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Proinflammatory action of the antiinflammatory drug infliximab in tumor necrosis factor receptorassociated periodic syndrome.

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ARTHRITIS & RHEUMATISM
Vol. 60, No. 2, February 2009, pp 619–625
DOI 10.1002/art.24294
© 2009, American College of Rheumatology
Proinflammatory Action of the
Antiinflammatory Drug Infliximab in
Tumor Necrosis Factor Receptor–Associated Periodic Syndrome
Belinda Nedjai,1 Graham A. Hitman,1 Niamh Quillinan,2 Robert J. Coughlan,2 Leigh Church,3
Michael F. McDermott,3 and Mark D. Turner1
Objective. Tumor necrosis factor receptor
(TNFR)–associated periodic syndrome (TRAPS) is an
autosomal-dominant autoinflammatory condition
caused by mutations in the TNFRSF1A gene. Unlike
other autoinflammatory diseases in which anti-TNF
therapy is largely a successful treatment option, therapy
with the anti-TNF drug infliximab is often ineffective in
patients with TRAPS. Moreover, in certain cases, infliximab actually triggers severe episodes of inflammation.
The aim of this study was to elucidate the mechanisms
underlying such a reaction.
Methods. Peripheral blood mononuclear cells
(PBMCs) were obtained from patients with TRAPS.
Both caspase 3 activity and NF-␬B subunit activity were
determined by enzyme-linked immunosorbent assay.
Cytokine secretion was assessed using a specific customized human multiplex bead immunoassay kit.
Results. Unlike findings in controls, cells from a
family of 9 patients, all of whom carried the T50M
mutation in TNFRSF1A, failed to respond to infliximab
through proapoptotic induction of caspase 3 activity.
Instead, we observed enhanced antiapoptotic c-Rel subunit activity, accompanied by a significant increase in
secretion of the proinflammatory cytokines interleukin1␤ (IL-1␤), IL-1 receptor, IL-6, IL-8, and IL-12.
Conclusion. Altered extracellular conformation of
TNFRI, resulting from the T50M mutation in
TNFRSF1A, results in failure of PBMCs to induce an
apoptotic response to infliximab. We hypothesize that
failure to shed infliximab-bound TNF/TNFRI from the
cell surface of cells from patients with the T50M mutation triggers c-Rel activation, and that this leads to a
marked increase in cytokine secretion and an increased
proinflammatory response. In light of these findings, we
strongly advise caution when prescribing infliximab as
anti-TNF therapy to patients with TRAPS.
Tumor necrosis factor receptor (TNFR)–
associated periodic syndrome (TRAPS), previously
known as familial Hibernian fever, is an autosomaldominant autoinflammatory condition caused by mutations in the TNFRSF1A gene (1). Autoinflammatory
disorders are defined by spontaneously relapsing and
remitting bouts of systemic inflammation in the absence
of pathogens, autoantibodies, or antigen-specific T cells.
These disorders can be monogenic (TRAPS, familial
Mediterranean fever, Muckle-Wells syndrome, and hyperimmunoglobulinemia D syndrome) or multifactorial
(Crohn’s disease and Behçet’s disease) and are associated with mutations of genes involved in inflammation
and/or apoptosis. TRAPS is characterized by recurrent
periodic fevers lasting longer than 1 week in conjunction
with severe abdominal pain, skin lesions, conjunctivitis,
and myalgias. In addition, type AA amyloidosis develops
in some patients, leading to renal impairment.
Anti-TNF therapy with either infliximab, etanercept, or adalimumab is widely used to successfully treat
autoinflammatory disorders, including Crohn’s disease
and psoriasis, as well as the autoimmune disease rheu-
Ms Nedjai and Drs. Hitman and Turner’s work was supported
by Barts and The London Charitable Foundation.
1
Belinda Nedjai, MSc, MPhil, Graham A. Hitman, MD,
FRCP, Mark D. Turner, PhD: Institute of Cell and Molecular Science,
Barts and The London School of Medicine and Dentistry, London,
UK; 2Niamh Quillinan, MB, BCh, MRCPI, Robert J. Coughlan, MD,
FRCPI: National University of Ireland, County Galway, Galway,
Ireland; 3Leigh Church, PhD, Michael F. McDermott, MB, MRCPI,
DMed: Leeds Institute of Molecular Medicine, and St. James’ University Hospital, Leeds, UK.
Address correspondence and reprint requests to Mark D.
Turner, PhD, Centre for Diabetes and Metabolic Medicine, Institute
of Cell and Molecular Science, 4 Newark Street, Whitechapel, London
E1 2AT, UK. E-mail: M.D.Turner@qmul.ac.uk.
Submitted for publication February 12, 2008; accepted in
revised form November 3, 2008.
619
620
NEDJAI ET AL
Table 1. Symptoms and therapeutic interventions in 9 members of a family with tumor necrosis factor receptor–associated periodic syndrome
Sex/age
F/63
M/41
M/38
M/36
F/79
F/23
M/50
M/69
F/39
Frequency of
attacks
Symptoms
Etanercept therapy
Started
Stopped
Restarted
Stopped
Additional medication
Fever, sweats, myalgias, abdominal
pain
Fever, sweats, myalgias, abdominal
pain, arthralgias; amyloidosis
since 2006
Fever, sweats, myalgias, abdominal
pain, arthralgias, conjunctivitis,
vomiting; amyloidosis since 2004
Rarely
Never
2–3/year, lasting
weeks
07/06
To date
2–3/year, lasting
weeks
01/01
07/01
10/04
To date
Fever, sweats, myalgias, severe
abdominal pain, eyelid swelling,
rare skin rash, arthralgias,
vomiting
Fever (attacks postpartum), usually
asymptomatic
10⫹/year, lasting
days to weeks
01/03
01/04
01/05
02/08
Postpartum;
asymptomatic
thereafter
6–8/year, lasting
days to weeks
Never
01/01
12/03
06/08
To date
Intermittent steroids
6–10/year, lasting
weeks
02/01
12/03
10/05
03/08
Intermittent steroids
Once/year, lasting
⬃7 days
10⫹/year, lasting
days to weeks
Never
Multiple joint and back pain, severe
abdominal pain, myalgias, night
sweats, pyrexia, conjunctivitis,
eyelid swelling, rare skin rash
Multiple joint and back pain, severe
abdominal pain, myalgias, night
sweats, pyrexia, conjunctivitis,
rare skin rash
Severe night sweats, abdominal/loin
pain (usually stress induced)
Multiple joint pains and myalgias,
abdominal pain, vomiting, night
sweats, pyrexia, skin rash/
induration, recurrent infection,
injection-site reactions
matoid arthritis and the infectious disease human immunodeficiency virus infection. However, in some patients
with TRAPS the disease is unresponsive to anti-TNF
therapy (2), and, additionally, infliximab may actually
worsen the disease. Specifically, within hours of administration, infliximab treatment has been associated with
severe exacerbation of TRAPS-associated inflammatory
symptoms in 2 patients with the R92Q variant (3), 1
patient with the C33Y variant (4), 1 patient with the
C30S variant (5), and 1 patient with the C43S variant(6).
This suggests that exacerbation of TRAPS might be a
feature of infliximab therapy. Elucidation of the mechanisms underlying the response to therapy is therefore of
paramount importance in order to efficiently target this
therapy to the appropriate patients.
PATIENTS AND METHODS
Materials. Unless stated otherwise, all materials were
obtained from Sigma-Aldrich (Poole, UK).
01/01
None
Intermittent steroids
Atorvastatin 20 mg/day,
ramipril 5 mg/day,
aspirin 75 mg/day,
intermittent steroids
Intermittent steroids
None
None
08/05
09/07
11/07
Lansoprazole, 30 mg/day
Participants. In order to conduct this study, we recruited 9 members from an Irish family in which several family
members have TRAPS due to a T50M mutation in the
TNFRSF1A gene (Table 1). After informed consent was obtained, blood samples were drawn at a time when the patients
were not experiencing an attack of TRAPS and were experiencing no symptoms of inflammation. Healthy control individuals were matched for age, sex, and ethnicity. All studies were
approved by the relevant local ethics committees.
The index case was referred to the Rheumatology
Department at the University Hospital Galway, for investigation of arthritis symptoms. This 50-year-old man became
symptomatic at the age of 3 years. He had a history of
recurrent fevers, with abdominal pain, myalgias, polyarthralgia, and a tender, diffuse, erythematous nonbullous skin rash.
Prednisolone, which was first administered at the age of 15
years, provided symptomatic relief, but colchicine was ineffective. He began receiving etanercept in 2001 and continued this
treatment for 2 years, but it was stopped due to loss of benefit
and severe injection-site reactions. Therapy with etanercept
was restarted in October 2005, although severe injection-site
reactions persisted, resulting in the patient again stopping
etanercept treatment in March 2008. To date, 7 of 12 affected
INFLIXIMAB AND TRAPS
members of this kindred have received etanercept treatment,
with limited success in all of them.
Cell separation and culture. Blood was collected into
sterile tubes containing EDTA/anticoagulant and was then
diluted by the addition of an equal volume of 0.9% NaCl. The
resulting solution was then layered over 3 ml of Lymphoprep
(Axis Shield, Dundee, UK) in a centrifuge tube and centrifuged at 800g for 20 minutes at room temperature. After
centrifugation, mononuclear cells formed a distinct band at
the medium interface. Peripheral blood mononuclear cells
(PBMCs) were removed from the interface, diluted with 0.9%
NaCl, and pelleted by centrifugation at 250g for 10 minutes.
Cells were then suspended in RPMI 1640 medium supplemented with 10% fetal bovine serum (Invitrogen, Paisley, UK),
26 mM NaCO3, and 1% penicillin–streptomycin and incubated
at 37°C for 4 hours prior to experimental manipulation, to
exclude the possibility of experimental anomalies arising as a
consequence of indirect effects resulting from extracellular
cytokines circulating in the patient’s blood.
Apoptosis. PBMCs were incubated either with or without 10 ␮g/ml or 100 ␮g/ml infliximab, IgG1, or etanercept, for
4 hours at 37°C. Cells were then harvested and lysed, and the
apoptotic status was determined using the EnzChek Caspase-3
Assay Kit #2 (Molecular Probes, Leiden, The Netherlands).
Reactions were carried out at room temperature, and fluorescence was measured using a Victor 1420 Multilabel Counter
(PerkinElmer Wallac, Milan, Italy), following excitation at
485 ⫾ 10 nm and emission at 530 ⫾ 12.5 nm (mean ⫾ SEM).
NF-␬B activity. TransAM NF-␬B Family Kits (Active
Motif, Rixensart, Belgium) were used for the study of specific
NF-␬B subunit pathways. Briefly, oligonucleotide containing
an NF-␬B consensus binding site was immobilized onto 96-well
plates. The binding of NF-␬B to its consensus sequence was
detected by adding 30 ␮l of complete binding buffer to each
well, and 1 ␮g of nuclear extract diluted in complete lysis
buffer was then added to each well. The plates were sealed and
incubated for 1 hour at room temperature, with mild agitation.
Each well was then washed 3 times with 200 ␮l 1⫻ wash buffer.
Antibody directed against one of the NF-␬B p50, p52, p65,
c-Rel, or RelB subunits was bound to the protein–oligonucleotide complex and detected following the addition of secondary
antibody conjugated to horseradish peroxidase. Developing
solution was added, and the plate was incubated for 2–10
minutes at room temperature. Absorbance was then measured,
using a Victor 1420 Multilabel Counter spectrophotometer
(PerkinElmer Wallac) at 450 nm, with a reference wavelength
of 655 nm.
Cytokine secretion. PBMCs were incubated with 100
ng/ml TNF or 100 ␮g/ml infliximab for 6 hours at 37°C.
Secreted cytokine concentrations were determined using a
specific customized human multiplex bead immunoassay kit
(Invitrogen) and were analyzed in duplicate, using a Luminex
100 instrument (Luminex, Riverside, CA). Data analysis was
performed using Luminex 100 IS software version 2.3.
Statistical analysis. Analysis of differences between 2
groups was performed using Student’s t-test for independent
samples. Comparisons between ⬎2 groups were performed by
one-way analysis of variance, followed by Dunnett’s 2-sided
post hoc test. All experimental data were gathered from a
series of independent experiments (n ⫽ 3). The results are
expressed as the mean ⫾ SEM.
621
Figure 1. Infliximab-induced inhibition of apoptosis in peripheral
blood mononuclear cells (PBMCs) from patients with the T50M
mutation. Blood was obtained from patients with tumor necrosis factor
receptor–associated periodic syndrome and healthy control subjects.
PBMCs were isolated and then incubated with or without 10 ␮g/ml or
100 ␮g/ml infliximab (IFX), IgG1, or etanercept (Etan) for 4 hours at
37°C. The molar concentrations were not different, because of the
similarity in molecular weights (149, 150, and 150 kd, respectively).
Cells were then harvested and lysed, and apoptosis was assayed. All
experimental data were gathered from a series of independent experiments (n ⫽ 3). Statistical analysis was performed by Student’s t-test
for independent samples. Values are the mean and SEM.
RESULTS
Infliximab-induced inhibition of apoptosis in
PBMCs from patients with the T50M mutation. We
examined the apoptotic status of PBMCs isolated from 9
healthy control subjects and 9 members of an Irish
family, all of whom had a T50M mutation in TNFRI
(Figure 1). In addition to reducing the circulating concentration of TNF through binding of the free molecule,
anti-TNF therapy using either infliximab, etanercept, or
adalimumab functions through the activation of apoptotic pathways in immune cells (7–9). It was therefore with
622
NEDJAI ET AL
Figure 2. Proinflammatory action of infliximab, as determined by measuring the activity of NF-␬B transcription factor subunits. Blood was
obtained from patients with tumor necrosis factor receptor–associated periodic syndrome and healthy control subjects, and PBMCs were isolated.
NF-␬B subunit activity in PBMCs, incubated with or without 100 ␮g/ml infliximab or IgG1 for 4 hours at 37°C, was detected using an enzyme-linked
immunosorbent assay directed against the NF-␬B p50, p52, p65, c-Rel, or RelB subunits. Absorbance was measured at 450 nm, with a reference
wavelength of 655 nm. All experimental data were gathered from a series of independent experiments (n ⫽ 3). Statistical analysis was performed
by Student’s t-test for independent samples. Values are the mean and SEM. OD ⫽ optical density (see Figure 1 for other definitions).
some surprise that we observed a marked inhibition of
apoptosis in PBMCs from family members with the
T50M mutation when cells were incubated with 10 ␮g/ml
or 100 ␮g/ml of infliximab, which are concentrations
similar to those routinely prescribed. This was also a
specific effect of infliximab, because this chimeric monoclonal antibody elicited a strong response, whereas
human IgG1 control did not significantly alter the
apoptotic status of PBMCs from either control subjects
or patients with the T50M mutation. In contrast to the
antiapoptotic effect of infliximab on cells from patients
with the T50M mutation, etanercept, a fusion protein
composed of the extracellular domain of TNFRII and
the hinge and Fc domains of IgG1, induced a modest
apoptotic response in cells from both control subjects
and patients with the T50M mutation.
Infliximab-induced up-regulation of NF-␬B c-Rel
subunit activity in PBMCs from patients with the T50M
mutation. Given the antiapoptotic response to infliximab of cells from patients with the T50M mutation, we
next determined whether infliximab might instead have a
proinflammatory action, by measuring the activity status
of the entire family of NF-␬B transcription factor subunits. We observed no change in the RelB or p52
subunits, but we did observe an increase in the proinflammatory p65 and p50 subunits, following 4 hours of
incubation with 100 ␮g/ml infliximab (Figure 2). However, this alone cannot account for the proinflammatory
response to the drug in cells from patients with the
T50M mutation, since the response was similar in both
control subjects and patients with the T50M mutation.
We therefore studied additional components of the
signaling network that determine the balance between
apoptotic and inflammatory outcomes. Significantly,
upon incubation with infliximab, we observed at least a
6-fold elevation in the level of c-Rel in all family
members with the T50M mutation studied (Figure 2),
which is in stark contrast to the results healthy control
subjects, in whom there was no pronounced change.
Effect of infliximab on cytokine secretion from
PBMCs. In order to determine the effect of infliximabmediated c-Rel activation upon the general PBMC
immune response, we performed a comprehensive series
of cytokine-secretion experiments. Fresh PBMCs were
first cultured in medium for a minimum of 4 hours, to
prevent potential signaling crosstalk from cytokines circulating in the bloodstream. Cells were then incubated
in fresh medium, with or without 100 ␮g/ml infliximab or
100 ng TNF, for 6 hours. There was a marked elevation
in the levels of the proinflammatory cytokines IL-6, IL-8,
IL-12, and IL-1R in cells from patients with the T50M
mutation compared with controls (Figure 3). This robust
response to infliximab of cells from patients with the
T50M mutation was also similar to that resulting from
incubation with TNF, although unlike TNF, infliximab
did not induce a proinflammatory response in healthy
control subjects. We also observed a pronounced elevation of IL-1␤ in cells from patients with the T50M
INFLIXIMAB AND TRAPS
623
Figure 3. Elevated secretion of the proinflammatory cytokines interleukin-1 (IL-6), IL-8, IL-12,
and IL-1 receptor (IL-1R) from cells from patients with the T50M mutation compared with
controls. Blood was obtained from patients with tumor necrosis factor (TNF) receptor–associated
periodic syndrome or healthy control subjects. PBMCs were isolated and then incubated with or
without 100 ng/ml TNF or 100 ␮g/ml infliximab for 6 hours at 37°C. Secreted cytokine
concentrations were determined using a specific customized human multiplex bead immunoassay
kit and analyzed in duplicate. All experimental data were gathered from a series of independent
experiments (n ⫽ 3). Statistical analysis was performed by Student’s t-test for independent
samples. Values are the mean and SEM. See Figure 1 for other definitions.
mutation that were incubated with infliximab; unfortunately, we were unable to perform statistical analysis on
these samples, due to control IL-1␤ levels being below
the detection threshold.
In contrast, we observed no significant differences between control cells and cells from patients with
the T50M mutation in the secretion of IL-2, IL-2R, IL-5,
IL-10, IL-13, IL-15, TNF, interferon-␣ (IFN␣), IFN␥,
granulocyte⫺macrophage colony-stimulating factor,
macrophage inflammatory protein 1␣ (MIP-1␣), MIP1␤, monokine induced by IFN␥, and monocyte chemotactic protein 1. In addition, we observed a reduction in
expression of the antiinflammatory cytokine IL-4 and
the proapoptotic cytokine IL-7 in cells from patients
with the T50M mutation that were incubated with
infliximab, but no reduction in IL-7 levels in control cells
and only a modest reduction in IL-4 expression in
response to infliximab (data not shown). Expression of
the proinflammatory mediator RANTES was also markedly reduced in control cells incubated with infliximab,
but was only partially reduced in cells from patients with
the T50M mutation.
DISCUSSION
Cells associated with the body’s immune system
express both TNFRI and TNFRII, both of which are
receptors that specifically bind the proinflammatory
cytokine TNF at the cell surface. However, of the 2
receptors, only TNFRI is able to induce apoptosis
directly, via activation of the caspase cascade (10,11).
After TNFRI binds TNF, the complex is internalized,
resulting in cytoplasmic recruitment of the proapoptotic
proteins, TRADD, FADD, and caspase 8 (12). An
intriguing insight into TRAPS biology came from the
recent observation, in patients carrying either cysteine or
threonine mutations in the extracellular cysteine-rich
domains of TNFRI, that proapoptotic stimulation of
neutrophils with TNF and cycloheximide failed to produce any induction of apoptosis (13). This is in stark
contrast to the reaction in healthy controls and patients
carrying the R92Q low-penetrance TRAPS mutation, all
of whom displayed a robust apoptotic response (13).
Interestingly, it has also been reported that conformational changes in the extracellular portion of TNFRI
interfere with receptor internalization and subsequent
activation of apoptotic pathways (12).
In addition to the failure to internalize TNFRI
receptors (12), the situation in patients with the T50M
mutation is likely to be compounded by the activation of
antiapoptotic c-Rel subunits. Up-regulation of c-Rel has
previously been shown to result in a concomitant upregulation of manganese superoxide dismutase, which in
624
turn leads to mitochondrial degeneration and resistance
to apoptotic induction (14). Consistent with these findings, infliximab failed to induce apoptosis in any of the 9
family members with TRAPS in this study, all of whom
have the T50M mutation. Moreover, not only did infliximab fail to induce apoptosis in cells from patients with
the T50M mutation, but instead there was significant
secretion of the proinflammatory cytokines IL-1␤, IL1R, IL-6, IL-8, and IL-12. This is consistent with previous reports of proinflammatory c-Rel–mediated IL-12
transcription in macrophages (15). Furthermore, the
strong proinflammatory IL-1␤/IL-1R response is also
consistent with a recent report implicating IL-1–
dependent genes in TRAPS (16). Taken together, these
results demonstrate a robust proinflammatory response
to infliximab in the family with the T50M mutation,
which is reflective of the adverse clinical reaction frequently observed in patients with TRAPS.
Importantly, in individuals without TRAPS,
TNF-bound receptor is rapidly cleaved by metalloproteinase enzymes, yielding soluble TNFRI. However,
certain TNFRSF1A mutations, including C52F and
T50M (1,17) and to a lesser extent H22Y, C33G, and
P46L (17), fail to shed TNFRI from the cell surface,
leading to a hyperinflammatory response. In addition,
C73R was recently shown to lead to elevated cell surface
expression (18), although in the case of this particular
mutation, there is no known shedding defect (19). We
hypothesize that mutations that alter the extracellular
conformation of TNFRI not only are unable to internalize TNFRI or to induce an apoptotic response, but
crucially, they also fail to shed infliximab-bound TNF/
TNFRI from the cell surface, and this leads to induction
of a proinflammatory response.
Infliximab has previously been shown to form
more stable binding complexes with soluble TNF than
etanercept and additionally, to have a much higher
binding avidity for transmembrane TNF (20). As a
consequence, infliximab was shown to be significantly
more effective in activating human endothelial cells (20).
Moreover, because TNFRII fusion proteins have high
rates of dissociation with TNF (20,21), indicative of
transient etanercept binding of TNF, we theorize that it
is this difference in binding specificity that underlies the
different responses to etanercept and infliximab observed in patients with TRAPS. Our findings are also
consistent with reports of the failure of anti-TNF therapy in patients with the C33Y mutation (2,4), in whom at
least certain cell types show a shedding defect (22). In
conclusion, we strongly advise caution when prescribing
infliximab as anti-TNF therapy for patients with TRAPS.
NEDJAI ET AL
ACKNOWLEDGMENTS
We thank Dr. Ian Chikanza (Barts and The London,
UK) for generously supplying infliximab, and all patients for
kindly consenting to participate in this study.
AUTHOR CONTRIBUTIONS
Dr. Turner had full access to all of the data in the study and
takes responsibility for the integrity of the data and the accuracy of the
data analysis.
Study design. Nedjai, Hitman, Turner.
Acquisition of data. Nedjai, Quillinan, Coughlan, Church.
Analysis and interpretation of data. Nedjai, Hitman, McDermott,
Turner.
Manuscript preparation. Nedjai, Hitman, McDermott, Turner.
Statistical analysis. Nedjai, Turner.
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between cell types. Arthritis Rheum 2004;50:2651–9.
DOI 10.1002/art.24290
Clinical Images: Beyond the classic triad: dermatologic manifestations of reactive arthritis
The patient, a 24-year-old man, presented with conjunctivitis, urethritis, synovitis, and enthesitis, and was diagnosed as having
reactive arthritis. Physical examination revealed geographic tongue (A) and keratoderma blennorrhagicum (B), conditions present
in 9–40% and ⬃10% of patients with reactive arthritis, respectively (1). Dermatologic manifestations of reactive arthritis are more
common in patients who test positive for HLA–B27 (1), and this allele was present in this patient.
1. Wu IB, Schwartz RA. Reiter’s syndrome: the classic triad and more.
J Am Acad Dermatol 2008;59:113–21.
Sheila M. Greenlaw, BA
University of Massachusetts Medical School
Lauren Alberta-Wszolek, MD
University of Massachusetts Medical School
and UMass Memorial Healthcare
Worcester, MA
Amit Garg, MD
Boston University School of Medicine
and Boston Medical Center
Boston, MA
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necrosis, factors, drug, infliximab, syndrome, proinflammatory, periodid, action, antiinflammatory, receptorassociated, tumors
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