Update on the Management of Hyperuricemia and Gout
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Bulletin of the NYU Hospital for Joint Diseases 2008;66(3):231-9 231
Update on the Management of Hyperuricemia and
Gout
Michael H. Pillinger, M.D., and Robert T. Keenan, M.D.
Abstract lead to joint destruction, joint infection, and, occasionally,
Gout is the most common inflammatory arthritis in the amputation and death. Moreover, accumulating evidence
United States, with more than three million sufferers. Man- suggests that gout and hyperuricemia are associated with,
agement of gout has changed relatively little in the past 50 and potentially contributory to, a number of serious and po-
years, despite the fact that many gout patients have contrain- tentially life-threatening problems, including hypertension,
dications to one or more currently available gout therapies. renal disease, and coronary artery disease. Accordingly, more
However, recent insights into gout pathophysiology suggest and better treatment options are needed for patients with gout
that time is ripe for a change. This article reviews recent and hyperuricemia. Included in this article are reviews of
updates in the management of gout, including new insights the most recent data on the potential importance of lifestyle
into dietary management that may permit better control of modification in the management of hyperuricemia and gout
hyuperuricemia. Also reviewed are the biological and clini- and new information regarding the appropriate use of cur-
cal data behind newly-developed drugs for gout that are rently available standard therapies for gout. A discussion
likely to receive wserious consideration for FDA approval, follows on agents that are newly available, nearly available,
and clinical use, in the foreseeable future. and potentially available in the future for the management
of hyperuricemia.
G
out is the most common inflammatory arthritis,
with more than three million sufferers in the U.S. Food and Drink: Lifestyle Modifications and
alone.1,2 The majority of cases of gout are managed the Management of Gout
by primary care physicians, with referral to rheumatologists Surf ‘N Turf
typically for more difficult cases. However, recent studies Clinicians have known, for more than a millennium, that
indicate that primary care management does not always dietary indiscretions may predispose to the risk of gouty
adhere to evidenced-based best practice.3 Moreover, even attack.4 Decreases in the consumption of meats (especially
in the hands of experienced rheumatologists, a significant organ meats), and other foods with high purine content
number of patients fail to achieve optimal response to appro- (such as seafood), have long been advised by clinicians.
priate therapy. In contrast to the view of gout as a relatively Given this well-established standard of practice, readers may
benign disease, poorly managed gout can be disabling and be surprised to know that, while many small studies have
established the role of diet in hyperuricemia and gout, few
Michael H Pillinger, M.D., is Associate Professor of Medicine studies that were rigorous, large scale, or both, have con-
and Pharmacology, NYU School of Medicine and with Robert T. firmed these initial observations. To address this deficiency,
Keenan, M.D., from the Division of Rheumatology, Department
Choi and colleagues utilized the Third National Health and
of Medicine, NYU Hospital for Joint Diseases, NYU Langone
Nutrition Survey (NHANES III), a database containing in-
Medical Center, New York, New York, and the Department of
Medicine, New York Harbor VA Healthcare System NY Campus, formation on approximately 15,000 patients.5 At entry into
New York, New York. this study, patients completed extensive questionnaires on
Correspondence: Michael H Pillinger, M.D., Division of Rheuma- their nutritional status, including information on diet and
tology, NYU Hospital for Joint Diseases, 301 East 17th Street, New alcohol intake, as well as general health information. Patients
York, New York 10003; michael.pillinger@med.nyu.edu. then underwent a detailed physical examination, as well as a
Pillinger MH, Keenan RT. Update on the management of hyperuricemia and gout. Bull NYU Hosp Jt Dis. 2008;66(3):231-9.232 Bulletin of the NYU Hospital for Joint Diseases 2008;66(3):231-9
laboratory testing, including serum uric acid determination. tion had not been determined, at least one investigator has
For the purposes of the study, the investigators divided the suggested that it may be the action of amino acids rather
patients into five quintiles based on daily consumption of than intact protein, competing as weak acids at renal urate
each of the foods of interest. In so doing, they confirmed transporters, that acts to block urate uptake and induce uri-
that patients with higher intakes of either meat or seafood cosuria.8 Whether dairy intake could have a urate-lowering
had increased risks of hyperuricemia. However, several action in patients with significant renal insufficiency has not
observations were also made that were less expected. Based been tested, but would seem to be unlikely under the current
on the risk of hyperuricemia with meat and seafood intake, model.
practitioners sometimes assume that protein per se carries The above studies link meat and seafood, but not protein
an increased risk of hyperuricemia. This study found that, or dairy, to high serum urate levels. But do these observa-
once corrected for purine intake, there was no correlation tions translate to a risk for the development of actual gouty
between dietary protein intake and uric acid levels. Thus, attacks? To assess this question, Choi and coworkers turned
the increased risk for elevated serum uric acid concentration to the Health Professionals Follow-up Study, in which more
when eating meat or seafood appears to reside, primarily if than 50,000 dentists, podiatrists, and other health care pro-
not exclusively, in the purine content of these foods. fessionals participated.9 In this study, male patients were
enrolled and followed prospectively for 12 years. Dietary
Got Milk? information and other medical history were collected at
Choi and coworkers also examined whether consumption of the time of enrollment. After excluding participants with
dairy products was associated with changes in serum uric preexisting gout or renal disease, they followed the remain-
acid concentration. A number of small observational and ing patients, identifying by self-report approximately 700
provocational studies, or either, performed over the past patients who developed new onset of gout during the study
decade have suggested that dairy intake may independently period. Consistent with the NHANES III data for hyper-
contribute to lower uric acid levels. NHANES III supports uricemia, patients in the upper quintiles of meat or seafood
these observations. In the studies by Choi and associates, consumption were at significantly more risk for gout than
patients with the highest intake of dairy products had average patients in the lower quintiles were at risk. In contrast, pa-
serum uric acid levels nearly 0.5 mg/dL lower than patients tients in the highest quintiles for dairy consumption were at
with the lowest levels of intake.5 significantly lower risk for new onset of gout than individuals
How might dairy consumption actively contribute to in the lowest quintiles. Thus, although no prospective trials
lower uric acid levels? Several additional small studies have yet examined the benefit of increased dietary dairy in
suggest the possibility that milk or milk components may lowering the risk of gouty attacks, these data suggest that
have a uricosuric effect. For example, Garrel and colleagues increasing dairy intake may be both an easy and effective
tested the effect of two isolated milk proteins, casein and way to improve the management of gout.
lactalbumin, using soy protein as a control, on 10 healthy Nutritionists have long known that some green vegetables,
volunteers between the ages of 20 and 30 years.6 Each par- particularly leafy vegetables, such as spinach, are high in
ticipant consumed 80 grams of casein, lactalbumin, or soy purines, and have consequently recommended that patients
protein, followed by measurement of serum and urinary with gout reduce their consumption of these vegetables.
urate levels for the next 180 minutes. Volunteers consuming However, Choi and associates found no correlation between
the casein or lactalbumin experienced rapid decreases in vegetable intake and gout risk. It is proposed that other, ben-
serum urate levels. In contrast, consumption of soy protein eficial compounds present in these vegetables, perhaps with
resulted in a rapid increase in serum urate levels. When the the capacity to induce renal urate excretion, might offset the
investigators assessed the urine urate levels, they observed adverse consequences of their high purine content. Further
that ingestion of any of the three proteins tested resulted in study will be required to understand the nature of these ef-
increased urinary urate excretion. Based on these observa- fects.
tions, they suggest that, rather than contributing to hyperuri-
cemia, ingested protein per se has a direct uricosuric effect, Beer Me, Marge: Alcohol and Hyperuricemia
to which the effects of the dairy proteins (and presumably Ancient Greek and Roman physicians were well aware of the
dairy products themselves) can be ascribed. What is notable capacity of alcoholic beverages to predispose one to gout,
about dairy products, however, is that they are extremely an observation that was also not lost on the great European
low in purines; in contrast, the soy protein control used in physicians of the 15th through 19th Centuries. It has been
the study was actually high in purine impurities. Thus, the presumed that all alcoholic beverages, including beer, wine,
investigators propose that it is the unique high protein and and hard liquors, carry increased risks for hyperuricemia.
low purine nature of dairy products that contributes to their Alcohol consumption has multiple mechanisms by which it
urate lowering effects. Support for the uricosuric effects can raise serum urate, including the generation and turnover
of proteins can be found in several physiologic studies.7 of ATP (adenosine triphosphate), diuresis and dehydration,
Although the mechanism for protein-mediated urate excre- the production of lactic and ketoacids, and the content ofBulletin of the NYU Hospital for Joint Diseases 2008;66(3):231-9 233
purines in some alcoholic beverages. came to be included in not only sweetened foods, but also in
As in the case of food, however, the effects of alcohol foods that did not previously include sweeteners. Sweetened
have been documented in many small, but few large or defini- beverages, including soft drinks and sports drinks, came into
tive studies. To address this deficiency, Choi and coworkers wider and wider use during this period as well. Indeed, recent
again employed the NHANES III and Health Professionals studies indicate that the average American currently consumes
databases.10,11 Using these data, these investigators confirmed more than 160 pounds of sugar annually and that the single
a nearly linear dose response between alcohol ingestion and biggest source of calories in the American diet (11%) is now
both serum urate and the risk of gout. When alcohol consump- soft drinks and fruit juices.15 Critically, it turns out that the
tion was further broken down by type of beverage, however, metabolism of fructose is unique, and that the metabolic deg-
an unexpected observation arose. Beer ingestion was most radation of fructose generates uric acid to a degree greater than
strongly correlated with hyperuricemia and gout (presumably that seen with other sugars. Indeed, both human and animal
because of the very high content of purines in beer and ale), studies have demonstrated that ingestion of fructose rapidly
hard liquor consumption increased serum urate and risk of leads to increases in serum urate.16 Strikingly, the increases
gout to an intermediate degree, but moderate consumption of in gout incidence and prevalence in the U.S. began to take
wine had little or no effect on either serum urate levels or the off around the 1960s just as fructose consumption began to
risk of gout. How could this be? The answer remains uncer- skyrocket.
tain, but wine in general is a more complex ferment than either To understand how fructose may induce hyperuricemia,
beer or hard liquor; wines contain a number of antioxidants we must briefly review the pathway of purine and uric acid
including polyphenols. Resveratrol, an antioxidant that in biosynthesis (Fig. 1).17 Purines are synthesized off a backbone
animal models has been shown to have life-extending proper- of 5-ribose pyrophosphate by the action of phosphoribosyl
ties, is also found in wine but not other alcoholic beverages. pyrophosphate (PRPP) synthase, resulting in the production
Moreover, wine contains less alcohol per volume than either of inosine monophosphate. However, inosine monophosphate
beer or liquor, suggesting a lower ratio of alcohol to other can also be generated by the action of AMP deaminase on
bioactive compounds. It is therefore possible that wine induces AMP. Inosine monophosphate may then be converted to
complex effects, either abrogating or offsetting the alcohol- inosine by 5’ nucleotidase, which, in turn, is converted to
based production of purines as a result of its other ingredients. hypoxanthine by the action of nucleoside phosphorylase.
In this regard, it is interesting to consider whether red wine, Hypoxanthine then serves as the substrate for xanthine and
which has a more complex structure (and is the only type of subsequent uric acid synthesis by xanthine oxidase. Under
wine containing significant quantities of resveratrol), might normal circumstances, several feedback loops act to reduce the
engender more anti-hyperuricemic properties than white.12 production of uric acid, including inhibition of AMP deami-
Studies addressing the relative effects of red and white wine nase by inorganic phosphate, and inhibition of 5’ nucleotidase
have yet to be performed, however. by elevated concentrations of ATP.
When fructose is ingested, it is acted upon by the enzyme
The Pepsi Generation: Fructose Intake and the fructokinase to produce fructose-1-phosphate, consuming in
Risk of Hyperuricemia and Gout
Osler suggested, more than one hundred years ago, that
sugar intake might contribute to the risk of gout.13 Recent
events and recent studies are beginning to bear him out. The
prevalence of gout has undergone a striking increase in the
last 50 years, simultaneous with increases in obesity and
diabetes. Indeed, studies suggest a three- to four-fold increase
in the frequency of gout in the U.S. during this period.14 To
understand a possible reason for this sea change, one must
consider the consumption of sugar. Until approximately the
17th Century, the primary source of sweetener in the western
diet was honey. Around that time—and concordant with the
trade routes and slave trade in the West Indies—cane sugar, or
sucrose—came into use, initially as a luxury only for the upper
classes. By the late 18th Century, agricultural, shipping, and Figure 1 Fructose metabolism and the generation of uric acid.
revised taxation policies permitted the middle class access to Enzymatic degradation of fructose results in phosphate trapping,
table sugar, and the industry grew, along with sugar consump- ATP depletion, and the liberation of ADP/AMP. Increased AMP
tion. The next truly large increase in sugar consumption came provides substrate for uric acid generation, and reductions in [ATP]
and [Pi] result in loss of feedback inhibition of uric acid produc-
around the 1960s with the use of high-fructose corn syrup on
tion. See text for details. (Adapted from: Mayes PA, Intermediary
a wide scale. This sweetener, manufactured from corn, is tasty, metabolism of fructose. Am J Clin Nutr. 1993;58(5 Suppl):754S-
stable, soluble, and cheap, and its use escalated rapidly as it 65S. With permission.)234 Bulletin of the NYU Hospital for Joint Diseases 2008;66(3):231-9
the process one molecule of ATP and generating ADP and between these two variables, suggesting the possibility that
inorganic phosphate (Pi). This enzymatic action is essentially caffeine, or some other component of coffee, might actually
irreversible, since fructose-1-phosphate acts as a phosphate contribute to a reduction in serum urate levels. In fact, these
sink, leading to Pi sequestration. As a result, instead of be- investigators concluded that it was unlikely that the active
ing regenerated to ATP, the ADP produced during fructose compound was caffeine, since increases in the consumption
metabolism is susceptible to conversion to AMP by adenylate of caffeine-containing green tea carried no similar associa-
kinase; AMP is then available to participate as a substrate for tion with hyperuricemia.
uric acid generation. Moreover, the depletion of both ATP Choi and associates reexamined the effects of caffeine
and Pi during fructose metabolism diminishes the activity using the NHANES III database and observed that heavy
of the feedback inhibitory loops, permitting the enzymatic coffee drinking (four or more cups) was associated with
processes involved in uric acid generation to accelerate. significant decrements in serum urate levels.27 Once again,
In addition to these observations, Vitart and associates it appeared unlikely that caffeine was the effector, since
have recently identified a novel renal urate transporter, increased consumption of tea had no effect. Moreover,
SLC2A9, whose genetic variants appear to influence serum consumption of decaffeinated coffee was also associated
urate concentrations.18 Since SLC2A9 has also recently been with lower serum urate levels. Thus, it appears likely that
established as a fructose transporter,19 these data suggest that a coffee component(s) other than caffeine must play a role
fructose may also alter serum urate through its effects on the in lowering uric acid. What this component may be, and its
modulation of urate transport. mechanism of action, remain a mystery; but it is worth not-
Do these biochemical effects of fructose ingestion ac- ing that coffee is actually a complex beverage and contains
tually result in human hyperuricemia? Small prospective a wide range of organic plant alkaloids.
studies have indicated the ability of diets high in fructose
to induce higher serum urate levels relative to diets high in Novel Therapeutics and New Horizons
glucose or low in carbohydrates.20 To address this question The currently available drugs for gout, NSAIDS (nonsteroi-
on a larger scale, Choi and colleagues again examined their dal antiinflammatory drugs), glucocorticoids, colchicine, and
databases.21-23 They observed a direct correlation between the urate-lowering therapies (allopurinol and probenecid) are
the degree of fructose intake overall, or measured as soft all well established and reasonably effective. However, there
drink consumption, and the risk of both hyperuricemia and are a number of good reasons to desire the availability of
gout. Males appeared to be more susceptible to the fructose new and different therapies. Rheumatologists are aware that
effect than females. Moreover, for individuals who consume some patients fail to respond to the most aggressive of cur-
diet soda, no correlation was seen between the amount of rent regimens. These are individuals who, despite maximum
consumption and any increase in hyperuricemia or gout, therapy, continue to have high serum urate levels, tophi, or
confirming that it is likely to be the fructose in soft drinks frequent gouty attacks, some a combination. Moreover, our
that is the main offender. current urate-lowering therapies are only moderately effec-
tive at reducing or resolving tophi, with probenecid carrying
Strange Brew: Coffee Consumption and the the additional potential risk of inducing renal stones when
Mitigation of Hyperuricemia used in the setting of a large total body urate burden. Addi-
Caffeinated beverages, such as coffee and tea, are drunk tionally, many patients with gout have significant and often
worldwide, and coffee is perhaps the most popular beverage multiple comorbidities that make the use of many of our
on the planet. By acting on various subtypes of adenosine current therapies undesirable or, in some cases, absolutely
receptors, caffeine stimulates wakefulness24 and may have contraindicated.
other potential actions, including the abrogation of hepatic To understand the extent to which our current gout drugs
fibrosis25 and mixed pro- and anti-inflammatory effects. may be contraindicated in the patient population, we recently
Since caffeine is also a diuretic, and diuretics tend to increase conducted a spot survey in an active department of a Veterans
the risk of hyperuricemia and gout (both by stimulating Affairs rheumatology clinic, which has a high gout case load.
proximal tubular sodium resorption, and by directly affect- We defined five potential contraindications to currently avail-
ing urate excretion), one might postulate that drinking caf- able gout therapies: 1. chronic kidney disease (CKD, serum
feinated beverages could contribute to hyperuricemia. Such creatinine greater than 1.6 mg/dl in patients over the age of
was the reasoning of Kiyohara and coworkers when they 50), 2. diabetes, 3. hypertension, 4. coronary artery disease,
tested the effects of coffee and tea on uric acid.26 To do so, and 5. allopurinol sensitivity (all by previous chart diagnosis
they surveyed 2240 Japanese Defense Officials receiving a or current history). We then asked what percentage of gout
pre-retirement physical. Dietary information was obtained patients presented with what condition(s). The presence of
and compared with the participants’ serum urate levels. these comorbid conditions in our gout patients was extremely
However, the investigators failed to observe a direct corre- high, perhaps as a consequence of the current epidemic of
lation between coffee consumption and hyperuricemia. On Syndrome X. When we subsequently defined hyperten-
the contrary, their study showed a clear inverse correlation sion, CKD, diabetes, and coronary artery disease as relativeBulletin of the NYU Hospital for Joint Diseases 2008;66(3):231-9 235
tent several other enzymes in the purine biosynthetic pathway,
febuxostat appears to inhibit xanthine oxidase exclusively.28
Whether and in what ways this increased selectivity turns out
to be advantageous remains to be determined. On a molar ba-
sis, febuxostat is also more a potent xanthine oxidase inhibitor
than allopurinol, with a lower IC50 demonstrated in vitro.29
Again, the benefit of this difference remains to be determined,
but suggests the possibility that febuxostat might permit cli-
nicians to more readily reach target serum urates within the
range of safe use of the drug. Finally, febuxostat is not renally
excreted, suggesting its possible utility in patients with CKD.
In this regard, however, it must be noted that Phase III studies
of the utility of febuxostat in patients with CKD have yet to be
reported; and again, rheumatologists are generally aware that
Figure 2 Prevalence of contraindications to specific gout drugs allopurinol doses can be escalated, albeit cautiously, in renal
among a clinic population. Gout patients presenting to a rheumatol- failure patients. One area in which febuxostat and allopurinol
ogy clinic over 4 consecutive weeks were assessed for contraindica- are similar is that they are both hepatically metabolized; it
tion to five separate gout agents, and the percentage affected was remains unclear the extent to which preexisting liver disease is
calculated, as described in the text. a contraindication to febuxostat use, but caution will certainly
be warranted, and in some patients, febuxostat use has been
contraindications for both NSAIDs and glucocorticoids, and associated with increases in serum liver enzyme levels.
CKD as a contraindication for colchicine or probenecid, we Febuxostat has been tested in Phase I, Phase II, and Phase
observed that a very high proportion of our patients (90%) III trials.30,31 Based on dose-finding studies, approval of fe-
had contraindications to at least one currently available gout buxostat in Europe will be limited to once-daily 80 and 120
drug. Worse, we observed that a significant proportion of mg doses, and these are the doses at which the Phase II study
our patients had contraindications to all, or most of the drugs was carried out. Taking as the primary endpoint a lowering of
available (Fig. 2). These observations have been borne out in serum urate to below 6.0 mg/dL, febuxostat 80 mg and 120
other studies, and suggest the need for more effective, safer, mg were each more effective at achieving the target urate
and better-tolerated therapies for gout. level than allopurinol 300 mg. Once again, it must be affirmed
that rheumatologists do not treat gout with a fixed dose of
Pipeline Therapies allopurinol, but rather titrate to the target serum urate level.
Febuxostat Accordingly, the statement that febuxostat 80 or 120 is more
For the past several years, rheumatologists have been watching effective than allopurinol 300 mg provides only limited insight
with interest the development of an alternative to allopurinol. into the relative utility of the agents. When the secondary
That development is now coming to fruition, with the recent endpoint of gout flares was examined, both febuxostat 80 mg
approval of febuxostat by the European Commission, the Eu- and 120 mg were more effective than allopurinol 300 mg at
ropean equivalent of the U.S. Food and Drug Administration. inducing early flares. Presumably, the efficacy of febuxostat,
Like allopurinol, febuxostat acts by inhibiting the enzyme in this regard, was a consequence of its more effective urate
xanthine oxidase, responsible for the conversion of hypoxan- lowering ability, since rheumatologists know well that rapid
thine to xanthine and then uric acid. Similar to allopurinol, lowering of serum urate can temporarily increase the risk
febuxostat is administered once daily, by mouth. However, of acute gout attacks. (In the studies reported, colchicines
febuxostat differs from allopurinol in several potentially or NSAID prophylaxis against acute attack was limited to
important aspects. In contrast to allopurinol, which is itself a the first 2 weeks of urate-lowering therapy, in contrast to the
purine structure, febuxostat is not a purine analog, but rather longer prophylaxis that is standard-of-care in the community).
a mixed inhibitor of xanthine oxidase.28 It is possible that this Later (3 to 12 months), the urate lowering capacity of the
chemically different structure may render febuxostat safe in two drugs appeared similar, with febuxostat demonstrating a
patients with allopurinol hypersensitivity. If this turns out to somewhat greater efficacy. The clinical significance of these
be the case, failure to cross-react with allopurinol would be differences remains uncertain.
extremely useful for physicians managing gout patients with
allopurinol hypersensitivity. Unlike allopurinol, febuxostat Pegylated Uricase
is also not susceptible to degradation by purine pathway Humans, along with their primate cousins and New World
enzymes, giving a longer half-life and potentially a more monkeys, experienced the mutational loss of the enzyme
kinetically consistent action. Also of interest is the fact that uricase in the Miocene era, approximately 20 million years
febuxostat is much more selective than allopurinol. Whereas ago.32 It would not be until the mid-twentieth Century,
allopurinol inhibits both xanthine oxidase, and to a lesser ex- however, that humans were able to consider the possibil-236 Bulletin of the NYU Hospital for Joint Diseases 2008;66(3):231-9
ity of exogenous uricase replacement.33,34 More recently, What might be the pluses and minuses of peguricase?
technological advances have permitted the production of Though much remains to be discovered, it is possible to
recombinant bacterial uricase (rasburicase), derived from speculate on the basis of the established properties of the
aspergillus and approved for use in preventing tumor lysis agent. First, it is clear that pegylated uricase has the capacity
syndrome.35 It was not long before rasburicase was being to dramatically lower serum urate, making it attractive as
explored, in a small number of refractory patients, for the a potential rescue therapy. Conceivably, patients who have
treatment of gout.36,37 In some cases, rasburicase was able to failed all other agents might be referred for peguricase. The
lower uric acid where other treatments had failed. Indeed, safety and efficacy of the agent in patients with renal failure
the ability of rasburicase to dramatically lower serum urate has yet to be described, but there is no a priori reason why
levels has led, in some instances, to an impressive resolution this agent should not be usable in this group of patients.
of tophi. Rasburicase is not generally suitable for chronic Moreover, in contrast to allopurinol and febuxostat, there is
use, however. For one thing, it is expensive: approximately no a priori reason to expect that the agent will be contrain-
$8,000 a dose. As a foreign protein, rasburicase has a very dicated in liver failure, though studies will need to be done.
short half-life in the bloodstream, requiring multiple doses Again, the early studies suggest that pegylated uricase may
to create extended effects. Moreover, as a foreign protein, be a good alternative therapy in patients whose total body
rasburicase is highly immunogenic, and with each succes- burden of uric acid is high, and who are in need of resolution
sive treatment tends to be more rapidly cleared by the im- of tophaceous deposits.
mune system. The prospect of immediate hypersensitivity Among the possible limitations and concerns regard-
reactions, including anaphylaxis, has also been a limiting ing the use of pegylated uricase is its expense. Compared
factor. Thus, while rasburicase is not generally suitable with the currently available gout therapies, all of which are
for extended use, it may have value as a bridge therapy in generic, any biologic agent is sure to be expensive. Given
selected patients.38 the currently high prevalence of gout, its applicability to the
To overcome the limitations of fungally derived uricase, general gout population, therefore, requires careful consider-
investigators decided upon a strategy beginning with the ation. Another issue is the fact that, while less immunogenic
platform of a recombinant mammalian uricase, derived from than rasburicase, pegylated uricase still has the capacity to
pig, but modified to reflect primate sequence at the carboxy serve as an immunogen. Hypersensitivity and anaphylactoid
terminus. They then explored the benefits of appending to the reactions have occurred, and even when these do not occur,
protein chains of methoxypolyethylene glycol (PEGylation, the ability of the immune system to recognize this agent
an established strategy for making proteins more stable and may engender a potential loss of utility of the agent over
less immunogenic in the blood).39 These researchers found that time; future studies should clarify whether these are issues
the optimal level of PEGylation was six PEG chains of 10 units of genuine concern. Another interesting question is how low
each. With this agent, called peguricase, in hand, Phase I trials a serum urate level is actually desirable. Not only does urate
were performed that identified optimal dosing of the agent have antioxidant capacity, but the action of uricase on urate
as 8 to 12 mg on a monthly or biweekly basis. Initial Phase I generates oxygen radicals; the degree and importance of
trials assessed the feasibility of subcutaneous administration; this phenomenon remains to be determined. Whether it will
interestingly, patients receiving subcutaneous peguricase had be useful to titrate the dose of pegylated uricase to achieve
an increased risk of antibodies, not to the protein, but to the serum urates that are low, but not too low, also remains to be
PEG; the presence of these antibodies correlated with a shorter determined. Finally, recent studies suggest that uric acid may
half-life of the agent.40 Subsequent switching to intravenous play a fundamental role in immune responses43,44; whether
administration reduced the extent of this problem, possibly lowering the serum urate with pegylated uricase could
because intravenous administration permitted peguricase to adversely affect the immune system is at least a theoretical
bypass exposure to dermal dendritic cells.41 In these Phase I question. One possible approach to balancing the efficacy,
trials, the administration of peguricase was highly effective cost, and potential toxicities of peguricase may be to em-
and durable in reducing serum urate levels, driving serum ploy it as induction therapy, switching to more conventional
urate concentrations down to near zero, with gradual reac- agents for maintenance once significant urate depletion has
cumulation only after several weeks. Subsequently, Phase been achieved.
II and Phase III trials have been completed; the results have
not yet been published, though some reports have been pre- Possible Future Approaches to Gout
sented in abstract form.39 These abstracts suggest the ability Management
of pegylated uricase to effectively lower serum urate; as in Anti-Cytokine Therapy
the case of febuxostat, early serum urate lowering appears to The response to crystals in a joint depends upon both the
be accompanied by an increase in attacks, but subsequently ability of uric acid crystals to activate complement, and
(on the order of months), the number of attacks is reduced. their ability to interact with and activate resident tissue
These abstracts also suggest the ability of pegylated uricase macrophages. The response of tissue macrophages to crys-
to reduce the bulk of tophaceous deposits.42 tals involves the activation of the NALP3 inflammasome, aBulletin of the NYU Hospital for Joint Diseases 2008;66(3):231-9 237
Figure 3 Uric acid activates the NALP3
inflammasome. Uric acid crystals, acting
on macrophages, activate the NALP3
inflammasone, an intracellular enzyme
complex, the function of which is to cleave
pro-IL-1 to create active IL-1. Active IL-
1 can then leave the cell, potentially to
auto-engage cell-surface IL-1 receptors
and stimulate additional inflammatory
responses, including the generation of
TNF-α. (Adapted from: Martinon F, Pétrilli
V, Mayor A, et al, Gout-associated uric
acid crystals activate the NALP3 inflam-
masome. Nature. 2006;440(7081):237-41.
With permission.)
multimolecular complex that employs the enzyme caspase melanocortin and is known to have activity at melanocortin
1 to convert the pro-form of IL-1β into the active form (Fig. receptors (MCR).51 Based on these observations, Getting and
3).45,46 Secretion of IL-1β contributes to the gouty inflam- coworkers have examined the possibility that ACTH may act
matory response in a number of ways, including stimulat- to inhibit inflammation via engagement of one or more MCR.
ing the up-regulation of adhesion molecules on vascular Using a rat model of acute gout, they confirmed the ability
endothelial cells. Secreted IL-1β also acts in an autacoid of ACTH, injected subcutaneously, to stimulate increases in
manner, to engage IL-1β receptors, activate the signaling plasma corticosterone levels, as well as to reduce signs of
molecule MyD88, and stimulate additional inflammatory inflammation such as neutrophil influx. However, they also
reactions.47 Given the apparent centrality of IL-1β to the demonstrated the ability of lower concentrations of ACTH,
initiation of gouty inflammation, So and colleagues tested injected directly into the joint to inhibit joint inflammation
the utility of anakinra, a soluble IL-1β receptor antagonist, without increasing corticosterone levels.52 Thus, ACTH
for the treatment of acute gout.48 Ten patients with acute gout, must have antiinflammatory properties independent of its
who either had failed or were unable to tolerate standard effect on glucocorticoid release. Further studies by Get-
therapy received anakinra daily for 3 days. All ten patients ting and associates have demonstrated the ability of MCR
experienced 50% to 100% improvement in their signs and antagonists to reverse the antiinflammatory effect of ACTH
symptoms, measured by an unvalidated gouty response and the ability of selective agonists of MCR—particularly
score. Most patients demonstrated response within 24 hours MCR3—to suppress gouty inflammation.52-54 These data
of treatment. Considering that anakinra is already available suggest that MCR3 agonists may be useful antiinflammatory
for the treatment of other rheumatic syndromes, these studies drugs. Whether such agents will prove useful in human gout
suggest that it may be a viable treatment option for at least has yet to be tested.
some patients with acute gout. Although biologic agents are
expensive, the use of anakinra for only a few days would Acknowledgment
be unlikely to present a major economic burden. Whether it The Authors wish to thank David Goldfarb for his close and
would also be cost effective as maintenance therapy would helpful reading of the text.
be a different matter.
Disclosure Statement
ACTH and Melanocortin Receptors: Old Becomes Neither author has financial or proprietary interest in the
New Again subject matter or materials discussed, including, but not
ACTH (adrenocorticotropic hormone) was the first steroid limited to, employment, consultancies, stock ownership,
pathway agent used in rheumatic disease. Although its use honoraria, and paid expert testimony.
in gout has largely been supplanted by prednisone, and References
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