire related to symptoms based on
Chinese diagnosis. These symptoms are used to find patterns of symptoms that
are predictive for a response on thearpy with biologicals.
To find predictive factors for respons on biologicals, urine and blood are
gathered to evaluate immunological characteristics, together with clinical
parameters.

Two-hundred patients will fill out short diaries during 28 consecutive days
with questions on their fatigue, mood state and disease-activity.

Not applicable