TIP-glucocorticoids research UMCU rheumatology; Cardiovascular risk factors and insulin resistency in reumatoid arthritis patients with and without glucocorticoids.

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. Hench*s discovery of GCs and their applicability in RA in 1948 (1)
was granted the Nobel prize, but the high dosages which were used that time
caused many adverse effects. Nevertheless, GCs are a frequently used
anti-inflammatory and immune suppressive medication; 75% of RA patients in the
USA and 25% of the RA patients in Europe commonly uses GCs in combination with
other medication. Despite the fact that nowadays long-term effective
*biologicals* (like anti-TNFα) are at hand, an important part of the patients
is dependent on GCs. Moreover, the use of GCs in RA proved to slow joint damage
(2), next to suppressing disease activity, and they are an inexpensive
alternative to the expensive biologicals.

GCs have not been exactly positioned in the treatment of RA, because of the
balance between the positive effects and fear for adverse effects. Several
initiatives from Utrecht have studied this balance (3,4), nevertheless it was
concluded repeatedly that the adverse effects of GCs were not documented in a
standardized manner. Only if that occurs properly, can the exact position of
GC-treatment be determined. Additionally, a clear adverse effect profile could
show future GC-like drugs what to deal with.

Adverse effects which are part of the metabolic syndrome, e.g. insulin
resistance, hypertension, waist circumference, hypertension, and dyslipidemia,
could cause major morbidity and play a big part in RA patients (5,6), in which
active disease appears to play an important role. GCs seem to play a confusing
role in relation to these type of adverse effects, because high dose GCs induce
these kind of adverse effects, while their disease modifying ability could have
a positive effect. An example of a positive effect was shown by aggressive
anti-rheumatic therapy, amongst which GCs, which proofed beneficial for the
lipidspectrum (7). The exact pathophysiology of the metabolic syndrome has not
unraveled entirely, both as what role disease activity and disease modifying
drugs play.


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 metabolic adverse affects of RA patients, who
(chronically) use GCs in order to reduce disease activity, compared to RA
patients who don*t use GCs.

- To study the relation between disease activity, treatment, and metabolic
syndrome / insulin resistance.

- Cross-sectional.

- Monitoring:
o 1 measurement.
o Patients from the non-GC group who start treatment with low-dose GCs after
their measurement, will receive an extra measurement.

Procedure of the measurement:
- Patients need to be fasting and to collect morning urine. During the visit of
the measurement, first a history taking and physical examination take place.
After this serum is collected, followed by an Oral Glucose Tolerance Test
(OGTT). After the OGTT X-rays of hand, feet, lungs and spinal cord, and an
Electrocardiogram (ECG) are made, if this has not been done the last 12 months.

The risks of participation 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."