Rheumatology 2005; 1 of 7doi:10.1093/rheumatology/kei090
Systemic cytokine levels and the effects of etanercept
in TNF receptor-associated periodic syndrome
(TRAPS) involving a C33Y mutation in TNFRSF1A
M. L. Nowlan, E. Drewe, H. Bulsara, N. Esposito, R. A. Robins,
P. J. Tighe, R. J. Powell and I. Todd
Objective. To investigate the levels of the pro-inflammatory cytokines IL-6, TNF-a, IL-1b, IL-8, IL-10 and IL-12p70 in the
plasma of patients with TNF receptor-associated periodic syndrome (TRAPS) in relation to CRP levels and treatment with
Methods. Cytokine concentrations were measured in sequential plasma samples obtained from eight patients with a C33Y
mutation in TNFRSF1A and diagnosed with TRAPS, using cytokine bead array. The TRAPS samples were compared with
samples from normal controls and rheumatoid arthritis patients.
Results. Levels of IL-6 were significantly elevated in C33Y TRAPS patients and these correlated with CRP levels in some
of the patients. IL-8 levels were also significantly elevated in the TRAPS patients. However, neither TNF-a nor IL-1b
demonstrated a similar increase. This differed from the patients with rheumatoid arthritis, for whom levels of IL-6, IL-8,
TNF-a, IL-1b and IL-10 were significantly elevated. The levels of detectable TNF-a in the TRAPS patients’ plasma were
elevated during etanercept treatment.
Conclusions. The cytokine profile of C33Y TRAPS differs from that of a typical autoimmune inflammatory condition such as
rheumatoid arthritis, as only IL-6 and IL-8 were elevated in C33Y TRAPS patients, as distinct from a generalized elevation
of pro-inflammatory cytokines. However, only some of the C33Y patients tested showed a relationship between elevated IL-6
and CRP. This is consistent with clinical observations that there is marked heterogeneity between individuals with TRAPS,
including those in the same family cohort. Although etanercept has a therapeutic effect in some TRAPS patients, it induces
increased plasma concentrations of TNF-a, possibly by increasing TNF-a stability.
KEY WORDS: TRAPS, TNF receptor, Pro-inflammatory cytokines, Etanercept.
TNF receptor-associated periodic syndrome (TRAPS) is an
auto-inflammatory condition, characterized by recurrent fevers,
myalgia, skin rashes and joint and abdominal pain. It is associated
with autosomal dominant mutations in the gene encoding the
55 kDa tumour necrosis factor receptor (TNFRSF1A, TNFR1,
CD120a, p55 TNFR) . Studies on the pro-inflammatory
cytokine profiles during attacks of TRAPS are limited but have
revealed low levels of soluble TNFRSF1A in some cases, and
elevated interleukin-6 (IL-6) during attacks . Actions of other
pro-inflammatory cytokines may relate to the clinical variability
notable across the spectrum of TRAPS patients. TRAPS patients
can also develop amyloidosis in association with a persisting acute-
phase response. Treatment with the TNFRSF1B (TNFR2):Fc
fusion protein etanercept (Enbrel) has therapeutic benefits in
some TRAPS patients and can control the clinical attacks,
and results in improvement of renal function and reduction in
amyloid deposition . Associated cytokine changes in TRAPS
patients have not been fully investigated. Other periodic fever
syndromes, such as familial Mediterranean fever (FMF) and
hyperimmunoglobulinaemia-D with periodic fever syndrome
(HIDS), are also characterized by an elevation of IL-6 during
attacks, high C-reactive protein (CRP) levels, and in some
instances this is followed by amyloidosis and renal failure [4–8].
Other cytokines that are elevated during attacks in FMF include
TNF-? , IL-8  and interferon-? [10, 11].
The acute-phase inflammatory response is associated with the
and acute-phase proteins such as CRP and serum amyloid A.
CRP is a clinically recognized marker of systemic inflamma-
tion and its production by the liver is modulated by IL-6. The
pro-inflammatory effects of TNF-? are mediated predominantly
through binding to TNFRSF1A  inducing NF?B activation,
increased gene transcription and cytokine production. The identi-
fication of numerous mutations in the ectodomain of TNFRSF1A
in TRAPS patients, and low serum levels of soluble TNFRSF1A
in certain cases further suggest a role for the receptor in the
generation of clinical attacks of TRAPS . Our studies with
transfected cell lines have shown that the ability of the various
mutant forms of TNFRSF1A to be expressed on the surface of
cells and to bind TNF-? varies and also that the shedding of
mutant receptors from the cell surface differs between cell types
IL-6 is not only a pro-inflammatory cytokine but can also
have anti-inflammatory feedback effects by inducing cytokine
Correspondence to: I. Todd, Division of Immunology, A Floor, West Block, Queen’s Medical Centre, Nottingham NG7 2UH, UK.
1 of 7
Division of Immunology and Institute of Infection, Immunity and Inflammation, School of Molecular Medical Sciences, University of Nottingham,
Queen’s Medical Centre, Nottingham, UK.
Received 17 March 2005; revised version accepted 1 August 2005.
? The Author 2005. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: firstname.lastname@example.org
Rheumatology Advance Access published November 15, 2005
by guest on June 12, 2013
antagonists such as IL-1 receptor antagonist (IL-1RA) and soluble
TNF receptors . IL-1? can also act as a pro-inflammatory
including itself, TNF-?, IL-6, IL-8 and IL-12, and can be induced
by acute-phase proteins such as CRP . Increased plasma
IL-1? has been correlated to disease activity in rheumatoid
Monocytes and fibroblasts produce IL-8, a chemoattractant
for neutrophils during inflammation, and this chemokine may
have a role in the dermatological manifestations notable in
affected muscles during attacks of TRAPS . IL-10 is usually
characterized as an anti-inflammatory cytokine, and has been
responses and a feedback mechanism may explain the periodicity
In this study, we have simultaneously measured CRP, IL-6,
IL-1?, TNF-?, IL-8, IL-10 and IL-12p70 levels in sequential
plasma samples from patients with C33Y mutation in the
TNFRSF1A gene (referred to here as C33Y TRAPS). These
patients are from the prototypical TRAPS family, whose condi-
tion was originally called familial Hibernian fever (FHF) .
We have also investigated the effect of etanercept treatment on
the plasma cytokine levels in these TRAPS patients, and changes
to their cytokine levels during disease attacks in relation to
changes in the CRP levels.
Plasma samples of eight TRAPS patients with a C33Y mutation
were collected at consecutive time points over a period of about
2yr (aged 25–75yr; five male, three female). The symptomatic
assessment of the patients at the time of obtaining each sample
was noted and classified as ‘well’, ‘mild attack’ or ‘attack’. The
medication was also recorded; specifically whether they were
receiving etanercept or not. Etanercept (Enbrel; Wyeth, UK) was
given subcutaneously at 25mg twice weekly to certain patients.
The patients frequently received prednisolone during attacks.
Peripheral blood was collected into 4ml EDTA (ethylenediamine
tetraacetate) Vacutainers (BD Biosciences, Oxford, UK) during
out-patient attendances. The blood was centrifuged at 700g for
8min within 30min of collection; the plasma was then aspirated
and frozen at ?80?C until analysis. Samples were also collected
anonymously from seven patients with recently diagnosed rheu-
matoid arthritis (RA) and 34 normal controls. All the patients
gave informed consent and the Nottingham Ethics Committee
approved this study. Immediately prior to the analysis of the
samples, they were thawed and aliquoted to prevent repeated
freeze/thawing. Some of the plasma samples required micro-
centrifugation to remove fibrin debris.
Cytokine bead array
A cytokine bead array kit (CBA; BD Biosciences) was used to
measure the inflammatory cytokines in the plasma samples. The
cytokines measured by this kit were IL-6, IL-1?, TNF-?, IL-8,
IL-10 and IL-12p70. The data were acquired on an Altra flow
cytometer (Beckman Coulter, High Wycombe, UK). The data
were then interpreted using BD cytometric bead array software
CRP levels were measured as part of the routine testing performed
on blood samples taken in the out-patient clinic.
Etanercept and TNF-?
To determine whether TNF-? can be detected by CBA or ELISA
when bound to etanercept, various dilutions of etanercept
(10–0.05?g/ml) were incubated at room temperature for 1h with
different concentrations of TNF-? (31–1000pg/ml; R & D Europe,
Abingdon, UK) in Tris-buffered saline with 0.1% bovine serum
albumin (Sigma-Aldrich, Poole, UK). These samples were frozen
at ?20?C until assayed by CBA or ELISA (Duoset kit; R & D
Europe). A TNF-sensitive L929 bioassay was used to assess the
bioactivity of the TNF-? when bound to etanercept . The L929
fibroblast cell line was obtained from the European Collection
of Animal Cell Cultures (Salisbury, UK); the cells were grown
in 96-well plates (Nunc; SLS, Nottingham, UK) at 4?104/100?l
overnight in Dulbecco’s Modified Eagle Medium (DMEM;
Invitrogen, Paisley, UK) supplemented with 10mM HEPES,
100U/ml penicillin, 100?g/ml streptomycin, 2mM L-glutamine
(all from Sigma) and 10% fetal bovine serum (FBS; Harlan
SeraLab, Loughborough, UK). Etanercept at 0.5?g/ml was
diluted in supplemented DMEM with TNF-? at 1ng/ml and
incubated for 1h at room temperature followed by 3h at 4?C.
A TNF-?-only control was also prepared. The etanercept/TNF-?
solutions were diluted on the L929 plate in doubling dilutions,
50?l per well; 50?l actinomycin-D–mannitol solution at 8?g/ml
in supplemented DMEM was also added. The plate was then
incubated overnight at 37?C, 5% CO2. It was washed with
phosphate-buffered saline and the cells were stained with 100?l
0.05% crystal violet (SLS) in 20% ethanol for 10min. The plate
was then washed with tap water and dried. The crystal violet was
eluted with 100?l methanol and the optical density was measured
at 550nm on an Emax Microplate Reader (Molecular Devices,
Graphpad Prism software (San Diego, California, USA) was
used to analyse the data. The analyses used are described with
CRP levels in TRAPS patients
CRP level is measured clinically as a surrogate for systemic
inflammation. The reference range for CRP levels is up to 10mg/l.
As shown in Fig. 1, the CRP levels of TRAPS patients can greatly
exceed this level. However, the C33Y TRAPS patients can be
suffering an ‘attack’ without an elevation of CRP because of
localized inflammation, such as myalgia, skin rashes, abdominal,
ocular and joint pain, rather than systemic symptoms, such as
fever. Alternatively, CRP levels can be elevated without signs
of clinical disease. As peripheral blood plasma cytokine levels
were being measured, we used CRP in this study to reflect the
systemic changes occurring during attacks. Figure 1 shows the
CRP profiles for Patients 1, 2, 3, 4, 5, 6 and 8 in relation to
etanercept treatment and clinical notes. CRP levels for Patients 5
and 6 did not rise above 10mg/l (normal range), even during
attacks: Patient 5 experienced relatively mild attacks only,
whereas Patient 6 was atypical in having a renal transplant as
a consequence of amyloidosis and received azathioprine and
cyclosporin. For Patient 7, there were only two samples available,
both with CRP levels above the normal range (31 and 87mg/l,
respectively): on both occasions the patient was described as
‘well’ and was not receiving any medication. Patient 1 did not
have a sustained response to etanercept and hence was prescribed
sirolimus instead. It can be seen that CRP did not always rise
during an ‘attack’ and often remained substantially elevated
even when the patient appeared clinically ‘well’. Most patients
2 of 7M. L. Nowlan et al.
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always had an abnormally high CRP level, except Patients 5 and 6,
in whom the CRP levels were low, as noted above. Etanercept
treatment generally resulted in a fall in CRP levels.
Correlation between CRP and proinflammatory cytokines
Table 1 shows the Spearman’s r values and P values for the
correlation between CRP and each cytokine for individual C33Y
TRAPS patients. Bonferroni correction for multiple comparisons
was performed and a P value of <0.008 was considered significant.
The data are given for four of the eight patients when not receiving
etanercept or sirolimus treatment. No data are given for Patients 2,
5, 6 or 7; Patients 2, 5 and 6 were on etanercept for the majority
of the sampling period and only three samples were available for
each patient while not receiving etanercept treatment; only two
samples were taken for Patient 7 as this patient manages the
condition well and does not attend clinic regularly. The data in this
table demonstrate heterogeneity between the patients. Patients 3
and 4 showed a significant correlation between IL-6 and CRP, as
would be expected in an inflammatory condition. There was a
similar trend for Patient 1 (Spearman’s r-value 0.75), although this
was not statistically significant. IL-8 was also closely related to
FIG. 1. Consecutive CRP levels in C33Y TRAPS patients in relation to treatment with etanercept (E), no etanercept (NE),
or sirolimus (S) and no sirolimus (NS) in Patient 1, and clinical notes of ‘attack’ (A), ‘well’ (W) and ‘mild attack’ (mA).
Cytokine and the effects of etanercept in TRAPS 3 of 7
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CRP in this patient, but again this did not reach statistical
significance. However Patient 8 did not show any correlation
between CRP and the cytokines. Apart from IL-6 in Patients 3
and 4, none of the other pro-inflammatory cytokines showed
significant correlation with CRP in TRAPS.
Examples of the relationships between IL-6 and CRP levels in
Patients 1, 3 and8 are shown in Fig. 2. For Patient 3, the IL-6 levels
closely mimicked changes in CRP, even when the patient was on
etanercept. As predicted by the absence of correlation in Patient 8
(Table 1), IL-6 and CRP levels did not mirror each other closely.
Patient 8 had never required etanercept treatment. In Patient 1,
the profiles for CRP and IL-6 were similar, whether on or off
treatment with sirolimus.
Normal cytokine ranges
Table 2 shows the median and range of cytokine levels in 34 normal
controls and seven RApatient samples in comparison with samples
taken from eight TRAPS patients without etanercept treatment.
For the TRAPS patients, the median and range of cytokine levels
are given for all samples assayed, and for the median cytokine
values for each patient. We used Kruskal–Wallis test followed
by Dunn’s multiple comparison post-test to compare the normal
controls, RA patients and the median TRAPS samples. The RA
patients had a generalized elevation of most of the cytokines: the
levels of IL-6 (P<0.001), TNF-? (P<0.001), IL-8 (P<0.001) and
IL-10 (P<0.001) were significantly higher than in controls. IL-6
and IL-8 were also significantly elevated in the median samples
from TRAPS patients compared with the normal controls
(P<0.01 for both); there was no significant difference between
the levels of these cytokines in the TRAPS patients and the RA
patients. The IL-1? levels in the TRAPS patients were significantly
lower than in the RA patients and normal controls. Unlike the
RA patients, TNF-? levels were not significantly raised in the
TRAPS patients. No significant difference in IL-12 levels was seen
between any of the groups.
As demonstrated in Fig. 3 (data from Patients 3, 4 and 5), levels
of TNF-? detected in plasma were elevated during etanercept
treatment, although the CRP levels were generally lowered. In
this assay it is not possible to distinguish whether this was due to
an increase in the production of TNF-? by the C33Y TRAPS
patients during etanercept treatment or whether the assay detects
TNF-? bound to, or stabilized by, etanercept, or indeed both.
To investigate this further, we mixed TNF-? with etanercept
in vitro andassessed whether the TNF-? could be detected by CBA,
ELISA and the L929 bioassay. In a dose-dependent manner, less
TNF-? was detected in the presence of etanercept than in its
absence, by CBA (data not shown) and ELISA (Fig. 4), indicating
that etanercept competitively inhibited interaction of TNF-?
with the antibodies used in these assays. However, it is of note
that etanercept competed only partially with the assay capture
antibody. Thus, as seen in Fig. 4, etanercept at 10?g/ml inhibited
detection of TNF-? only slightly more than 1?g/ml etanercept did
and, at both of these etanercept concentrations, detection of
500pg/ml TNF-? was reduced by only about 50%. This suggests
that the TNF-? that is detected at high levels in the plasma of
C33Y TRAPS patients during etanercept treatment is not all
FIG. 2. Heterogeneity in the relationship between IL-6 (squares)
and CRP levels (circles) for TRAPS patients 1, 3 and 8.
TABLE 1. Correlation between cytokine and CRP levels in C33Y TRAPS patients, without etanercept treatment, or sirolimus treatment in Patient 1
Patient 1Patient 3Patient 4 Patient 8
r valueP valuer valueP valuer valueP valuer valueP value
P<0.008 is considered evidence of a significant difference.
4 of 7M. L. Nowlan et al.
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bound to etanercept. The L929 bioassay confirmed that TNF-?
bound to etanercept was not biologically active death of the L929
cells occurred at above 31pg/ml TNF-? alone, but no killing
occurred when the cells were treated with etanercept and TNF-?
plasma could not be interpreted because of complement-mediated
cytotoxicity, and heat inactivation of complement in these samples
was not practical as this might also denature both the TNF-?
and the etanercept. However, overall our findings indicate that
detectable levels of TNF-? were elevated in the plasma of TRAPS
patients on etanercept treatment.
In this study, we investigated the relationship between systemic
CRP levels and pro-inflammatory cytokines in patients with C33Y
TRAPS. CRP is used clinically to assess systemic inflammatory
responses within the patients, and consequently we anticipated
that elevations in CRP would reflect increased levels of pro-
inflammatory cytokines. Some TRAPS patients develop amy-
loidosis, and it would be interesting to measure serum amyloid A
(SAA) levels as an additional acute-phase reactant. However,
SAA is not measured routinely for purposes of clinical monitoring
in the C33Y TRAPS patients, and was not undertaken as part
of the present study. The relationship between CRP and pro-
inflammatory cytokines varied markedly between individual
patients and reflects the variation in severity of symptoms seen
clinically. However, in some patients there was a strong correlation
between CRP levels and the pro-inflammatory cytokine IL-6. This
would be anticipated since IL-6 controls CRP production,
although not all the C33Y TRAPS patients showed a significant
correlation. As shown in RA patients, the levels of the other pro-
inflammatory cytokines might also be expected to be elevated;
however, this was rarely the case in the TRAPS patients. There is
a suggestion that IL-8 is involved in the inflammatory response
in C33Y TRAPS, but there was no correlation between IL-8 levels
and CRP for most of the patients. However, for Patient 1 P¼0.034
(Table 1). IL-8 is a neutrophil chemoattractant and increased
levels would be expected in an inflammatory condition.
IL-1? levels were significantly lower in the C33Y TRAPS
patients’ samples than in samples from the RA patients or the
normal controls. Circulating levels of IL-? are recognized to be
low and difficult to detect . Many of the C33Y TRAPS patient
samples were given the value of 0 as they were below the standard
curve. However, treatment with recombinant IL-1RA (anakinra)
proved successful in C34Y TRAPS patients , implying a role
for IL-1-mediated inflammation in TRAPS.
A further unexpected finding is the greatly elevated TNF-?
levels detected in plasma during etanercept treatment, despite the
fact that beneficial effects of etanercept are seen in some TRAPS
patients [e.g. 23]. However, elevated circulating levels of TNF-?
have also been detected in other groups of patients during
etanercept treatment, e.g. patients with multiple myeloma  or
OKT3-associated acute clinical syndrome . Indeed, some of
the early studies with etanercept in lipopolysaccharide (LPS)-
treated mice showed that etanercept prolongs the half-life of
TNF-? and reduces its loss from the murine circulation while
at the same time protecting against LPS-induced shock . This
suggests that etanercept, like naturally produced soluble TNF
receptors , binds and neutralizes TNF-?, but also stabilizes
TNF-?, prolonging its half-life. There is also evidence that TNF-?
dissociates from etanercept relatively rapidly [26, 28, 29]; it may
then reassociate unless prevented from doing so. This may explain
FIG. 3. Treatment with etanercept results in elevation in
detectable TNF-? levels (squares) and decrease in CRP levels
(circles) as demonstrated in patients 3, 4 and 5.
TABLE 2. Comparison of pro-inflammatory cytokine levels (pg/ml)
between plasma samples from normal controls (n¼34), RA patients
(n¼7) and TRAPS patients (n¼8 patients, total of 41 samples)
Cytokine NormalRAAll samples Median samples
57.3 (0–265.5) 129.8 (0–711)
15.8c(8.8–31.2) 15.5 (0–260)
10.0c(6.0–45.8) 3.1 (0–29.6)
9.3c(3.2–28.7) 5.3 (2.1–17.1)
15.5b(7.4–24.4) 4.1 (0–31.6)
20.2 (0–39.7)4.8 (0–17.9)
normal controls and RA patients, for all the TRAPS patient samples
and for the median TRAPS patient samples.
cP<0.001 in Kruskal–Wallis test with Dunn’s multiple comparison
post-test is considered evidence of a significant difference from normal
Cytokine and the effects of etanercept in TRAPS5 of 7
by guest on June 12, 2013
why, in the competitive inhibition assays that we performed
(e.g. Fig. 4), etanercept could not fully inhibit detection of
TNF-? in the CBA or ELISA assays, since TNF-? released by
etanercept would bind effectively irreversibly to the capture anti-
TNF-? antibodies. Similarly, the plasma of etanercept-treated
TRAPS patients is likely to contain a depot of TNF-? bound to
etanercept when this plasma is analysed in a CBA or ELISA assay,
the TNF-? that dissociates from etanercept will be rapidly and
effectively irreversibly bound by the anti-TNF-? capture anti-
bodies used in the assays, resulting in the detection of apparently
elevated levels of TNF-?. The therapeutic effect of etanercept in
TRAPS indicates that it reduces the bioavailability of TNF-?
in vivo, as we also found that it did in vitro in the L929 assay; but
this TNF-? is detectable in antibody-based assays where the anti-
TNF-? capture antibodies compete effectively with etanercept in
Despite the therapeutic effect of etanercept in TRAPS, our
results do not clearly indicate a special role for TNF-? in the
pathogenesis of TRAPS TNF-? levels did not correlate with CRP
(Table 1) and were not significantly elevated compared with
healthy controls, whereas they were elevated in RA patients
(Table 2). It may be that various forms of inhibition of pro-
inflammatory cytokine activity will be beneficial in TRAPS, as
reported for the IL-1 antagonist anakinra  in addition to
etanercept. In particular, we found that in some of the C33Y
TRAPS patients only IL-6 levels are elevated and correlate with
CRP levels, suggesting that IL-6 may be a promising target for
therapy in TRAPS. Studies using anti-IL-6 monoclonal antibody
in cancer showed a reduction in CRP levels , and anti-IL-6
receptor antibody has had clinical benefit in RA and Crohn’s
disease [31, 32].
In summary, we have shown marked heterogeneity between
C33Y TRAPS patients in their cytokine profiles, in particular IL-6
levels in relation to the CRP levels. Systemic IL-6 and CRP levels
were elevated in most C33Y TRAPS patients but did not always
correlate. This indicates that TRAPS is a heterogeneous condition,
even within a family with the same TNFRSF1A mutation. This
heterogeneity suggests that the faulty TNFRSF1A is not the only
factor in TRAPS and that other genetic and/or environmental
factors may play a role. In addition, the cytokine response in
the C33Y TRAPS patients did not appear to follow the pattern
seen in autoimmune inflammatory conditions, such as RA: in RA
patients, many of the pro-inflammatory cytokines were elevated,
whereas in some of the C33Y TRAPS patients only IL-6 appeared
to be truly elevated.
We are grateful to Dr Peter Lanyon for providing the RA
patients’ samples. This work was funded by The Jones 1986
Charitable Trust and by RCPath and International Journal of
Experimental Pathology Fellowship awarded to E.D.
The authors have declared no conflicts of interest.
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0 250500 75010001250
Original TNF (pg/ml)
FIG. 4. Etanercept alters the detection of TNF-? by ELISA in a
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