a pilot study to investigate the hepcidin levels in patients with rheumatoid arthtitis treated with IL-6R blockade

Anemia is a common condition in patients. Anemia is most frequently due to
absolute iron deficiency (i.e. blood loss) or functional iron deficiency due to
chronic inflammatory conditions (Anemia of Chronic Disease , ACD).
This latter form of iron deficiency can largely be attributed to the inhibition
of the release of stored iron from the Reticulo-Endothelial System (RES) as a
result of increased levels of circulating hepcidin (1,2).
The peptide hormone hepcidin is produced by the hepatocytes and the key
regulator of systemic iron homeostasis (2,3). Hepcidin leads to internalization
and subsequent degradation of iron exporter ferroportin, which is present on
the cell surface of macrophages and enterocytes (4).
In chronic inflammatory diseases such as rheumatoid arthritis, Chron*s disease,
chronic renal or heart failure and cancer, hepcidin production is elevated.
This results in a decrease of iron absorption from the intestine and the
sequestration of iron in the RES (5), leading to hypoferremia, a reduction of
iron available for erythropoiesis, and anemia.
This induction of hepatic hepcidin production upon inflammatory stimuli has
been shown to be predominantly induced by interleukin (IL)-6 by Janus Kinase
(JAK)-signal transducer and activator of transcription (STAT)-3 signalling
(6,7,8,9). More specific, Nemeth, Rivera, and colleagues showed that IL-6
induced hepcidin expression in hepatic cells (10). They have replicated this
effect using conditioned medium from endotoxin-treated macrophages and shown
that a neutralizing antibody against IL-6 blocked hepcidin induction. Other
inflammatory cytokines did not stimulate hepcidin production; in fact, TNF-*
inhibited it. Complementary experiments carried out in human volunteers by 2
different research groups in LA (USA) and Nijmegen (the Netherlands) showed
that IL-6 and LPS infusion stimulated urinary hepcidin excretion within 2
hours and 6 hours, respectively, and induced hypoferremia (7,10). Accordingly,
treatment with an IL-6 antibody significantly reduced serum hepcidin levels in
two patients with multicentric Castleman*s disease. In both cases , the level
of serum hepcidin dramatically dropped within 24 h after the first dose of
anti-IL-6R(11).
Taken together, these data provide strong support for the conclusions that IL-6
is a primary inducer of hepcidin expression and that increased hepcidin
expression results in hypoferremia. This is gratifyingly consistent with
clinical observations that hypoferremia occurs very quickly after the onset of
inflammation.
If inflammatory induction of hepcidin by IL-6 causes hypoferremia, it is
logical to predict that inhibition of hepcidin expression, activity or blockage
of the IL-6 receptor will ameliorate the anemia of inflammation. Anti-IL-6R is
the most readily available antagonist of hepcidin. Clinical trials on
effectivity and safety will be required to define appropriate indications for
its use in anaemia of chronic disease. This pilot study investigates hepcidin
kinetics in RA patients treated with anti-IL-6R.

Primary objective:

To determine the hepcidin levels before, 2, 4, 8 and 24 hours after the
administration of anti-IL-6R in patients with RA.


Secondary objective:

To determine the levels of Iron, transferrin , (calculation of transferrin
saturation), ferritin, Hb, CRP and IL-6 before, 2, 4,8 and 24 hours after
anti-IL-6R administration in patients with RA.

The study is an observational pilot study.
Blood samples will be taken before, 2, 4, 8 and 24 hours after the
administration of anti-IL-6R in patients with RA

No burden or risks with participation.