Autoantibody production in anti-TNF-alpha-treated patients.

Abstract

Targeting tumor necrosis factor alpha (TNF-alpha) has offered an additional therapeutic strategy against several rheumatic inflammatory disorders. The current use of TNF-alpha inhibitors allows physicians who manage these diseases and patients themselves to testify to an extraordinary efficacy, even though caution for possible adverse events must be maintained. Among these, the occurrence of autoimmune phenomena, encompassing new autoantibody formation and triggering of clinical manifestations, continues to be noted in published reports. Here, we review the current knowledge regarding the autoimmune phenomena linked to anti-TNF-alpha therapy in patients with rheumatic inflammatory disorders.

Full text

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Autoantibody Production
in Anti-TNF-?-Treated Patients
CRISTIANO ALESSANDRI, ROSSANA SCRIVO,
FRANCESCA ROMANA SPINELLI, FULVIA CECCARELLI,
LEONARDO MAGRINI, ROBERTA PRIORI, AND GUIDO VALESINI
Dipartimento di Clinica e Terapia Medica, Section of Rheumatology, Sapienza
Universit` a di Roma, Policlinico Umberto I, Roma, Italy
ABSTRACT: Targeting tumor necrosis factor alpha (TNF-?) has offered
an additional therapeutic strategy against several rheumatic inflamma-
tory disorders. The current use of TNF-? inhibitors allows physicians
who manage these diseases and patients themselves to testify to an ex-
traordinary efficacy, even though caution for possible adverse events
must be maintained. Among these, the occurrence of autoimmune phe-
nomena, encompassing new autoantibody formation and triggering of
clinical manifestations, continues to be noted in published reports. Here,
we review the current knowledge regarding the autoimmune phenomena
linked to anti-TNF-? therapy in patients with rheumatic inflammatory
disorders.
KEYWORDS: autoantibodies; human antichimeric antibodies (HACA);
infliximab; rheumatic inflammatory disorders
INTRODUCTION
Throughoutthelastdecadenewadvancesinknowledgeaboutthepathogenic
mechanisms underlying rheumatic inflammatory chronic diseases favored the
development of the so-called biological agents, arranged using recombinant
DNA technology (TABLE 1).
Tumor necrosis factor alpha (TNF-?) has been recognized as a key cytokine
intheinflammatorycascadeleadingtorheumatoidarthritis(RA),juvenileidio-
pathicarthritis(JIA),psoriaticarthritis(PsA),ankylosingspondylitis(AS),and
inflammatory bowel disease. TNF-? antagonists, while extremely efficacious,
may induce adverse events as well as the production of autoantibodies.1–7The
emergence of antinuclear antibodies (ANAs) and anti-double-stranded DNA
antibodies (anti-dsDNA) has been frequently reported; however, the clinical
Address for correspondence: Prof. Guido Valesini, Dipartimento di Clinica e Terapia Medica,
Sapienza Universit` a di Roma, viale del Policlinico 155, 00161 Roma, Italy. Voice: +39-06-49974631;
fax: +39-06-49974633.
guido.valesini@uniroma1.it
Ann. N.Y. Acad. Sci. 1110: 319–329 (2007). C ?2007 New York Academy of Sciences.
doi: 10.1196/annals.1423.034
319

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320 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
TABLE 1. Main biological agents developed for therapeutic purposes
Name Target moleculeIndications
Abatacept
Adalimumab
Alefacept
Anakinra
Eculizumab
Tocilizumab
HuMAX-15
Clenoliximab
Etanercept
Infliximab
Rituximab
CD80/CD86
TNF-?
CD2
IL-1
C5
IL-6 receptor
IL-15
CD4
TNF-?
TNF-?
CD20
RA
RA, AS, PsA
RA, PsA, psoriasis
RA
RA
RA
RA
RA
RA, JIA, AS, PsA, psoriasis
RA, AS, PsA, IBD
RA, SLE, lymphoma
RA = rheumatoid arthritis; IBD = inflammatory bowel disease; AS = ankylosing spondylitis;
PsA = psoriatic arthritis.
implications and the mechanisms underlying this phenomenon remain to be
clarified. On the other hand, the titer of anticyclic citrullinated antibodies
(anti-CCP) and rheumatoid factors (RFs) associated with RA seems to de-
crease, paralleling clinical response to anti-TNF-? therapy.4,8–10Moreover,
the appearance of antibodies directed against the TNF-? blocking agent is
possible mostly in patients at risk for loss of clinical response and adverse
reactions.11,12Finally, these compounds may rarely elicit autoimmune con-
ditions, such as lupus-like syndromes, demyelination, autoimmune hepatitis,
uveitis, and psoriasis.
NEW APPEARANCE OF NO DISEASE-ASSOCIATED
AUTOANTIBODIES FOLLOWING ANTI-TNF-? AGENTS
The induction of autoantibodies ranges widely from one anti-TNF-? to an-
other, even though the variability may also depend on the methods applied,
especially for anti-dsDNA antibodies (TABLE 2). The isotype of anti-dsDNA
antibodiesinducedinthecontextofTNF-?blockadeisconfinedalmostexclu-
sively to IgM or IgA, which disappear upon interruption of treatment.4,5,13,14
Conversely, the IgG isotype, more frequently observed in systemic lupus ery-
thematosus(SLE),israrelydetectable,suggestingthatonlyshort-termhumoral
immune response is moved by TNF-? blockade. The appearance of antiphos-
pholipid antibodies (anti-PL) following TNF-? inhibitors may be overesti-
mated because of other serological interferences or concomitant infections. In
fact, experimental models prove that infectious agents, through a molecular
mimicry mechanism, may induce anti-PL antibodies as well as clinical mani-
festations of antiphospholipid syndrome (APS).15In a long-term follow-up of
eight patients receiving etanercept, the emergence of anticardiolipin (anti-CL)
antibodies mainly in concomitance with upper respiratory tract infections was

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ALESSANDRI et al. 321
TABLE 2. Cumulative prevalence of autoantibodies in patients treated with different
TNF-? blocking agents
RASpA
AdalimumabEtanerceptInfliximabEtanercept Infliximab
ANAs28% (8)
12% (13)
11% (44)
27% (45)
12% (63)
0% (5)
55% (13)
53% (1)
82% (2)
69% (5)
92% (6)
95% (13)
81% (14)
7%b(1)
44%b(2)
16%d(2)
45%b(5)
8%c(6)
2%b(13)
42%†(15)
IgM 10%
IgG 7% (4)
IgG 0% (5)
IgM and/or
IgG 28% (14)
IgM 5%
IgG 1% (17)
30% (14)
89% (2)
87% (6)
85% (14)
9% (18)
Anti-dsDNA7%a(8)
4%c(44)
13%c(45)
0%b(5)
2–4% (64)
15%b(14)
57%b(2)
17%b(2)
40%c(6)
56%b(14)
0%d(18)
Anti-CL IgM and/or
IgG 4% (8)
IgG 0% (5)
IgM and/or
IgG 25% (16)
15–30% (64)
IgM 1%
IgG 3% (6)
NOTE: In all studies ANAs were detected by indirect immunofluorescence and anti-CL antibodies
by ELISA. Corresponding references, in italics, are in parentheses.
aEnzyme immunoassay;bindirect immunofluorescence;cradioimmunoassay;dELISA.
observed; none of the patients had a clinically evident APS and antibiotic ther-
apy normalized anti-CL antibody levels in all but one patient.7Nevertheless,
the Stockholm TNF-? follow-up registry documented an increased frequency
of both IgM and IgG anti-CL antibodies in patients treated with etanercept or
infliximab,withinfliximabassociatedwithworseclinicalresultsandmorefre-
quentseriousinfusionreactions.16Thisobservationwasnotconfirmedbyother
authors.17Other reactivities, such as anti-ENA, antihistone, antimyeloperoxi-
dase, antiproteinase 3, antimitochondrial, antismooth muscle, and antithyroid
antibodies, were rarely found after anti-TNF-? therapy.5,14,18,19
AUTOIMMUNE DISEASES ASSOCIATED
WITH THE USE OF ANTI-TNF-? AGENTS
Data from prospective and longitudinal studies clearly show that, despite
the high reported rate of ANAs and anti-dsDNA antibodies following treat-
ment with TNF-? inhibitors, overt clinical manifestations rarely occur, even

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322 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
during long-term follow-up.2,6,13,14,18A French national retrospective survey
reported 22 cases of drug-induced SLE in patients treated with anti-TNF-?
agents for inflammatory arthritides: a subset of patients had only skin involve-
ment, while a second group showed systemic manifestations, though ANAs
were present in all the patients.20Generally, discontinuation of the anti-TNF-
? led to a prompt resolution of symptoms within 18 weeks, but a case of
etanercept-induced subacute cutaneous lupus was also reported, in which the
lesions cleared with local corticosteroids and there was no need to withdraw
the therapy.21In some cases the appearance of SLE subsequent to the admin-
istration of anti-TNF-? agents has been questioned on the basis that pretreat-
ment antibody levels were not available or some of the clinical manifestations
used to classify the patient as SLE were actually present before starting ther-
apy.22,23On the contrary, positive de-challenge and re-challenge cases repre-
sent the strongest evidence that the TNF-? antagonists may induce features of
SLE.24,25
The use of TNF-? antagonists has revealed the potential for demyelinating
events:26–28the neurological involvement include optic neuritis, confusion,
encephalitis, myelitis, seizures, paresthesias, progressive weakness, Guillain–
Barr´ e syndrome, and chronic inflammatory demyelinating polyneuropathy,
often associated with demyelinating lesions that subside either partially or
completely upon stopping therapy.29
Recent published cases are focusing attention on a somewhat paradoxical
effect of biological agents: the propensity of inducing the immune-mediated
disordersthattheagentsthemselveshavebeenengagedtotreat,suchaspsoria-
sisanduveitis.ThedifferentTNF-?antagonistsnowadaysavailablehavebeen
shown to significantly reduce psoriatic skin lesions;30however, new onset or
exacerbation of psoriasis during anti-TNF-? treatment in patients affected by
RA,spondyloarthritis(SpA),orBeh¸ cet’sdiseasehavebeenreported.31–33This
phenomenon seems to be a class effect rather than a drug-specific effect and
mayrelatetothealteredimmuneresponsecausedbytheinhibitionofTNF-?in
susceptible individuals.34,35Similarly, though a positive effect of anti-TNF-?
ontheincidenceofflaresofanterioruveitishasbeendescribedinmanypatients
with severe AS and JIA,36–38a case of uveitis following etanercept treatment
for AS emerged.39It is possible that an increase in the population of autoreac-
tive T cells favored by TNF-? blockade, in conjunction with a peculiar profile
of adhesion molecules and cytokine pattern in susceptible subjects, may incite
the ocular inflammation.40
Finally, we recently observed a patient with PsA where infliximab induced
an autoimmune hepatitis with antismooth muscle and anti-dsDNA antibodies;
this resolved with the discontinuation of the drug and there was no relapse
after introducing etanercept.41
In conclusion, even if the appearance of autoimmune disorders has been
reportedinpatientswithinflammatoryimmune-mediateddiseasestreatedwith

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ALESSANDRI et al. 323
anti-TNF-? agents, a causal link is not certain because of the tendency to
overlap among different autoimmune diseases.42,43
MECHANISMS OF NO DISEASE-ASSOCIATED
AUTOANTIBODY INDUCTION
The molecular mechanisms responsible for autoantibody formation re-
main to be elucidated. Certainly, they are not restricted to disease back-
ground since their presence is demonstrable in different inflammatory con-
ditions.1–6,8,13–19,44–46A dysregulation of apoptosis with exposition of nuclear
antigens and consequent accumulation of nucleosomes has been evoked to
explain autoantibody occurrence in patients treated with anti-TNF-? agents.47
Besides,TNF-?favorstheupregulationoftheadhesionmoleculeCD44,which
has a role in the clearance of apoptotic neutrophils by phagocytes.48The re-
duced clearance of apoptotic debris may be also dependent on the significant
downregulation of C-reactive protein (CRP), usually operating in the removal
of such materials, observed after anti-TNF-? treatment;3,49this reflects the
findingsinserumamyloidPknockoutmice,50wherethelackofthismolecule,
a murine analogue of CRP, leads to an abnormal chromatin clearance and the
development of antibodies against nucleosomal constituents.
The protective role of TNF-? against autoimmunity is also expressed by the
capacity of stimulating CD8+ cytotoxic T lymphocytes to eliminate autore-
active B cells,51which may result in contrasting autoantibody induction, as
supported by animal models.29
In conclusion, the autoimmune phenomena associated with therapies aimed
at inhibiting TNF-? seem to be of poor clinical relevance and should not
represent a limitation to their use in daily practice. Nevertheless, the relatively
shortexperienceandtheabsenceofpredictivefactorsforcomplicationscannot
be ignored, and hence the need for close monitoring of patients undergoing
such treatments should remain imperative.
DISEASE-ASSOCIATED AUTOANTIBODY MODULATION
IN RA PATIENTS TREATED WITH ANTI-TNF-? AGENTS
Several studies have investigated the modifications of disease-associated
autoantibodies in RA patients during treatment with TNF-? inhibitors in the
effort to identify prognostic markers for clinical response. We reported a de-
crease in the titer of RF and anti-CCP antibodies after 24 weeks of infliximab
therapy in RA patients:9OF interest, a significant downregulation of these au-
toantibodies was observed only in sera of those who were clinically improved
according to ACR criteria. In another study the progressive reduction of RF

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324 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
andanti-CCPantibodytiterswasreportedbothinresponderandnonresponder
RA patients treated with infliximab.4Although anti-CCP antibodies were not
modulated by infliximab in a few reports,52,53other authors demonstrated that
lower levels of these antibodies at baseline were predictive of clinical response
to infliximab in RA patients.54The mechanisms by which infliximab reduces
autoantibodytitersmaybepartiallyduetothedecreaseinsynovium-infiltrating
inflammatory cells, with diminished production of autoantibodies.55
Data regarding etanercept and adalimumab are also conflicting. A signif-
icant reduction in the serum levels of RF and anti-CCP antibodies follow-
ing etanercept treatment was reported by different authors,8,10and, again, the
progressive reduction of autoantibody serum levels mirrored the response to
treatment.8On the contrary, a recent report showed that etanercept, but not
adalimumab, induced a significant increase in serum IgG and IgA RF:56Since
the total serum immunoglobulin isotype levels were unaltered, the increase of
RF might derive from an elevated number of post-switch cells, an activation
of RF-producing memory B cells or a switching of IgM RF-producing B cells.
More recently, IgA RF levels appeared significantly higher in nonresponder
RA patients than in responders, suggesting that the IgA-RF isotype may be
useful for predicting response to therapy with TNF-? inhibitors.57
IMMUNIZATION AGAINST TNF-? BLOCKING AGENTS
The detection of an immune response directed to the murine component
of the chimeric anti-TNF-? antibody infliximab58led to verification of the
potential immunogenicity of all anti-TNF-? drugs. The incidence of human
antichimeric antibodies (HACAs) has been reported to range widely, depend-
ing on the dosing regimen of the drug and on the use of concomitant im-
munosuppressanttherapy.58–60Interestingly,aninductionregimenfollowedby
scheduled maintenance infusions decreases the likelihood of antibody forma-
tion, probably by generating immune tolerance.61In a study conducted in 106
RA patients treated with infliximab, HACAs were detected in 13% of patients
after the first two infusions, with the incidence rising up to 30% and 44% at
3 and 6 months, respectively.11The immunization was associated with an in-
creasedriskoflossofefficacyandadversereactions,eventhoughconcomitant
methotrexate (MTX), but not other DMARDs, was capable of reducing the in-
cidenceofHACAs.11FastclearanceofinfliximabbyHACAsmayexplainwhy
some patients do not respond to treatment. This hypothesis was supported by
a negative correlation between the presence of HACAs with infliximab levels
and clinical response and suggests a neutralizing effect of these antibodies.62
Even fully human monoclonal antibody, adalimumab, can trigger an im-
mune response, leading to the development of human anti-human antibodies
(HAHAs). The results of the ARMADA trial show an incidence of HAHAs
lower than 1% in RA patients who were taking concomitant MTX,44while an

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ALESSANDRI et al.325
incidence of 12% has been described in patients treated with adalimumab as
monotherapy.63Surprisingly, a recent study reported a high prevalence (87%)
ofHAHAinagroupof15RApatients:12outofthe13patientswhodeveloped
the antibodies discontinued the therapy—half because of lack of efficacy and
half for adverse events.12
As expected, the fusion protein etanercept has a low immunogenicity pro-
file; in fact, fewer than 2% of patients developed antietanercept antibodies in
controlled clinical trials.64These antibodies are not neutralizing and do not
influence the clinical response to this compound.64
ACKNOWLEDGMENT
Dr. C. Alessandri is a recipient of a grant from Fondazione Umberto Di
Mario.
REFERENCES
1. CHARLES, P.J., R.J. SMEENK, J. DE JONG, et al. 2000. Assessment of antibodies to
double-stranded DNA induced in rheumatoid arthritis patients following treat-
mentwithinfliximab,amonoclonalantibodytotumornecrosisfactoralpha:find-
ings in open-label and randomised placebo-controlled trials. Arthritis Rheum.
43: 2383–2390.
2. DE RYCKE, L., E. KRUITHOF, N. VAN DAMME, et al. 2003. Antinuclear antibodies
following infliximab treatment in patients with rheumatoid arthritis or spondy-
larthropathy. Arthritis Rheum. 48: 1015–1023.
3. VERMEIRE, S., M. NOMAN, G. VAN ASSCHE, et al. 2003. Autoimmunity associated
with anti-tumor necrosis factor a treatment in Crohn’s disease: a prospective
cohort study. Gastroenterology 125: 32–39.
4. BOBBIO-PALLAVICINI,F.,C.ALPINI,R.CAPORALI,etal.2004.Autoantibodyprofile
in rheumatoid arthritis during long-term infliximab treatment. Arthritis Res.
Ther. 6: R264–R272.
5. ERIKSSON, C., S. ENGSTRAND, K.-G. SUNDQVIST, et al. 2005. Autoantibody forma-
tion in patients with rheumatoid arthritis treated with anti-TNF?. Ann. Rheum.
Dis. 64: 403–407.
6. FERRARO-PEYRET, C., F. COURY, J.G. TEBIB, et al. 2004. Infliximab therapy in
rheumatoidarthritisandankylosingspondylitis-inducedspecificantinuclearand
antiphospholipid autoantibodies without autoimmune clinical manifestations: a
two-year prospective study. Arthritis Res. Ther. 6: R535–R543.
7. FERRACCIOLI, G., F. MECCHIA, E. DI POI, et al. 2002. Anticardiolipin antibodies in
rheumatoidpatientstreatedwithetanerceptorconventionalcombinationtherapy:
direct and indirect evidence for a possible association with infections. Ann.
Rheum. Dis. 61: 358–361.
8. ATZENI, F., P. SARZI-PUTTINI, D. DELL’ACQUA, et al. 2006. Adalimumab clinical
efficacy is associated with rheumatoid factor and anti-cyclic citrullinated pep-
tide antibody titer reduction: a one-year prospective study. Arthritis Res. Ther.
8: R3.

Page 8

326ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
9. ALESSANDRI, C., M. BOMBARDIERI, N. PAPA, et al. 2004. Decrease of anti-cyclic
citrullinated peptide antibodies and rheumatoid factor following anti-TNF alpha
therapy (infliximab) in rheumatoid arthritis is associated with clinical improve-
ment. Ann. Rheum. Dis. 63: 1218–1221.
10. CHEN, H.A., K.C. LIN, C.H. CHEN, et al. 2006. The effect of etanercept on anti-
cyclic citrullinated peptide antibodies and rheumatoid factor in patients with
rheumatoid arthritis. Ann. Rheum. Dis. 65: 35–39.
11. BENDTZEN,K.,P.GEBOREK,M.SVENSON,etal.2006.Individualizedmonitoringof
drug bioavailability and immunogenicity in rheumatoid arthritis patients treated
with the tumor necrosis factor-inhibitor infliximab. Arthritis Rheum. 54: 3782–
3789.
12. BENDER, N.K., C.E. HEILIG, B. DROLL, et al. 2007. Immunogenicity, efficacy and
adverse events of adalimumab in RA patients. Rheumatol. Int. 27: 269–274.
13. CARAMASCHI, P., D. BIASI, M. COLOMBATTI, et al. 2006. Anti-TNF? therapy in
rheumatoid arthritis and autoimmunity. Rheumatol. Int. 26: 209–214.
14. DERYCKE,L.,D.BAETEN,E.KRUITHOF,etal.2005.Infliximab,butnotetanercept,
induces IgM anti-dsDNA antibodies as main antinuclear reactivity: biological
and clinical implications in autoimmune arthritis. Arthritis Rheum. 52: 2192–
2201.
15. BLANK, M., I. KRAUSE, M. FRIDKIN, et al. 2002. Bacterial induction of autoanti-
bodies to beta2-glycoprotein-I accounts for the infectious etiology of antiphos-
pholipid syndrome. J. Clin. Invest. 109: 797–804.
16. JONSDOTTIR, T., J. FORSLID, A.M. VAN VOLLENHOVEN, et al. 2004. Treatment with
tumor necrosis factor ? antagonists in patients with rheumatoid arthritis induces
anticardiolipin antibodies. Ann. Rheum. Dis. 63: 1075–1078.
17. VISVANATHAN,S.,C.WAGNER,J.SMOLEN,etal.2006.IgGandIgManticardiolipin
antibodiesfollowingtreatmentwithinfliximabplusmethotrexateinpatientswith
early rheumatoid arthritis. Arthritis Rheum. 54: 2840–2844.
18. SELLAM, J., Y. ALLANORE, F. BATTEUX, et al. 2005. Autoantibody induction
in patients with refractory spondyloarthropathy treated with infliximab and
methotrexate. Joint Bone Spine 72: 48–52.
19. ALLANORE, Y., J. SELLAM, F. BATTEUX, et al. 2004. Induction of autoantibody in
refractoryrheumatoidarthritispatientstreatedbyinfliximab.Clin.Exp.Rheuma-
tol. 22: 756–758.
20. MARCELLI, C., E. BOUCQUILLARD, J.L. SIAME, et al. 2005. Systemic lupus erythe-
matosus induced by anti-tumour necrosis factor alpha therapy: a French national
survey. Arthritis Res. Ther. 7: R545–R551.
21. BLEUMINK,G.S.,E.J. TERBORG,C.G.RAMSELAAR,etal.2001.Etanercept-induced
subacute cutaneous lupus erythematosus. Rheumatology (Oxf.) 40: 1317–
1319.
22. FERRACCIOLI, G.F., R. ASSALONI & A. PERIN. 2002. Drug-induced systemic lupus
erythematosus and TNF-alpha blockers. Lancet 360: 645.
23. CAIRNS, A.P., M.K. DUNCAN, A.E. HINDER, et al. 2002. New onset systemic lupus
erythematosus in a patient receiving etanercept for rheumatoid arthritis. Ann.
Rheum. Dis. 61: 1031–1032.
24. MOHAN,A.K.,E.T.EDWARDS,T.R.COTE,etal.2002.Drug-inducedsystemiclupus
erythematosus and TNF-alpha blockers. Lancet 360: 646.
25. SHAKOOR, N., M. MICHALSKA, C.A. HARRIS, et al. 2002. Drug-induced sys-
temic lupus erythematosus associated with etanercept therapy. Lancet 359: 579–
580.

Page 9

ALESSANDRI et al. 327
26. ENAYATI, P.J. & K.A. PAPADAKIS. 2005. Association of anti-tumor necrosis factor
therapy with the development of multiple sclerosis. J. Clin. Gastroenterol. 39:
303–306.
27. BERTHELOT, C.N., S.J. GEORGE & S. HSU. 2005. Distal lower extremity paresthesia
and foot drop developing during adalimumab therapy. J. Am. Acad. Dermatol.
53(Suppl. I): S260–S262.
28. BENSOUDA-GRIMALDI, L., D. MULLEMAN, J.P. VALAT, et al. 2007. Adalimumab-
associated multiple sclerosis. J. Rheumatol. 34: 239–240.
29. KRAUSE, I., G. VALESINI, R. SCRIVO, et al. 2003. Autoimmune aspects of cytokine
and anticytokine therapies. Am. J. Med. 115: 390–397.
30. PAPP, K.A. 2006. The long-term efficacy and safety of new biological therapies
for psoriasis. Arch. Dermatol. Res. 298: 7–15.
31. KARY, S., M. WORM, H. AUDRING, et al. 2006. New onset or exacerbation of
psoriatic skin lesions in patients with definite rheumatoid arthritis receiving
tumour necrosis factor ? antagonists. Ann. Rheum. Dis. 65: 405–407.
32. SFIKAKIS,P.P.,A.ILIOPOULOS,A.ELEZOGLOU,etal.2005.Psoriasisinducedbyanti-
tumor necrosis factor therapy. A paradoxical adverse reaction. Arthritis Rheum.
52: 2513–2518.
33. MATTHEWS, C., S. ROGERS & O. FITZGERALD. 2006. Development of new-onset
psoriasis while on anti-TNF? treatment. Ann. Rheum. Dis. 65: 1529–1530.
34. BERG,E.L.,T.Y OSHINO,L.S.ROTT,etal.1991.Thecutaneouslymphocyteantigen
is a skin lymphocyte homing receptor for the vascular lectin endothelial cell-
leukocyte adhesion molecule 1. J. Exp. Med. 174: 1461–1466.
35. FLIER, J., D.M. BOORSMA, P.J. VAN BEEK, et al. 2001. Differential expression of
CXCR3targetingchemokinesCXCL10,CXCL9,andCXCL11indifferenttypes
of skin inflammation. J. Pathol. 194: 398–405.
36. BRAUN, J., X. BARALIAKOS, J. LISTING, et al. 2005. Decreased incidence of anterior
uveitisinpatientswithankylosingspondylitistreatedwiththeanti-tumornecrosis
factor agents infliximab and etanercept. Arthritis Rheum. 52: 2447–2451.
37. SHARMA, S.M., A.V. RAMANAN, P. RILEY, et al. 2006. Use of infliximab in ju-
venile onset rheumatological disease associated refractory uveitis: efficacy in
joint and ocular disease. Ann. Rheum. Dis. Published online 14 Dec 2006 [doi:
10.1136/ard. 2006 065441].
38. BIESTER, S., C. DEUTER, H. MICHELS, et al. 2006. Adalimumab in the therapy of
uveitis in childhood. Br. J. Ophthalmol. 91: 319–324.
39. REDDY, A.R. & O.C. BACKHOUSE. 2003. Does etanercept induce uveitis? Br. J.
Ophthalmol. 87: 925.
40. VON ANDRIAN, U.H. & C.R. MACKAY. 2000. T-cell function and migration: two
sides of the same coin. N. Engl. J. Med. 343: 1020–1034.
41. GERMANO V., A. PICCHIANTI DIAMANTI, G. BACCANO, et al. 2005. Autoimmune
hepatitis associated with infliximab in a patient with psoriatic arthritis. Ann.
Rheum. Dis. 64: 1519–1520.
42. LAZARUS, M.N. & D.A. ISENBERG. 2005. Development of additional autoimmune
diseases in a population of patients with primary Sj¨ ogren’s syndrome. Ann.
Rheum. Dis. 64: 1062–1064.
43. MCDONAGH,J.E.&D.A.ISENBERG.2000.Developmentofadditionalautoimmune
diseases in a population of patients with systemic lupus erythematosus. Ann.
Rheum. Dis. 59: 230–232.
44. WEINBLATT, M.E., E.C. KEYSTONE, D.E. FURST, et al. 2003. Adalimumab, a fully
human anti-tumor necrosis factor monoclonal antibody, for the treatment of

Page 10

328 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
rheumatoidarthritisinpatientstakingconcomitantmethotrexate.TheARMADA
Trial. Arthritis Rheum. 48: 35–45.
45. FURST, D.E., M.H. SCHIFF, R.M. FLEISCHMANN, et al. 2003. Adalimumab, a fully
human anti-tumor necrosis factor-alpha monoclonal antibody, and concomitant
standard antirheumatic therapy for the treatment of rheumatoid arthritis: results
of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). J. Rheumatol.
30: 2563–2571.
46. GARCIA-PLANELLA,E.,E.DOMENECH,M.ESTEVE-COMAS,etal.2003.Development
of antinuclear antibodies and its clinical impact in patients with Crohn’s disease
treated with chimeric monoclonal anti-TNF alpha antibodies (infliximab). Eur.
J. Gastroenterol. Hepatol. 15: 351–354.
47. PITTONI, V. & G. VALESINI. 2002. The clearance of apoptotic cells: implications for
autoimmunity. Autoimmun. Rev. 1: 154–161.
48. HART,S.P.,G.J.DOUGHERTY,C.HASLETT,etal.1997.CD44regulatesphagocytosis
of apoptotic neutrophil granulocytes, but not apoptotic lymphocytes, by human
macrophages. J. Immunol. 159: 919–925.
49. GEWERZ, H., Z. XIAO-HUI & T.F. LINT. 1995. Structure and function of pentraxins.
Curr. Opin. Immunol. 7: 54–64.
50. BICKERSTAFF, M.C., M. BOTTO, W.L. HUTCHINSON, et al. 1999. Serum amyloid P
component controls chromatin degradation and prevents antinuclear autoimmu-
nity. Nat. Med. 5: 694–697.
51. VIA,C.S.,A.SHUSTOV,V.RUS,etal.2001.InvivoneutralizationofTNF-alphapro-
motes humoral autoimmunity by preventing the induction of CTL. J. Immunol.
167: 6821–6826.
52. DE RYCKE, L., X. VERHELST, E. KRUITHOF, et al. 2005. Rheumatoid factor, but
not anti-citrullinated protein antibodies, is modulated by infliximab treatment in
rheumatoid arthritis. Ann. Rheum. Dis. 64: 299–302.
53. CARAMASCHI, P., D. BIASI, E. TONOLLI, et al. 2005. Antibodies against cyclic cit-
rullinated peptides in patients affected by rheumatoid arthritis before and after
infliximab treatment. Rheumatol. Int. 26: 58–62.
54. BRAUN-MOSCOVICI,Y.,D.MARKOVISTS,O.ZINDER,etal.2006.Anti-cycliccitrulli-
nated protein antibodies as a predictor of response to anti-tumor necrosis factor-
alpha therapy in patients with rheumatoid arthritis. J. Rheumatol. 33: 497–500.
55. SMEETS,T.J.,M.C.KRAAN,M.E.VANLOON,etal.2003.Tumornecrosisfactoralpha
blockade reduces the synovial cell infiltrate early after initiation of treatment,
but apparently not by induction of apoptosis in synovial tissue. Arthritis Rheum.
48: 2155–2162.
56. YAZDANI-BIUKI, B., E. STADLMAIER, A. MULABECIROVIC, et al. 2005. Blockade of
tumour necrosis factor alpha significantly alters the serum level of IgG- and
IgA-rheumatoid factor in patients with rheumatoid arthritis. Ann. Rheum. Dis.
64: 1224–1226.
57. BOBBIO-PALLAVICINI,F.,R.CAPORALI,C.ALPINI,etal.2006.HighIgArheumatoid
factor levels are associated with poor clinical response to TNF? inhibitors in
rheumatoid arthritis. Ann. Rheum. Dis. 66: 302–307.
58. BAERT, F., M. NOMAN, S. VERMEIRE, et al. 2003. Influence of immunogenicity on
the long term efficacy of infliximab in Crohn’s disease. N. Engl. J. Med. 348:
601–608.
59. FARRELL, R.J., M. ALSAHLI, Y.T. JEEN, et al. 2003. Intravenous hydrocortisone
premedicationreducesantibodiestoinfliximabinCrohn’sdisease:arandomized
controlled trial. Gastroenterology 124: 917–924.

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ALESSANDRI et al. 329
60. AYBAY, C., S. OZEL & C. AYBAY. 2006. Demonstration of specific antibod-
ies against infliximab induced during treatment of a patient with ankylosing
spondylitis. Rheumatol. Int. 26: 473–480.
61. MAINI, R.N., E.W. ST CLAIR, F.C. BREEDVELD, et al. 1999. Infliximab (chimeric
anti-tumornecrosisfactoralphamonoclonalantibody)versusplaceboinrheuma-
toid arthritis patients receiving concomitant methotrexate: a randomized phase
III trial. ATTRACT Study Group. Lancet 354: 1932–1939.
62. HARAOUI, B., L. CAMERON, M. OUELLET, et al. 2006. Anti-infliximab antibodies
in patients with rheumatoid arthritis who require higher doses of infliximab to
achieve or maintain a clinical response. J. Rheumatol. 33: 31–36.
63. VAN DE PUTTE, L.B.A., C. ATKINS, M. MALAISE, et al. 2004. Efficacy and safety of
adalimumab as monotherapy in patients with rheumatoid arthritis for whom pre-
vious disease modifying antirheumatic drug treatment has failed. Ann. Rheum.
Dis. 63: 508–516.
64. KLARESKOG, L., J. WAJDULA, P. Y EH, et al. 2005. Low autoantibody and anti-
etanerceptantibodyformationandlackofimpactonclinicaloutcomesfollowing
5 years of treatment with Enbrel?in patients with rheumatoid arthritis. Arthritis
Rheum. 52(Suppl.): S348.