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???????????????????????????(??) TNF???????? ????
??????? vs rasburicase (????????????) ????????
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Severe gouty arthritis refractory to
anti-inflammatory drugs treatment with
anti-tumour necrosis factor alpha as a new
therapeutic option. Tausche AK, Richter K,
Grassler A, Hansel S, Roch B, Schroder HE. Ann
Rheum Dis. 2004 Oct63(10)1351-2. We report the
case of a 53 year old man with a history of gouty
arthritis extending over several years. He had
had an acute kidney failure(?????) 2 years
previously because of nephrolithiasis(????) with
urate calculi(?????).
9
CASE REPORT (1)
At the first consultation the patient had severe
painful gouty arthritis (three to four attacks a
week) of the joints of the big toes, the ankle
joints, and different finger joints as well as in
joints of the hands, shoulders, and knees. In
addition to the polyarticular joint
manifestation, multiple gouty tophi were present
in the subcutaneous tissue (fig 1).
10
CASE REPORT (2)
The medical history of the patient showed he had
arterial hypertension and hypertriglyceridaemia.
He consumed 20-25 units of alcohol weekly.
Standard treatment was impractical because the
patient had developed incompatibility with
allopurinol and benzbromarone, which manifested
as diarrhoea and a generalized exanthema.
Laboratory tests showed a raised white blood cell
count (WBC) of 9.4 x 10 to 9/l (9400/µl) an
erythrocyte sedimentation rate (ESR) 55 mm/1st h,
C reactive protein (CRP) 61.0 mg/l (6.1 mg/dl),
serum uric acid 580 µmol/l (9.7 mg/dl).
Transaminases were normal apart from a
?-glutamyltransferase of 282 U/l.
11
CASE REPORT (3)
Clinical examination, including cardiovascular
and respiratory systems, an electrocardiogram,
and a chest radiograph were normal. Abdominal
ultrasound was also normal apart from showing
hepatomegaly. The radiographs of all symptomatic
joints showed impressive signs of destructive
gouty arthritis (fig 2).
12
CASE REPORT (4)
Despite exhaustive treatment with colchicine,
diclofenac, methylprednisolone, and opioids, the
arthritis attacks did not improve considerably
(table 1 ). After obtaining the latest detailed
information about the patient and his informed
consent, treatment with etanercept (Enbrel) 25 mg
subcutaneously twice weekly was started. As table
1 shows the frequency (gouty attacks per week)
and the intensity (number of painful joints) of
the gouty arthritis decreased considerably after
four injections of etanercept. Laboratory tests
showed a noticeable decrease of the inflammation,
with WBC of 7.4 x 10 to 9/l (7400/µl) ESR 6
mm/1st h, CRP 6.1 mg/l (0.61 mg/dl). During the
anti-inflammatory treatment, antihyperuricaemic
treatment with probenecid and urine akalisers was
maintained the level of serum uric acid remained
roughly the same. Thus, treatment with the
tumour necrosis factor a (TNFa) inhibitor
etanercept in a patient with a complex gouty
arthritis impressively reduced the clinical
manifestations of gout, and uric acid depots were
depleted generally.
serum uric acid 580 µmol/l (9.7 mg/dl)
serum uric acid 560 µmol/l (9.4 mg/dl)
13
DISCUSSION 1
Effective treatment exists to prevent the
complications of symptomatic hyperuricaemia.
However, severe gouty arthritis together with
tophaceous manifestations are rarely Seen. In
most cases standard treatment with colchicine,
non-steroidal anti-inflammatory drugs, and
moderate doses of glucocorticosteroids is
sufficient to control the inflammation of gouty
attacks. In our patient the conservative
treatment of the gout, including opioids for
analgesia, did not control the attacks. The use
of etanercept produced a noticeable decrease in
all the pathological clinical and laboratory
findings (table 1).
14
DISCUSSION 2
TNFa plays an important part in different
inflammatory diseases. Today, anti-TNFa is widely
used in the treatment of different kinds of
arthritis and primary vasculitis. Acute and
chronic gouty arthritis is an inflammatory
disease, in which activation of certain white
blood cells occurs owing to the presence of a
foreign substance-namely, urate crystals. The
activation of monocytes and macrophages releases
TNFa into the synovial fluid. Increased
concentrations of TNFa are detectable in joints
of gouty arthritis.In certain cases,gout can
mimic rheumatoid arthritis. We describe the
first published case of severe,recurrent
tophaceous gouty arthritis refractory to
anti-inflammatory treatment in a patient who was
subsequently treated successfully with a TNFa
inhibitor.Of particular interest is the
possibility of maintaining antihyperuricaemic
treatment during the antiphlogistic protection of
etanercept, especially as there is a massive
excavation of uric acid from the depots owing to
the antihyperuricaemic treatment.
15
TNF????????
????RA???new standard-??????????- Medical
Practice 22465-471,2005
16
etanercept or rasburicase
Tausche el al described a case of severe
tophaceous gouty arthritis, which was treated
with etanercept. They showed that anti-tumour
necrosis factor a (TNFa) treatment can reduce the
incidence of gouty attacks, which corresponds
with the observation that TNFa is activated in
patients with gouty arthritis. Clearly, this is a
costly symptomatic approach that is only in
addition to the main treatment, which is lowering
the serum uric acid (SUA) level in order to
deplete urate depots and prevent gouty attacks
and joint damage in the long term. In the case
presented, uricosuric treatment could only lower
SUA levels from 0.58 mmol/l to 0.56 mmol/l
despite high doses of 2-3 g probenecid a day.
This is in contrast with our experience. In our
population of 95 undersecretors (defined as uric
acid excretion in urine lt6.0 mmol/day during
normal diet) monotherapy with probenecid 500 mg
twice daily lowers SUA levels by 35 (mean (SD)
0.l7 (0.05) mmoU1), whereas probenecid 500 mg
twice daily in combination with allopurinol 200
mg daily lowers SUA levels by 48 (0.27 (0.08)
mmol) in patients with an adequate renal
function (endogenous creatinine clearance gt50
ml/min). In the case presented by Tausche el al
we would like to suggest another option for
treating patients with severe tophaceous
gout-that is, treatment with rasburicase. This
recombinant form of urate oxidase very
effectively metabolises uric acid in allantoin,
which dissolves readily and is excreted by urine.
So far one patient has been treated by applying
rasburicase and urate depots were readily
depleted (Moolenburgh JD el al, submitted paper)
In our opinion, for a case of severe tophaceous
gout, When an expensive treatment is indicated,
rasburicase should be considered as a potentially
very effective treatment before using anti-TNFa.
Authors' reply Like Reinders et al, we have
found that in the defined normal" population of
undersecretors, conventional treatment
effectively lowers serum uric acid (SUA) levels
to the norm. In those critical cases of severe
tophaceous gout, as presented by us, the multiple
tophi in the tissue and joints contain around 50
g or more uric acid. Despite the escalation of
antihyperuricaemic (uricosuric and uricostatic)
drugs, the SUA levels cannot be lowered
significantly because of uric acid mobilisation
from these depots and secondary shift to the
serum. Therefore, measurement Of SUA levels
alone does not verify the efficiency of
treatment In view of our own experience
(unpublished data), we agree with Reinders et al
that the recombinant urate oxidase rasburicase
should be introduced into the treatment of severe
tophaceous gout if conventional uric acid
lowering treatment is not effective or
contraindicated. These cases are extremely rare
and occur in under 0.01 of the population of
undersecretors. There are two principles in the
treatment of gout firstly, uric acid lowering
treatment with uricostatic and uricolytic agents
and, secondly, anti-inflammatory treatment
Of gouty quacks. Both of these treatment regimens
should follow a ''step scheme". In the uric acid
lowering treatment rasburicase might rank as the
last step in treatment of patients with
tophaceous gout. When gouty arthritis is
refractory to treatment (with non-steroidal
anti-inflammatory drugs, steroids, opioids) it is
useful to introduce tumour necrosis factor a
(TNFa) blockades, as we showed in the published
case. Because two different principles of action
can be followed there seems to be no need to
answer the question of priority of one of these
treatments. Rasburicase should not be considered
before TNFa blockade but, rather, the two should
be combined if conventional treatment is not
sufficient. The main dilemma of both treatments
in the first instance is not the high cost but
the missing approval by the FDA in severe
tophaceous gout. Unfortunately, valid data are
lacking, for instance, about the best way of
application (dosage, application interval) owing
to the absence of clinical studies. Shortly after
infusion of rasburicase instant uric acid
metabolisation with abrupt decrease of SUA is
observed. The resultant shift of uric acid from
tissues to blood may cause a higher intensity of
gouty attacks, and as we observed in one patient
with urate nephropathy the worsening of renal
function. We are very interested to learn of the
article proposed by Moolenburgh el al. Tausche
AK, Schroder HE.
Reinders MK, van Roon EN, Brouwers JR, Jansen TL.
A costly therapeutic dilemma in tophaceous gout
is etanercept or rasburicase preferable? Ann
Rheum Dis. 2005 Mar64(3)516
17
rasburicase ????????????
Abstract We recently encountered a destructive
case of tophaceous gout in a 57-year-old patient.
Despite perfect therapy compliance, the patient
failed in the conventional urate-lowering
treatment, accounting for the ongoing urate
retention and accumulation with progressive
tophaceous bulky disease. Application of an
experimental scheme of uricolytical therapy on
this patient was able to reduce bulky disease
significantly. In modern medicine, potent
urate-debulking medication with urate oxidase
(uricase) derivatives is at our disposal, and it
is a challenge for rheumatologists to install the
right strategy including innovative approaches
with potent uricolytic therapy on the right
patient at the right time.
J. D. Moolenburgh, M. K. Reinders and T. L. Th.
A. Jansen Rasburicase treatment in severe
tophaceous gout a novel therapeutic option Clin
Rheumatol. 2005 Oct 251-4
18
Mechanism on HLA-DRa expression
J. D. Moolenburgh, M. K. Reinders and T. L. Th.
A. Jansen Rasburicase treatment in severe
tophaceous gout a novel therapeutic option Clin
Rheumatol. 2005 Oct 251-4
19
mechanism Mechanism on HLA-DRa expression
IFN-g receptor
Jak2
Jak2
Jak1
Jak1
Nucleus
GAS
CIITA gene
20
mechanism Mechanism on HLA-DRa expression
IFN-g receptor
Jak2
Jak2
Jak1
Jak1
Nucleus
GAS
CIITA gene
21
Pathways of urate
Alexander So, Bernard Thorens J Clin Invest.
2010120(6)1791-1799
22
Cytokine and chemokines that play a role in gouty
inflammation
IL-1ß Endothelial adhesion Monocyte, dendritic
cells inflammatory macrophage Endogenous
pyrogen TNFa Cellular activation Monocyte,
macrophage, lining cell Endothelial
adhesion Phagocytosis IL-6 ? Monocyte,
macrophage Granulocyte colony-stimulating
factor Neutrophil survival and proliferation Endot
helium, macrophage CXCL1 (KC, Groa) Neutrophil
chemotaxis Macrophage, neutrophil CXCL8
(IL-8) Neutrophil chemotaxis Macrophage,
endothelium CCL2 (monocyte chemoattractant
protein-1) Monocyte and dendritic cell
chemotaxis Mast cell degranulation CCL3
(macrophage inflammatory protein-1) Neutrophil
chemotaxis Monocyte, macrophage
Busso and So Arthritis Research Therapy 2010
12206
23
Enzymatic activity of uricase (uric acid oxidase)
Robert Terkeltaub Gout. Novel therapies for
treatment of gout and hyperuricemia Arthritis
Research Therapy 200 236, 2009.
24
Molecular models of the uricase tetramer and of
the PEGylated uricase pegloticase containing
strands of 10 kDa polyethylene glycol (PEG)
linked to each uricase tetramer.
Robert Terkeltaub Gout. Novel therapies for
treatment of gout and hyperuricemia Arthritis
Research Therapy 200 236, 2009.
25
The NLRP3 inflammasome and IL-1ß processing and
secretion in crystal-induced inflammation.
Robert Terkeltaub Gout. Novel therapies for
treatment of gout and hyperuricemia Arthritis
Research Therapy 200 236, 2009.
26
Composition of the NALP3 inflammasome and its
activation by monosodium urate
Busso and So Arthritis Research Therapy 2010
12206
27
Cytokine and chemokines that play a role in gouty
infl ammation
Cytokine Actions contributing to gouty Cytokine
inflammation Produced by References IL-1ß
Endothelial adhesion Monocyte, dendritic cells
inflammatory 11,12,20,25 macrophage
Endogenous pyrogen TNFa Cellular activation
Monocyte, macrophage, lining cell 11,12
Endothelial adhesion Phagocytosis IL-6 ?
Monocyte, macrophage 11,17 Granulocyte
colony-stimulating factor Neutrophil survival and
proliferation Endothelium, macrophage 11,17
CXCL1 (KC, Groa) Neutrophil chemotaxis
Macrophage, neutrophil 11 CXCL8 (IL-8)
Neutrophil chemotaxis Macrophage, endothelium
36,37 CCL2 (monocyte chemoattractant
protein-1) Monocyte and dendritic cell chemotaxis
11 Mast cell degranulation CCL3
(macrophage infl ammatory protein-1) Neutrophil
chemotaxis Monocyte, macrophage 11
Busso and So Arthritis Research Therapy 2010
12206
28
Multiple steps are needed to trigger inflammation
in gout
Busso and So Arthritis Research Therapy 2010
12206
29
??
???????????????????????????(??) TNF???????? ????
??????? vs rasburicase (????????????) ????????
?????????????????
30
??????????????????
??? ???? 201059(2)178-183
31
????????????????????
??? ???? 201059(2)178-183
32
????????????
???????? ?????????????? 2010 59 231-236
33
????????????????????????
???????? ?????????????? 2010 59 231-236