Deep profiling of lipid changes in patients with active ulcerative colitis treated with either tofacitinib or infliximab

Recently tofacitinib is registered for the treatment of moderately to severly
active ulcerative colitis (UC). In the tofactinib clinical development program
(OCTAVE), mild elevations in serum lipid levels in a proportion of those
receiving tofacitinib were described without further side effects. Mild
alterations in the lipid profile are also observed in patients with
inflammatory bowel disease (IBD) treated with infliximab (IFX). Although an
overall increase in total cholesterol and low density lipoprotein cholesterol
(LDL-C) is unwanted, an increase in high density lipoprotein cholesterol
(HDL-C) as a result of treatment might protect against cardiovascular events.
Moreover, these findings are consistent with the previously observed inverse
relationship between active inflammation and serum lipid levels in chronic
inflammatory disease including rheumatoid arthritis (RA) and psoriatic
arthritis (PA). The mechanisms by which the inflammatory process can lead to
these lipid changes are not fully understood.

To evaluate the tofacitinib and infliximab treatment-induced changes in plasma
lipids and lipoproteins and to provide insight in the underlying mechanism in
relation to the inflammatory status in patients with active UC.

This is a multicentre, prospective, observational, open label lipid mechanism
of action study. Patients with active ulcerative colitis will initiate
tofacitinib twice daily or infliximab infusions with a follow up period of 52
weeks measuring lipid levels at different time points. Tofacitinib induction
therapy 10mg twice daily orally for 8 weeks followed by maintenance therapy of
5mg twice daily. Infliximab induction therapy 5mg/kg at weeks 0, 2 and 6 and
subsequently maintenance therapy of infliximab every 8 weeks 5mg/kg

One study arm receives tofacitinib film-coated tablets for oral use of 10mg
twice daily during the induction phase with a duration of 8 weeks, before
continuing to the maintenance phase where tofacitinib will be prescribed twice
daily either 10mg or 5mg.
The other study arm receives infliximab intravenously in a dose of 5mg/kg in
weeks 0, 2 and 6 following the induction scheme from our protocol, continuing
with the same dose every 8 weeks during the maintenance phase.

Patients participating in this study will come to their habitual check-ups at
the department of Gastroenterology and Hepatology following the protocol of the
administered drug. One extra visit will be planned during the induction phase,
between week 4 and 6, since the OCTAVE trial showed interesting increase in
lipid profile in this time period. As additional burden, they will be asked to
collect an extra blood sample in the diagnostic centre combined with fecal
testing at home at certain time points during a study period of one year. They
will be asked to fill out questionnaires by telephone. In the OCTAVE
intervention studies upon which our main study parameters are based, despite
increasing cholesterol levels, major adverse cardiac events (MACE) were
infrequent and occurred in patients with multiple cardiovascular risk factors.2
These results were similar to those reported for rheumatoid arthritis (RA), a
larger study with longer follow-up3 and for other UC agents. Benefits of the
proposed therapies are the anti-inflammatory effects on UC disease activity.
This study will have direct impact on the management of patients with
ulcerative colitis by determining how tofacitinib and infliximab are involved
in the cardiovascular risk with regard to the lipid profiles before, during and
after therapy. If tofacitinib exerts a similar effectivity on disease activity
and a similar mode of action in altering the lipid spectrum compared to
infliximab, tofacitinib as an oral drug might potentially be regarded as a
first line therapy as well after failure of conventional treatment in the
treatment of active UC.