Top Institute Pharma (TIP) - research UMCU-rheumatology:
*Metabolic adverse events/co-morbidity in chronic rheumatoid arthritis patients*

Rheumatoid arthritis (RA) is a frequently occurring, chronic auto-immune
disease characterized by the
inflammation of joints, which leads to damaged cartilage and bone, and the
impaired ability to move. In
addition to long-term medication, like methotrexate, glucocorticoids (GCs) are
often used for treatment.

Co-morbidities which are part of the metabolic syndrome, e.g. insulin
resistance, hypertension, and dyslipidemia, can play a big role in RA-patients.
Active disease / inflammation appears to play an important part in these
co-morbidities: RA-patients have an increased chance of getting an
cardiovascular event, and a aggessive anti-rheumatic treatment has a postive
effect on the lipid spectrum. The exact role that disease activity and disease
modifying drugs play in the pathophysiology of the metabolic syndrome,
nevertheles hasn't been identified yet.

This research is part of the TI-Pharma project 'glucocorticoids'; This project
studies the influence of GCs and inflammation on insulin resistence and
metabolic syndrome. The pharmaceutical concern Organon evaluates a new compound
which selectively inhibits inflammation through GC-receptors, without causing
the metabolic/endocrine adverse events which are feared greatly, e.g. insulin
resistence, hypertension, and dyslipidemia. To determine the added value of
these new compounds with respect to these adverse events compared to
conventional GCs, these adverse events should first be examined adequately. The
department of endocrinology of the VUMC studies the influence of low-to-medium
dose GCs on the metabolic syndrome in healthy volunteers. With a 7-point
glucose tolerence test the beta-cel function is studied by looking at the
glucose, insuline/C-peptide ratio at 7 time-points over 2 hours. The department
of rheumatology of the VUMC studies metabolic syndrome using similar
measurements in early RA patients. Our department, rheumatology UMCU, also
evaluates metabolic syndrome and insulin resistence in the same manner, but in
RA-patients with a long disease duration (>2 year diagnosis RA). Because GCs
play a prominent role in the treatment of RA, the GC-load is studied as being
part of disease activity.

The relevance of the entire TI-Pharma project is the above mentioned
positioning of GCs in the treatment of RA, which is happening in the context of
new -under development- GC-like compounds, like the one in our TI Pharma
project. When metabolic adverse events of new GC-like compounds are studied,
then this should be positioned against the adverse events of the conventional
GCs. In our part of the project we therefore not only thoroughly study
metabolic syndrome in patients with chronic inflammation, but we also perform
the basic study against which future anti-inflammatory / anti-rheumatic
medications can mirror.


1. Hench P. Effects of cortisone in the rheumatic diseases. Lancet.
1950;2(17):483-4.
2. Kirwan JR, Bijlsma JWJ, Boers M, Shea BJ. Effects of glucocorticoids on
radiological progression in
rheumatoid arthritis. Cochrane Database SystRev. 2007(1).
3. Da Silva JA, Jacobs JW, Kirwan JR, Boers M, Saag KG, Ines LB, et al. Safety
of low dose glucocorticoid
treatment in rheumatoid arthritis: published evidence and prospective trial
data. Annals of the Rheumatic
Diseases. 2006;65(3):285-93.
4. Hoes JN, Jacobs JWG, Boers M, Boumpas DT, Buttgereit F, Caeyers N, et al.
EULAR evidence based
recommendations on the management of systemic glucocorticoid therapy in
rheumatic diseases. Report of
a task force of the EULAR Standing Committee for International Clinical Studies
Including Therapeutics
(ESCISIT). Ann Rheum Dis (in press). 2007.
5. Dessein PH, Tobias M, Veller MG. Metabolic syndrome and subclinical
atherosclerosis in rheumatoid
arthritis. JRheumatol. 2006;33(12):2425-32.
6. Pamuk ON, Unlu E, Cakir N. Role of insulin resistance in increased frequency
of atherosclerosis detected
by carotid ultrasonography in rheumatoid arthritis. JRheumatol.
2006;33(12):2447-52.
7. Boers M, Nurmohamed MT, Doelman CJ, Lard LR, Verhoeven AC, Voskuyl AE, et
al. Influence of
glucocorticoids and disease activity on total and high density lipoprotein
cholesterol in patients with
rheumatoid arthritis. Annals of the Rheumatic Diseases. 2003;62(9):842-5.

- To systematically determine the influence of disease activity of RA on the
metabolic syndrome of patients with chronic RA (disease duration > 2 years).

- Studie-design: Cross-sectional.
- Monitoring:
o 1 measurement.

The risks of this study are minimal.
With regards to the laboratory tests and OGTT the risks are neglectable, and
with regards to the radiation burden:
category IIb: "To justify risks in cat. IIa the benefit will probably be
related to increases in
knowlegde leading to health benefit. For risks in cat. IIb the benefit will be
more directly aimed at the cure
or prevention of disease."