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.
Article: Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor alpha: findings in open-label and randomized placebo-controlled trials.[show abstract] [hide abstract]
ABSTRACT: To compare the incidence of anti-double-stranded DNA (anti-dsDNA) antibodies in rheumatoid arthritis (RA) patients receiving either single or multiple doses of a chimeric anti-tumor necrosis factor alpha (anti-TNFalpha) antibody or placebo infusions, with or without methotrexate, in open-label, randomized, placebo-controlled trials. Multiple sera obtained from 156 patients before and after treatment with infliximab and from 37 patients treated with placebo infusions were tested for anti-dsDNA antibodies by 3 methods: Crithidia luciliae indirect immunofluorescence test (CLIFT), a commercial Farr assay (Ortho Diagnostics radioimmunoassay [RIA]) in which the antigen source is mammalian DNA, and a Farr assay employing 125I-labeled circular plasmid DNA (Central Laboratory of The Netherlands Red Cross Blood Transfusion Service [CLB] RIA). Patients with positive findings on the CLIFT were also tested for antibodies to histones (H1-H5) and chromatin and for IgM rheumatoid factors (IgM-RFs). None of the RA patients had a serum sample that was positive for anti-dsDNA antibodies by the CLIFT prior to infliximab therapy. Of the 22 patients who developed a positive CLIFT result, 11 (7% of 156 exposed to infliximab) also had positive findings on the Ortho RIA at a concentration of >10 units/ml and another 8 (5%) were positive at a concentration of >25 units/ml. In all but 1 patient, the anti-dsDNA antibodies were solely of the IgM isotype. Only 1 patient had detectable anti-dsDNA antibodies by the CLB RIA. All sera containing anti-dsDNA by the CLIFT contained antibodies to chromatin, and sera from 2 patients also contained antibodies to histones. IgM-RF titers showed a significant reduction following infliximab therapy in these 22 patients. One patient developed anti-dsDNA antibodies of IgG, IgA, and IgM isotype and had positive results on both Farr assays (peaking at 22 weeks and resolving by 54 weeks); this was associated with a reversible lupus syndrome. Anti-dsDNA antibodies of IgM class are induced by infliximab therapy; the frequency is dependent on the assay method used. Only 1 of the 156 patients who were treated with infliximab developed a self-limiting clinical lupus syndrome; that patient developed high titers of anti-dsDNA antibodies of IgG, IgM, and IgA class, as detected by the CLIFT and by 2 different Farr assays.Arthritis & Rheumatism 11/2000; 43(11):2383-90. · 7.87 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: Research on autoantibody formation in patients treated with TNF alpha inhibitors has produced contradictory results. To study the prevalence of autoantibodies in patients with rheumatoid arthritis treated with the TNF alpha inhibitor infliximab. 53 patients (48 female, 11 male) treated with infliximab for rheumatoid arthritis were followed for autoantibody production before treatment and after 14, 30, and 54 weeks. Six patients treated with etanercept were studied for comparison. The analyses included antibodies against nuclear antigens (ANA), extractable nuclear antigens, double stranded (ds)DNA (by ELISA, IIF on Crithidia luciliae for IgM and IgG, and Farr assay), nucleosomes, cardiolipin, smooth muscle, mitochondria, proteinase 3, and myeloperoxidase antigens. The number of patients treated with infliximab who developed antibodies against dsDNA of both IgG and IgM class (tested by IIF) increased significantly. The prevalence of patients positive for IgG class increased to 66% at 30 weeks and 45% at 54 weeks, and of IgM class to 85% and 70%, respectively. The titre and number of patients expressing antibodies against nucleosomes and ANA also increased significantly. The number of rheumatoid factor or anticardiolipin positive patients was stable and there was no increase in antibodies against the other antigens. A lupus-like syndrome was seen in one patient. No patient treated with etanercept developed any of these autoantibodies. Patients treated with infliximab may develop anti-dsDNA antibodies of both IgM and IgG class, anti-nucleosome antibodies, and ANA, with a gradual increase until 30 weeks.Annals of the Rheumatic Diseases 04/2005; 64(3):403-7. · 8.73 Impact Factor
Article: Anticardiolipin antibodies in rheumatoid patients treated with etanercept or conventional combination therapy: direct and indirect evidence for a possible association with infections.[show abstract] [hide abstract]
ABSTRACT: To assess the occurrence of anticardiolipin antibodies (ACA) (as well as of anti-DNA antibodies) in patients with rheumatoid arthritis treated with etanercept or combination therapy. Eight patients treated with etanercept 25 mg twice weekly were studied for a period of 85 weeks. A control group of 39 patients with rheumatoid arthritis undergoing combination treatment (methotrexate (MTX) + cyclosporin A or MTX + chloroquine) were studied for the same period of time. The occurrence of anticardiolipin antibodies (ACA-IgG) and anti-DNA was examined, together with the possible occurrence of infections due to bacteria capable of inducing B cell activation. In 5/8 patients receiving etanercept an increase of ACA-IgG was seen, while anti-DNA became positive in 3/8 patients. A nasal or bronchial infection due to Staphylococcus aureus (Staph aureus) or a urinary tract infection due to E coli, occurred in all five cases. Antibiotic treatment produced a return to normal of ACA-IgG, and also of anti-DNA, in all cases except one. The infectious agent was eradicated in all subjects but one. In the control group Staph aureus was found in the nasal swab in 10/39 subjects; ACA-IgM (followed by ACA-IgG) appeared at the same time as infection occurred in 6/10, while no infection related to the increased ACA-IgM was recorded in the other four. Bacterial DNA, especially that enriched in CpG motifs, is a powerful immunostimulant that may, in some cases, lead to ACA or anti-DNA positivity, once tumour necrosis factor alpha is blocked. Eradication of the infections leads to a rapid decrease of ACA-IgG and of anti-DNA levels.Annals of the Rheumatic Diseases 05/2002; 61(4):358-61. · 8.73 Impact Factor
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
KEYWORDS: autoantibodies; human antichimeric antibodies (HACA);
infliximab; rheumatic inflammatory disorders
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
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;
Ann. N.Y. Acad. Sci. 1110: 319–329 (2007). C ?2007 New York Academy of Sciences.
320 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
TABLE 1. Main biological agents developed for therapeutic purposes
Name Target moleculeIndications
RA, AS, PsA
RA, PsA, psoriasis
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
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-
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
ALESSANDRI et al. 321
TABLE 2. Cumulative prevalence of autoantibodies in patients treated with different
TNF-? blocking agents
IgG 7% (4)
IgG 0% (5)
IgG 28% (14)
IgG 1% (17)
Anti-CL IgM and/or
IgG 4% (8)
IgG 0% (5)
IgG 25% (16)
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
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
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
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
shown to significantly reduce psoriatic skin lesions;30however, new onset or
exacerbation of psoriasis during anti-TNF-? treatment in patients affected by
phenomenon seems to be a class effect rather than a drug-specific effect and
susceptible individuals.34,35Similarly, though a positive effect of anti-TNF-?
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
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
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
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
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
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
324 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
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
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-
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-
methotrexate (MTX), but not other DMARDs, was capable of reducing the in-
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
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%)
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
Dr. C. Alessandri is a recipient of a grant from Fondazione Umberto Di
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