Effect of Adalimumab on Inflammatory Activity in Atherosclerotic Lesions in Patients with Reumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease which has been
associated with a sharply increased risk of cardiovascular disease (CVD) and
CVD-associated mortality. The pathobiology of this increased risk is largely
unknown. Traditional cardiovascular risk factor only partly explain the CVD
risk in these patients, suggesting that chronic inflammation itself contributes
to atherosclerotic plaque development and/or instability. Strategies to reduce
cardiovascular risk in RA include modification of traditional risk facors (e.g.
antihypertensive treatment, cholesterol lowering agents), as well as
anti-inflammatory treatment. Direct evidence that anti-inflammatory treatment
reduces CVD risk in RA is limited. Methotrexate, for example, appears to be
associated with reduced CVD risk(1), but randomised clinical trials to provide
high-grade evidence are lacking.
An intriguing hypothesis to explain the increased CVD risk is that the chronic
inflammatory state in RA enhances inflammation in atherosclerotic lesions.
Circulating pro-inflammatory cytokines, for example, may activate inflammatory
cells in atherosclerotic plaque. Limited evidence collected to date indeed
suggests that RA patients have an increased propensity to shown more pronounced
inflammation in atherosclerotic leasions.(2) Atherosclerosis is caused by
several mechanisms of which chronic arterial wall inflammation is the driving
force.(3) The biological composition and especially inflammatory state of an
atherosclerotic plaque, rather than the degree of stenosis, are the major
determinants of acute clinical events.
18-fluorodeoxyglucose positron emission tomography (18-FDG-PET) has recently
emerged as a promising modality for quantification of plaque inflammation.
Evidence collected to date indicates that this method is reproducible, valid
and responsive to treatment effects. Particularly in the regions of the aortic
arch and carotid arteries, PET provides reproducible 18-FDG uptake
quantification.(4;5) The degree of 18-FDG uptake in these regions has been
shown to correlate with histopathological measures of plaque inflammation,
which in turn correlate with CVD risk.(6) Apart from the background knowledge
of the importance of inflammtion in inducing plaque instability, the
applicability of this concept to 18-FDG uptake was recently confirmed in a
study showing that 18-FDG-uptake in atherosclerotic lesions was the strongest
predictor of CVD events.(7) In this study, 18-FDG uptake by large outweighed
the predictive value of calcified lesions, providing further support for a
crucial role of inflammation in plaque, and for 18-FDG-PET to detect this
inflammation. Finally, preliminary evidence suggests that 18-FDG-PET
quantification of plaque inflammation also is a variable which responds to
treatment, as evidenced by reduction in 18-FDG uptake in carotid vessels
following treatment with simvastatin.(8)
There is accumulating evidence for an increased carotid intima media thickness
(cIMT), a well established marker for subclinical atherosclerosis, in RA
patients in comparison to controls. A recent meta-analysis of the 22 controlled
investigations revealed a 0.09 mm cIMT increase in RA in comparison to
controls (9). However, this increase is smaller than expected in view of the
doubled CVD risk in RA. This observation fits in the above-mentioned hypothesis
that plaques might be
more prone to rupture due to the inflammatory state. Moreover, there are some
suggestions from the literature for an impressive reduction of the cIMT when
TNF blocking agents are administered.(10,11) This effect was not observed with
MTX. However, these two studies suffer from a poor design and obviously a
methodological sound styd is still required.
In summary, RA causes CVD presumably in part through plaque inflammation,
plaque inflammation can be imaged by 18-FDG-PET, and the effects of
anti-inflammatory treatment on plaque inflammation are unknown. These
considerations provide a rationale for studying the effects of
anti-inflammatory treatment on inflammation as a crucial aspect of plaque
phenotype. In addition, effects of antiinflammatory agents on intima-media
thickness may provide additional information on plaque burden.

(1) van Halm VP, Nurmohamed MT, Twisk JW, Dijkmans BA, Voskuyl AE.
Disease-modifying antirheumatic drugs are associated with a reduced risk for
cardiovascular disease in patients with rheumatoid arthritis: a case control
study. Arthritis Res Ther 2006; 8:R151.
(2) Aubry MC, Maradit-Kremers H, Reinalda MS, Crowson CS, Edwards WD, Gabriel
SE. Differences in atherosclerotic coronary heart disease between subjects with
and without rheumatoid arthritis. J Rheumatol 2007; 34:937-942.
(3) Ross R. Atherosclerosis -- An Inflammatory Disease. The New England
Journal of Medicine 1999; 340:115-126.
(4) Rudd JHF, Myers KS, Bansilal S, Machac J, Rafique A, Farkouh M et al.
18Fluorodeoxyglucose Positron Emission Tomography Imaging of Atherosclerotic
Plaque Inflammation Is Highly Reproducible: Implications for Atherosclerosis
Therapy Trials. Journal of the American College of Cardiology 2007; 50:892-896.
(5) Rudd JHF, Myers KS, Bansilal S, Machac J, Pinto CA, Tong C et al.
Atherosclerosis Inflammation Imaging with 18F-FDG PET: Carotid, Iliac, and
Femoral Uptake Reproducibility, Quantification Methods, and Recommendations. J
Nucl Med 2008; 49:871-878.
(6) Tawakol A, Migrino RQ, Bashian GG, Bedri S, Vermylen D, Cury RC et al. In
Vivo 18F-Fluorodeoxyglucose Positron Emission Tomography Imaging Provides a
Noninvasive Measure of Carotid Plaque Inflammation in Patients. Journal of the
American College of Cardiology 2006; 48:1818-1824.
(7) Rominger A, Saam T, Wolpers S, Cyran CC, Schmidt M, Foerster S,
Nikolaou K, Reiser MF, Bartenstein P, Hacker M. 18F-FDG PET/CT identifies
patients at risk for future vascular events in an otherwise asymptomatic cohort
with neoplastic disease. J Nucl Med. 2009;50:1611-20.
(8) Tahara N, Kai H, Ishibashi M, Nakaura H, Kaida H, Baba K et al.
Simvastatin Attenuates Plaque Inflammation: Evaluation by Fluorodeoxyglucose
Positron Emission Tomography. Journal of the American College of Cardiology
2006; 48:1825-1831.*
(9)***Van Sijl, Peters MJL, Knol DL, de Vet HC, Gonzalez-Gay MA, Smulders YM,
et al. Carotid Intima Media Thickness in Rheumatoid Arthritis as Compared to
Control Subjects Sem Arthritis Rheum 2010. [Epub ahead of print]
(10) Del Porto F, Laganà B, Lai S, Nofroni I, Tinti F, Vitale M et al.
Response to anti-tumour necrosis factor alpha blockade is associated with
reduction of carotid intima-media thickness in patients with active rheumatoid
arthritis.Rheumatology (Oxford). 2007;46:1111-5
(11) Ferrante A, Giardina AR, Ciccia F, Parrinello G, Licata G, Avellone G
et al.Long-term anti-tumour necrosis factor therapy reverses the progression of
carotid intima-media thickness in female patients with active rheumatoid
arthritis. Rheumatol Int. 2009 Apr 23. [Epub ahead of print]

Primary:
to compare inflammatory activity in atherosclerotic lesions between patients
with active RA and controls, and to address the potential of anti-inflammatory
therapy to reduce inflammatory atherosclerosis in RA patients.

Secondary:
1] to identify clinical and biochemical determinants of inflammatory activity
in atherosclerotic lesions in RA patients
2] to compare the potential of methotrexate and anti-TNF treatment with
adalimumab (Humira) to reduce inflammatory atherosclerosis
3] to assess the potential of anti-inflammatory drugs to reduce intima-media
thickness

After recruitment at the outpatient clinics all patients will be invited to
undergo baseline examination at the VUmc, which will include history, physical
examination, ECG, ultrasound examinations, blood- and urine collection and
18-FDG-PET. Afterward, the patients in whom adalimumab (Humira) is indicated
will start with the prescribed treatment as soon as possible. The patients in
the control group will be followed at the outpatient clinic by their regular
rheumatologist. Follow-up 18-FDG-PET will be performed 3-6 months after
initiation of therapy. Changes in cIMT will be assessed after 6 and 12 months
following anti-inflammatory treatment with methotrexate or dalimumab (Humira)
and in individuals with osteoarthritis. Also, changes in IMT will be assessed
after 24, 36, 48 and 60 months following adalimumab (Humira).
If a participant does not qualify any more for study participation, such as
when a participant using adalimumab (Humira) is bound to switch to another drug
due to therapy failure or side-effects, these participants will be excluded out
the study, but will be taken into account in post-hoc intention-to-treat
analyses.

18-FDG-PET-scan will be performed twice within a 3-4 month period. Chances for
allergic reactions or spurious findings on scanning are extremely low and
therefore the burden for patients minimal.
At each visit, participants will be asked about medication use, functional
status, pain and will be physically examined for swollen and tender joints and
blood pressure. Also, blood will be drawn from which levels of inflammatory
markers, lipids, glucose and insulin will be determined (for which patients
will need to be in a fasting state). Furthermore, an ultrasound examination of
the carotid arteries will be performed at each visit.