Intima-media thickness evolution after treatment with infliximab in patients with rheumatoid arthritis.

Abstract

Atherosclerosis is a well known progressive disease that recognizes risk factors such as diabetes, hypertension, smoking, dyslipidemia, and inflammation. Mechanisms underlying atherosclerotic processes during inflammation are not completely understood, but cytokines are also involved, in particular tumor necrosis factor-alpha (TNF-alpha). Chronic inflammatory diseases such as rheumatoid arthritis (RA) are commonly associated with atherosclerotic complication. Little is known about the role of treatment of chronic inflammatory disease on the evolution of atherosclerosis in this kind of disease. Usually, evolution of atherosclerosis is monitored by intima-media thickness and the presence of plaques on several arteries such as common carotid.
The aim of the study was to monitor atherosclerosis evolution in seven RA patients on common treatment with infliximab (an anti-TNF-alpha drug) compared with seven RA patients during common treatment but not treated with infliximab.
We selected 14 patients with RA according to the American College of Rheumatology classification criteria. Seven patients were selected before and after common treatment for RA based on nonsteroidal anti-inflammatory drugs (NSAIDs), methotrexate, and steroids (12 months), and seven patients before and after treatment based on infliximab associated with NSAIDs, methotrexate, and steroids (12 months). Ultrasound vascular imaging was performed to screen intima-media thickness and the presence of atherosclerotic plaques on common carotid artery and identify evolution of atherosclerosis.
After 12 months, patients that were treated with infliximab showed significant worsening of atherosclerosis with an increase of intima-media thickness and the presence of further atherosclerotic plaques compared to patients that were treated traditionally and showed a nonsignificant increase of the same parameters.
Treatment based on anti-TNF-alpha such as infliximab shows a worsening evolution of atherosclerosis based on our data. If these data are associated with a poor clinical outcome such as atherothrombosis of cerebral vessels and/or coronary vessels, this should be evaluated by further studies.

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International Journal of General Medicine 2009:2 141–144
International Journal of General Medicine
141
S H O RT R E P O RT
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Intima-media thickness evolution after treatment
with infliximab in patients with rheumatoid
arthritis
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Pierpaolo Di Micco1,2
Paola Ferrazzi1
Luca Librè1
Loredana Mendolicchio1
Ilaria Quaglia1
Monica De Marco1
Anna Colombo1
Monica Bacci1
Lidia Luciana Rota1
Corrado Lodigiani1
1Thrombosis Center, Istituto Clinico
Humanitas, Rozzano (MI), Italy;
2Internal Medicine, Fatebenefratelli
Hospital of Naples, Italy
Correspondence: Pierpaolo Di Micco
Internal Medicine, Fatebenefratelli
Hospital of Naples, via san giacomo dei
capri 69-80131 – Naples, Italy
Email pdimicco@libero.it
Background: Atherosclerosis is a well known progressive disease that recognizes risk factors
such as diabetes, hypertension, smoking, dyslipidemia, and inflammation. Mechanisms underlying
atherosclerotic processes during inflammation are not completely understood, but cytokines are
also involved, in particular tumor necrosis factor-α (TNF-α). Chronic inflammatory diseases
such as rheumatoid arthritis (RA) are commonly associated with atherosclerotic complication.
Little is known about the role of treatment of chronic inflammatory disease on the evolution of
atherosclerosis in this kind of disease. Usually, evolution of atherosclerosis is monitored by intima-
media thickness and the presence of plaques on several arteries such as common carotid.
Aim: The aim of the study was to monitor atherosclerosis evolution in seven RA patients on
common treatment with infliximab (an anti-TNF-α drug) compared with seven RA patients
during common treatment but not treated with infliximab.
Patients and methods: We selected 14 patients with RA according to the American College
of Rheumatology classification criteria. Seven patients were selected before and after common
treatment for RA based on nonsteroidal anti-inflammatory drugs (NSAIDs), methotrexate,
and steroids (12 months), and seven patients before and after treatment based on infliximab
associated with NSAIDs, methotrexate, and steroids (12 months). Ultrasound vascular imaging
was performed to screen intima-media thickness and the presence of atherosclerotic plaques on
common carotid artery and identify evolution of atherosclerosis.
Results: After 12 months, patients that were treated with infliximab showed significant
worsening of atherosclerosis with an increase of intima-media thickness and the presence of
further atherosclerotic plaques compared to patients that were treated traditionally and showed
a nonsignificant increase of the same parameters.
Discussion: Treatment based on anti-TNF-α such as infliximab shows a worsening evolution
of atherosclerosis based on our data. If these data are associated with a poor clinical outcome
such as atherothrombosis of cerebral vessels and/or coronary vessels, this should be evaluated
by further studies.
Keywords: atherosclerosis, infliximab, rheumatoid arthritis, intima-media thickness
Background
Atherosclerosis is a well known progressive disease with risk factors that were
recognized by the Framingham study (ie, aging, hypercholesterolemia, hypertension,
diabetes, smoking, and family history of atherothrombosis).1 Recently inflammation
has been recognized as an additional atherosclerotic risk factor.2 Mechanisms under-
lying atherosclerotic processes during inflammation are not completely understood,
but increased production of reactive oxygen species (ROS) seems to be involved and
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seems to negatively interfere with reverse cholesterol
transport and triggering atherosclerotic processes.3–5
Chronic inflammatory diseases such as rheumatoid
arthritis (RA) are frequently associated with accelerated
atherosclerosis6 and with severe clinical presentations.7
Moreover, several markers of inflammation such as
C-reactive protein (CRP) are frequently increased in patients
with atherosclerosis. On the other hand, any cytokine
is increased during inflammation and are involved in
atherosclerotic processes. Some authors report increased
levels of several cytokines during RA such as intercellular
adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6), and
tumor necrosis factor-α (TNF-α).8–10
It is still unknown whether treatment of inflammatory
disease may improve the prognosis of atherosclerotic com-
plication in patients with RA. In particular, data about the
evolution of atherosclerosis in patients with RA taking ongo-
ing anti-TNF-α drugs such as infliximab are lacking.
This article evaluates the atherosclerotic evolution of
patients with RA on ongoing treatment with infliximab
compared to patients on ongoing common treatment by the
evaluation of intima-media thickness (IMT) and/or the pres-
ence of atherothrombotic plaques on common carotid with
ultrasound imaging.
Patients and methods
Patients
We selected 14 consecutive patients affected by RA accord-
ing to the American College of Rheumatology classification
criteria. Patients were randomly divided into two different
groups and assigned to two different treatment programs:
group A included patients selected for therapy based on treat-
ment with nonsteroidal anti-inflammatory drugs (NSAIDs)
on demand, steroids (per os, daily), methotrexate (intra-
muscular, weekly), and inflixmab (3 mg\kg at time 0 and
every eight weeks for one year); group B acted as a control
group and included patients selected for common treatment
based on NSAIDs on demand, steroids (per os, daily), and
methotrexate (intramuscular, weekly).
Group A included seven patients (six females and one
male; median age, 56 years), while group B included seven
patients (six females and one male; median age, 53 years).
Atherosclerosis evolution
Identification of atherosclerosis was performed with
ultrasound imaging with a 7–10 Mhz linear probe (Vivid 4;
GE Milan, Milan, Italy) in order to detect atherosclerotic
plaques and the presence and the evolution of IMT.
Ultrasound imaging was performed at the beginning of
treatment (time 0) and after 12 months (time 1) of treatment
for both groups.
Detection of IMT was performed three times on
common carotid of both sides at the origin and at the bulb
for all patients according to guidelines suggested by the
Italian Society for Angiology and Vascular Medicine. The
median value of three detections was considered as the main
value.
The imaging evaluation was performed as a double-blind
evaluation by two different physicians.
Clinical score
Disability related to RA for all patients was monitored
according to the Health Assessment Questionnaire (HAQ)
disability index11,12 and Disease Activity Score using 28
joint counts (DAS 28)11,12 at the beginning and at the end of
treatment (ie, time 0 and time 1).
Laboratory prognostic markers
Values of CRP were analyzed at time 0 and time 1 in order
to have a laboratory follow-up screening of the evolution of
RA in all selected patients in both groups.
Statistical analysis
Statistical analysis was performed with Student’s t-test for
paired data. Data were considered to be significant if p value
was  0.05.
Results
Our results are summarized in Table 1. We found an improve-
ment of clinical score (ie, DAS 28) in both groups at time
0 and time 1, which was statistically significant (p = 0.04
and p = 0.003, respectively).
Neither differences nor improvements were found in both
groups for disability score (ie, HAQ) at time 0 and time 1,
which was statistically nonsignificant (p = 0.3 and p = 0.3,
respectively).
Levels of CRP were similar in both groups at time 0 and
time 1, which was statistically nonsignificant (p = 0.8 and
p = 0.1, respectively).
Patients from group A being treated by ongoing inf-
lixmab and common therapy (NSAIDs, steroids, and
methotrexate), showed worsening IMT at time 1 compared
to time 0, which was statistically significant, while patients
from group B showed light worsening of IMT at time 1
compared to time 0 and this value was not statistically
significant.

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IMT evolution after treatment with infliximab in RA patients
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Discussion
Patients affected by RA are more at risk of developing
myocardial infarction and/or ischemic stroke when com-
pared to the general population13,14 because the presence
of chronic inflammation associated with the possible
presence of further atherothrombotic risk factors such
as hypertension, diabetes, smoking, dyslipidemia, and
family history of atherothrombosis. In recent years several
biological drugs have been associated with common treat-
ment of chronic inflammatory disease such as RA, based
on NSAIDs, steroids, and methotrexate.15 Prognosis, evalu-
ated by disability and activity score, seems to be better for
patients who have added biological drugs (ie, inflixmab,
etanercept, adalimumab, anakinra, etc)16 to traditional
therapy.
Infliximab, an anti-TNF-α drug, is one of the most
common biological drugs used for the treatment of RA.16
Treatment based on the administration of infliximab showed
several improvements in the prognosis of RA, in particular
advantages were found in several reports for disability
index (eg, HAQ) and also for the disease activity score
(eg, DAS 28).16 Improvements were discovered not only
on the global assessment, on the evolution of pain, and on
fatigue, but also for serological markers such as improve-
ment of CRP levels and for the improvement of endothelial
dysfunction.17–19 However, several side effects of treat-
ment based on infliximab were reported. A higher risk a
priori of infection development20,21 has been underlined by
several reports as the risk of recurrence of herpes zoster.22
Furthermore, from a cardiovascular point of view, several
side effects have been reported for patients in ongoing treat-
ment with infliximab such as congestive heart failure23,24 and
an unassociated improvement of arterial stiffness.16
Data about the evolution of atherosclerosis for patients
in ongoing treatment with infliximab are lacking in the
literature. Our data showed an improvement of clinical
parameters evaluated with the DAS 28 score for both
groups with RA. On the other hand, no different values were
discovered in both groups when we consider the disability
index (ie, HAQ) and CRP levels at times 0 and 1. Further
data regarding the clinical follow-up of chronic inflamma-
tory disease are lacking in our study and this aspect may be
considered as a partial study limitation.
However, the aim of our study is to focus on the evolu-
tion of the atherosclerosis in patients with RA treated or
untreated with infliximab. Interestingly, patients with RA
treated with infliximab showed worsening of asymptomatic
atherosclerosis analyzed by IMT and increasing evidence of
atherosclerotic plaques while the increase of IMT for patients
with RA treated with traditional drugs (ie, without infliximab)
was slight. We may speculate that the worsening of athero-
sclerosis in group A may be related to the possible influence
of other traditional atherosclerotic risk factors that have not
been considered in our report. However, although data on the
influence of traditional atherosclerotic risk factors are lack-
ing and actually should be considered as a study limitation,
we should consider two further relevant aspects: first of all,
we should relate this aspect to the altered metabolism of
lipoprotein during treatment with infliximab that has been
reported in the literature,25,26 but we may also consider that
the natural history of RA, in particular its mortality, seems
to be influenced mainly by atherothrombosis.27 Therefore,
for this reason, patients treated with inflixmab may show a
more advanced increase in IMT and asymptomatic plaques.
We may speculate on the adverse cardiovascular outcome of
such patients with RA treated with infliximab and this could
also be in agreement with previous reports that reported an
increased incidence of heart failure during treatment. It is
not clear whether this aspect of treatment based on inflixmab
may be a class effect or a dose-dependent effect or may be
associated with an increased incidence of atherothrombosis
of in any vascular region is not clear and should be evaluated
by further prospective studies focusing on the incidences of
thrombotic events.
Table 1 Clinical, imaging and laboratory follow up of patient with RA
Group A Group B
Time 0Time 1pTime 0Time 1pNormal values
IMT (mm)
0.84 ± 0.271.17 ± 0.39
0.026, s
1.07 ± 0.25 1.13 ± 0.24
0.2, ns
0.07
DAS 28
7.0 ± 1.4 4.8 ± 2.0
0.04, s
6.4 ± 1.254.9 ± 1.96
0.003, ns
HAQ
1.78 ± 0.751.41 ± 0.67
0.3, ns
1.36 ± 0.641.11 ± 0.74
0.3, ns
PCR (mg\dL)
2.54 ± 1.992.42 ± 2.79
0.8, ns
2.16 ± 2.101.45 ± 2.05
0.1, ns0.0–1.0
Abbreviations: DAS, Disease Activity Score; HAQ, Health Assessment Questionnaire; IMT, intima-media thickness; ns, not significant; PCR, polymerase chain reaction;
RA, rheumatoid arthritis.

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References
1. Castelli WP. Epidemiology of coronary heart disease: the Framingham
study. Am J Med. 1984;76(2A):4–12.
2. Novo S, Corrado E. Role of inflammation and infection in vascular
disease. Acta Chir Belg. 2005;105:567–579.
3. Parke AL, Ioannides C, Lewis DFV, Parke DV. Molecular pathology of
drugs-disease interaction in chronic autoimmune inflammatory diseases.
Inflammopharmacology. 1991;1:3–36.
4. Parke AL, Parke DV, Avery Jones F. Diet and nutrition in rheumatoid
arthritis and other chronic inflammatory diseases. J Clin Biochem Nutr.
1996;20:1–26.
5. Halliwell B, Gutteridge JMC. Free radicals in biology and medicine.
New York, NY: Oxford University Press; 2000.
6. Jurcut ¸ C, Jurcut ¸ R, Ta ˘na ˘sescu C. Cardiovascular risk and rheumatoid
arthritis: from mechanisms of atherosclerosis to therapeutic approach.
Rom J Intern Med. 2004;42:659–669.
7. Van Doornum S, McColl G, Wicks IP. Accelerated atherosclerosis:
an extraarticular feature of rheumatoid arthritis? Arthritis Rheum.
2002;46:862–873.
8. Ridker PM, Hennekens CH, Roitman-Johnson B, Stampfer MJ, Allen J.
Plasma concentration of soluble intercellular adhesion molecule 1 and
risks of future myocardial infarction in apparently healthy men. Lancet.
1998;351:88–92.
9. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentra-
tion of interleukin-6 and the risk of future myocardial infarction in
apparently healthy men. Circulation. 2000;101:1767–1772.
10. Bruunsgaard H, Skinhøj P, Pedersen AN, Schroll M, Pedersen BK.
Ageing, tumour necrosis factor-alpha (TNF-alpha) and atherosclerosis.
Clin Exp Immunol. 2000;121:255–260.
11. Pascual-Ramos V, Contreras-Yáñez I, Villa AR, Cabiedes J,
Rull-Gabayet M. Medication persistence over two years of follow-up
in a cohort of early rheumatoid arthritis patients: associated factors and
relationship with disease activity and with disability. Arthritis Res Ther.
2009;11:R26.
12. Macedo A, Oakley S, Gullick N, Kirkham B. An examination of work
instability, functional impairment, and disease activity in employed
patients with rheumatoid arthritis. J Rheumatol. 2009;36:225–230.
13. Lévy L, Fautrel B, Barnetche T, Schaeverbeke T. Incidence and risk
of fatal myocardial infarction and stroke events in rheumatoid arthritis
patients. A systematic review of the literature. Clin Exp Rheumatol.
2008;26:673–679.
14. Aviña-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM,
Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid
arthritis: a meta-analysis of observational studies. Arthritis Rheum.
2008;59:1690–1697.
15. Zintzaras E, Dahabreh IJ, Giannouli S, Voulgarelis M, Moutsopoulos HM.
Infliximab and methotrexate in the treatment of rheumatoid arthritis:
a systematic review and meta-analysis of dosage regimens. Clin Ther.
2008;30:1939–1955.
16. Van Doornum S, McColl G, Wick IP. Tumor necrosis factor antagonists
improve disease activity but not arterial stiffness in rheumatoid arthritits.
Rheumatology. 2005;44:1428–1432.
17. Hürlimann D, Forster A, Noll G, et al. Anti-tumor necrosis factor-alpha
treatment improves endothelial function in patients with rheumatoid
arthritis. Circulation. 2002;106:2184–2187.
18. Sidiropoulos PI, Siakka P, Pagonidis K, et al. Sustained improvement
of vascular endothelial function during anti-TNFalpha treatment in
rheumatoid arthritis patients. Scand J Rheumatol. 2009;38:6–10.
19. Gonzalez-Juanatey C, Testa A, Garcia-Castelo A, Garcia-Porrua C,
Llorca J, Gonzalez-Gay MA. Active but transient improvement of
endothelial function in rheumatoid arthritis patients undergoing long-
term treatment with anti-tumor necrosis factor alpha antibody. Arthritis
Rheum. 2004;51:447–450.
20. Weisman MH. What are the risks of biologic therapy in rheumatoid
arthritis? An update on safety. J Rheumatol Suppl. 2002;65:33–38.
21. Listing J, Strangfeld A, Kary S, et al. Infections in patients with
rheumatoid arthritis treated with biologic agents. Arthritis Rheum.
2005;52:3403–3412.
22. Strangfeld A, Listing J, Herzer, et al. Risk of herpes zoster in patients
with rheumatoid arthritis treated with ant-TNF-alpha agents. JAMA.
2009;301:737–744.
23. Curtis JR, Kramer JM, Martin C, et al. Heart failure among younger
rheumatoid arthritis and Crohn’s patients exposed to TNF-alpha
antagonists. Rheumatology (Oxford). 2007;46:1688–1693.
24. Slørdal L, Spigset O. Heart failure induced by non-cardiac drugs. Drug
Saf. 2006;29:567–586.
25. Saiki O, Takao R, Naruse Y, Kuhara M, Imai S, Uda H. Infliximab but
not methotrexate induces extra-high levels of VLDL-triglyceride in
patients with rheumatoid arthritis. J Rheumatol. 2007;34:1997–2004.
26. Popa C, van den Hoogen FH, Radstake TR, et al. Modulation of
lipoprotein plasma concentrations during long-term anti-TNF
therapy in patients with active rheumatoid arthritis. Ann Rheum Dis.
2007;66:1503–1507.
27. Levy L, Fautrel B, Barnetche T, Schaeverbeke T. Incidence and risk
of fatal myocardial infarction and stroke events in rheumatoid arthritis
patients. A systematic review of the literature. Clin Exp Rheumatol.
2008;26:673–679.