Update on Crystal-Induced

Arthritides
a,b, c
Hossam El-Zawawy, MD, MS *, Brian F. Mandell, MD, PhD

KEYWORDS
 Gout  Geriatrics  Treat to target  Comorbidities

KEY POINTS
 The clinical presentation of gout in the elderly includes more patients with atypical features
and offers more of a challenge in clinical differential diagnosis.
 The treatment of gout depends on the stage of the disease as well as the health status and
comorbidities of the patient.
 Acute gout attacks are functionally disabling and can lead to a substantial decrease in
quality of life. Treatment is aimed at quickly resolving pain and inflammation.
 Definitive curative therapy is to dissolve all of the urate deposits by using urate-lowering
therapy; once that is accomplished, attacks will no longer occur.

INTRODUCTION

Microcrystalline disease, predominantly owing to monosodium urate (MSU) deposition

(gout) is the most common cause of inflammatory arthritis. The prevalence of clinical
gout increases with age in both men and women1 to approximately 8% in men over
the age of 75.2 This increase occurs for several reasons, to be outlined elsewhere in
this article. Gouty arthritis is preceded in patients with hyperuricemia by the clinically
silent deposition of MSU in and around intraarticular structures as well as in tendons,
bursae, and soft tissues. Deposition of MSU occurs when the serum concentration of
urate (SUA) exceeds its solubility which is approximately 6.8 mg/dL. The deposition oc-
curs generally over years, so it is not surprising that older individuals with hyperuricemia
(defined as having a SUA >6.8 mg/dL), who have had more time for deposition to occur,
are at increased risk to develop gouty arthritis as well as frank tophaceous deposits. The
most common reason that SUA levels are increased is the inefficient urate transport
from serum into urine and the GI tract via specific transporters under genetic control.

Disclosure Statement: The authors have nothing to disclose.

a
Charles E. Schmidt College of Medicine, Florida Atlantic University, 777 Glades Road, Boca
Raton, FL 33431, USA; b Department of Rheumatic and Immunologic Diseases, Cleveland Clinic
Florida, 2950 Cleveland Clinic Boulevard, Weston, FL 33331, USA; c Department of Rheumatic
and Immunologic Disease, Cleveland Clinic Lerner College of Medicine, 9500 Euclid Avenue,
A50, Cleveland, OH 44195, USA
* Corresponding author.
E-mail address: [email protected]

Clin Geriatr Med - (2016) -–-

http://dx.doi.org/10.1016/j.cger.2016.08.010 geriatric.theclinics.com
0749-0690/16/ª 2016 Elsevier Inc. All rights reserved.
2 El-Zawawy & Mandell

Additional contributors to SUA elevations, many of which accompany aging, include

obesity, medications (including most diuretics, Table 1), decreased glomerular filtra-
tion rate, and ingestion of beer (including nonalcoholic) and mineral spirits. Women’s
SUA levels increase after menopause, because estrogen has a uricosuric effect.3
Although hyperuricemia and gout are strongly associated with insulin resistance,
obstructive sleep apnea, hypertension, and the metabolic syndrome, it seems that
the common and perhaps only independent factor required for gout to develop is sus-
tained hyperuricemia to a level greater than 6.8 mg/dL.4
Because deposited MSU remains in equilibrium with the SUA, a core principle in
treating patients with gout is that maintenance of the SUA significantly below its satu-
ration threshold will ultimately result in the dissolution of the MSU deposits and pre-
vent the occurrence of acute gout attacks. The lower the level that the SUA is
maintained, the more rapid the dissolution of the deposits and the sooner the resolu-
tion of gout attacks. This principle holds true for young and elderly patients. With usual
therapy, the dissolution takes months to years to occur and this needs to be consid-
ered when making treatment plans in the very old and others in whom quality of life
may dictate need for rapid improvement. The inverse relationship between rate of res-
olution and SUA level is the basis for why the ultimate target for SUA in those patients
with visible/palpable tophi is typically lower (<5.0 mg/dL) than those without tophi
(<6.0 mg/dL) because these tophi presumably reflect a higher total urate burden,
which in turn will take longer to dissolve. Whatever the final SUA target, orally dosed
urate-lowering therapy (ULT) should generally be initiated at a low dose and slowly
escalated to the dose necessary to achieve and maintain the desired SUA. Slow esca-
lation should be prescribed to decrease the chance of a “mobilization” attack of gout
from the sudden decrease in urate level and to hopefully reduce the likelihood of the
patient having an allopurinol hypersensitivity reaction.5
Acute gout attacks can be treated successfully with any of several classes of anti-
inflammatory medications. Corticosteroids, nonsteroidal antiinflammatory drugs
(NSAIDs) and interleukin-1 antagonists have been demonstrated in clinical studies
to resolve gout attacks. The choice of agent used to treat acute gout is generally
dictated by the patient’s comorbidities, the potential for adverse interactions with
other medications, and personal tolerance of the different antiinflammatory drugs.
Older patients often have several of these confounding issues, often making treatment
decisions more complicated and limiting therapeutic options.

GOUT PRESENTATION IN THE GERIATRIC POPULATION CAN DIFFER FROM CLASSIC

GOUT SEEN IN MIDDLE-AGED MEN

Gout in middle-aged and younger patients classically presents as a recurrent and

intermittent disease of the lower extremity of males. The gender difference parallels

Table 1
Drug induced hyperuricemia

Mechanism Drugs
Increased uric acid production Cytotoxic chemotherapy, filgrastim, ribavirin/interferon
Reduced renal clearance of uric acid Angiotensin-converting enzyme inhibitors,
cyclosporine, thiazide and loop diuretics,
ethambutol, tacrolimus, low-dose aspirin (mild)
Increased urate production and Niacin
decreased clearance
 Update on Crystal-Induced Arthritides 3

the average serum urate level, which is higher in men. After menopause, women expe-
rience an increase in their SUA owing to the loss of the estrogen’s uricosuric effect,
which can be attenuated by estrogen replacement therapy. For example, in a recent
emergency department-based clinical study comparing prednisolone therapy with
indomethacin, the average age of enrolled patients was 65 years and 79% were
men. Of the participating women in the study, approximately 90% were postmeno-
pausal.6 As the population ages, the gender disparity of gout narrows, which is related
to the delayed onset of hyperuricemia in women. Beyond this observation, there may
be other incompletely understood differences between how men and women react to
hyperuricemia.
The clinical presentation of gout in the elderly includes more patients with “atypical”
features and generally offers more of a diagnostic dilemma. Involvement of joints
already damaged by osteoarthritis are seemingly prone to acute gout. This may be
owing in part to decreased local solubility of urate as a result of altered proteoglycan
composition. Gout attacks in distal finger joints as well as tophus formation at the site
of Heberden’s nodes of osteoarthritis can be misinterpreted as “inflammatory osteo-
arthritis” (Fig. 1). This pattern has most frequently been described in postmenopausal
women on diuretics, but also can occur in men. Some authors have described an
increased frequency of polyarticular attacks in older patients.7,8 If more indolent,
then this type of presentation may mimic rheumatoid arthritis or chronic calcium pyro-
phosphate deposition disease (“pseudogout”). Because bacterial septic arthritis is
more common in the elderly, this important consideration must be resolved definitively
by synovial fluid analysis and culture. In patients with severe dementia who cannot

Fig. 1. Tophus on index finger.

4 El-Zawawy & Mandell

clearly articulate their health issues, gout attacks may manifest as fever and/or a
further change in cognitive status. Axial involvement with gout has historically been
felt to be uncommon, but recent imaging studies indicate that gout can and does
involve the spine. Indeed, gout in the spine has been misdiagnosed as compression
fracture, metastatic cancer, and infection.9,10 Unfortunately, these possibilities may
not be easily distinguished from tophaceous gout by advanced imaging such as nu-
clear or MR scanning.

TREATMENT OF GOUT

The treatment of gout depends on the stage of the disease as well as the health status
and comorbidities of the patient. Acute attacks need to be diagnosed appropriately
and ameliorated promptly to relieve the patient’s pain, hopefully without introducing
complications related to the therapy. Particularly in patients who have suffered previ-
ous attacks of gout, long-term treatment decisions become paramount in importance.
Options include (1) treatment with uric acid–lowering agents, which can both dissolve
the excess MSU deposits and prevent further gout attacks, (2) treatment with prophy-
lactic low dose antiinflammatory medication, such as daily colchicine to reduce the
number and severity of attacks, and (3) watchful waiting, with ad hoc treatment of
additional attacks when they occur with high-dose antiinflammatory medications.
Each approach has associated risks and benefits.

MANAGEMENT OF ACUTE GOUT ATTACKS

Acute gout attacks are functionally disabling and can lead to a substantial decrease in
quality of life. Treatment is aimed at quickly resolving pain and inflammation. In most
cases, the choice of the medication will be dictated by the patient’s comorbid condi-
tions. There are 4 main groups of medications to treat acute gout attacks: NSAIDs,
glucocorticoids (systemic or intraarticular, adrenocorticotrophic hormone), anti–inter-
leukin-1 (eg, anakinra, an interleukin-1 receptor antagonist), and colchicine. It must al-
ways be kept in mind that treatment of the acute attacks of gout does not address the
primary disease process, which is the abnormal deposition of MSU.
NSAIDs are effective and are the traditional “gold standard” therapy for the treat-
ment of acute gout attacks. All NSAIDs are typically effective when given at full anti-
inflammatory doses. This includes celecoxib, a cyclooxygenase-2 selective NSAID,
although much higher dosing than usual was used in the trial demonstrating its effi-
cacy (1200 mg load on day 1 followed by 400 mg bid as opposed to 200 mg bid).11
However, NSAID use is potentially associated with a number of adverse reactions,
including acute kidney injury, gastric and intestinal ulcers and bleeding, fluid retention,
platelet dysfunction, and, less commonly, headache and confusion (particularly with
indomethacin). Virtually all of these complications seem to occur more frequently in
the elderly. Additionally, several studies suggest a slight increased risk of myocardial
infarction or composite cardiovascular adverse outcomes in patients taking NSAIDs,
and perhaps cyclooxygenase-2 selective drugs in particular. For these reasons, there
has been a trend in many communities for physicians to use alternatives to NSAIDs to
treat acute gout attacks, especially in the elderly.
Corticosteroids have been used for years to treat attacks of gout, although there are
few clinical trials documenting efficacy. A recent “pragmatic” trial demonstrated equal
efficacy of 30 mg/d of prednisolone as for indomethacin in treating acute gout.6
Although prednisone and other antiinflammatory steroids have many well-
recognized severe metabolic and other side effects with chronic use, their short-
term use may be safer than that of high-dose NSAIDs in treating acute gout attacks.
 Update on Crystal-Induced Arthritides 5

Nevertheless, hyperglycemia, sodium/fluid retention, and various degrees of agitation

may occur, and patients and their caregivers should be warned regarding these
adverse effects. In a study of 13 patients, which included 6 patients (age range, 66–
85 years), gout attacks resolved completely within 7 to 10 days using glucocorticoids.
The steroid dose was started at 20 to 50 mg and tapered over a mean duration of
10 days.12 If possible, steroid therapy should be continued in full dose until the attack
resolves, and then tapered over several days to off (or back to the baseline dose if the
patient was taking a steroid chronically). “Medrol dose packs” (blister packs of a
defined dose of a tapering regimen of methylprednisolone pills) can be used to provide
simplified instructions. However, sometimes the duration of therapy with dose packs
is insufficient and the attack never fully resolves or even rebounds, requiring additional
therapy. Intraarticular steroid injections are quite effective and their use limits the po-
tential for systemic side effects. Infection should be excluded and close follow-up of
patients receiving intraarticular injection is necessary. Some anatomic locations are
difficult to inject, such as the small joints of the fingers and toes and midfoot joints.
Intramuscular adrenocorticotrophic hormone is effective, but it is expensive and it
has essentially the same metabolic side effects as prednisone. The benefits of steroids
in terms of avoiding renal and gastrointestinal complications may be outweighed in
some patients by the fluid retention, hyperglycemia, and cognitive effects.
Colchicine has efficacy in relieving the pain and inflammation of acute gout, and
low-dose treatment with 3 pills (1.8 mg total) over 24 hours will lessen the pain and
signs of inflammation.13 However, it may not resolve the attack completely, and other
analgesic and/or antiinflammatory medications are required frequently. Some patients
have learned that they can abort an impending gout attack if they initiate colchicine
therapy as soon as they feel a suspicious twinge. But for many, perhaps most, other
approaches to resolve the attack may be preferable. That being said, chronic low-
dose colchicine (0.6–1.2 mg/d) can be effective for prophylaxis against attacks and,
if the patient is taking prophylactic colchicine, the dosage should not be changed in
the setting of an acute gout attack.
The primary inflammatory mediator of the acute gout attack is likely interleukin-1;
thus, it is not surprising that specific interleukin-1 antagonists are strikingly successful
at treating and aborting acute attacks. Several studies now document the impressively
favorable and very prompt response of many (not all) patients with acute gout in
response to treatment with short courses of daily subcutaneous 100 mg doses of ana-
kinra.14,15 Anakinra is a short-acting, soluble, interleukin-1 receptor antagonist that
has been used successfully in several reports of hospitalized patients, often with
comorbidities limiting the therapeutic options or with prior resistance to corticosteroid
therapy. Notably, several patients with successful outcomes had serious infections
that were being treated concurrently and/or had recently undergone surgery. Anakinra
shares none of the short-term metabolic, renal, or cardiovascular complications of
NSAIDs or steroids. Unfortunately, this agent is relatively expensive and it does not
presently have a US Food and Drug Administration (FDA) indication for use in treating
gout. In the general rheumatology community, and for older inpatients with multiple
comorbidities, this approach to treating inpatients with gout has growing popularity.
Patients with high body mass index may benefit from 200 mg/d instead of 100 mg/
d (higher than suggested by the package insert).
Narcotics have variable efficacy in treating the pain of the acute attack and generally
should not be relied on as a sole therapy, because it does not address the underlying
inflammatory process. This is particularly true in the elderly in whom the risk of falling
may be significantly increased by the combination of pain from the gout and the
adverse central nervous system effects of the narcotics.
6 El-Zawawy & Mandell

PROPHYLACTIC ANTIINFLAMMATORY THERAPY FOR PATIENTS WITH GOUT

Between attacks, patients may be asymptomatic. Unless the serum urate is low-
ered, urate will continue to deposit in and around joint structures. Definitive curative
therapy consists of dissolution of all urate deposits. However, this may take years of
oral ULT. An alternative, quality of life–driven approach is to provide low-dose pro-
phylactic antiinflammatory therapy and only treat attacks as they occur. Low-dose
oral colchicine, with appropriate attention to dosing adjustments based on the esti-
mated glomerular filtration rate and potential drug interactions, is generally well-
tolerated and reasonably effective in many patients for the purposes of reducing
the expected frequency of gout flares. This approach may be limited by the fact
that some patients will experience gastrointestinal intolerance with nausea or diar-
rhea. More serious complications can arise with chronic ingestion, usually in the
setting of decreased renal function and/or with decreased colchicine metabolism
owing to effects of other drugs. A painful axonal neuropathy and vacuolar myopathy
has been well-described,16 as has multiorgan failure and death. A number of studies
have demonstrated pharmacokinetic interactions with colchicine and other drugs,
with clarithromycin arguably being the most clinically significant such interaction
based on case reports (Table 2).17 Close attention and monitoring of the creatinine
kinase and blood counts is warranted if the patient is also taking a statin, ketocona-
zole, or other drugs that affect the multidrug transporter or the cytochrome P450
system.18
In elderly patients with recurrent or tophaceous gout and who are otherwise
healthy, ULT should be considered. As ULT is introduced, a seeming paradoxic in-
crease in gout attacks (mobilization attacks) may occur. For this reason, antiinflam-
matory prophylaxis is generally used for approximately 6 months after initiation of
the ULT, and even longer if tophi are detected on physical examination. Colchicine
is used most commonly. Drug levels are not routinely available so empiric dosing is
usually 0.6 mg 1 to 2 times per day, with attendant dose adjustments in the setting
of renal disease. In colchicine-intolerant patients but without relevant comorbid-
ities, low-dose NSAID therapy (ie, naproxen 250 mg bid) may be used to prevent
mobilization attacks, generally being coprescribed with gastric protection. Clinical
experience with transplant patients suggests that low-dose prednisone may not be
as effective as these other prophylactic agents, but sometimes it is the best
option.19

Table 2
Important drug interactions with Colchicine and allopurinol

Drugs That May Interact Adverse Effects

Colchicine CYP3A4 inhibitors At higher risk of myotoxicity and
Strong (clarithromycin, neurotoxicity, especially with the
ketoconazole, itraconazole) strong inhibitors (particularly
Moderate (diltiazem, verapamil, clarithromycin)
erythromycin)
P-glycoprotein ABCB1
Cyclosporine, ranozaline and
verapamil
Allopurinol AZA Myelosuppression owing to increased
AZA metabolites (mercaptopurine)
Warfarin May increase anticoagulant effects

Abbreviation: AZA, azathioprine.

 Update on Crystal-Induced Arthritides 7

URATE-LOWERING THERAPY

Lowering purine intake, following a heart healthy diet, and avoidance of beer or
excessive mineral spirit alcohol ingestion is generally recommended for all patients
with gout. A recent cross-sectional analysis of nutrition and serum uric acid in 2
Caucasian cohorts of 9734 and 3031 subjects,20 and an earlier study of 47,150
men, examined the relationship between diet and gout with the SUA.21 These
studies confirmed some long-standing beliefs, namely that consuming meat, sea-
food, beer, and liquor increases gout risk. Other risk factors identified were con-
sumption of soft drinks sweetened with sugar or fructose, adiposity, hypertension,
and diuretic use. In contrast, diets rich in protein, wine, and purine-rich vegetables
were not associated with gout flares. Low-fat dairy products may have a protective
effect. Weight loss was also found to be protective. Unfortunately, low purine diets
are not very palatable, difficult to adhere to, and are minimally effective at best,
lowering serum urate by only 1 to 2 mg/dL. Thus, medications are generally required
to treat hyperuricemia and reduce the SUA to a target level of less than 6 mg/dL; a
target that is, significantly below the estimated urate saturation point in biological
fluids of 6.8 mg/dL.
Preventing recurrent gout attacks and tophi formation requires the long-term reduc-
tion in the SUA and then maintaining it at below the saturation point. This can be
achieved by enhancing renal excretion of uric acid (probenecid, lesinurad, losartan),
decreasing urate synthesis (allopurinol and febuxostat), or by converting urate to
the more soluble metabolite allantoin through use of uricase. Infused uricase (pegloti-
case) essentially supplements with an enzyme that is, absent in humans.
The lower the SUA, the more rapidly tophi are resolved and the sooner that gout at-
tacks stop. However, some epidemiologic studies now suggest that patients with sus-
tained low serum urate levels may be at increased risk for (and progress more rapidly
with) Parkinson’s disease or vascular or nonvascular dementia.22 The practical impli-
cations of these observations are not yet clear, but it may be prudent in those with fea-
tures of Parkinson’s disease or mild cognitive impairment to avoid prolonged
hypouricemia. In such patients, low SUA can be attained at the outset of treatment
to dramatically decrease the urate burden and stop attacks from happening, but
then the SUA can be allowed to drift up closer to the actual saturation point of
6.8 mg/dL.23 This concern regarding prolonged hypouricemia must be contrasted
with a growing body of data indicating that higher SUA levels contribute to the pro-
gression of chronic kidney disease,24 heart failure, and all-cause mortality.
Currently, the use of uricosuric therapy is limited in the United States. Probenecid
has been the major medication for this purpose (losartan and fenofibrate have some
uricosuric activity). Probenecid has limited popularity owing to a belief that it has rela-
tive limited efficacy and to the fact that it may increase the risk for renal stones. In pa-
tients with close to normal renal function, who do not excrete significant (more than
approximately 800 mg) uric acid daily, who can drink plenty of fluids and can alkalinize
their urine, it may be quite efficacious. It can also be used concurrently with a xanthine
oxidase inhibitor (eg, allopurinol).
Lesinurad has just been approved by the FDA. It is a potent and fairly specific antag-
onist of the urate reabsorbing transporter URAT1, and when used as mandated by the
FDA label along with a xanthine oxidase inhibitor, it is strikingly effective at reducing
the SUA.25 Nephrolithiasis has not been a problem, but the occurrence of acute kidney
injury was noted in clinical trials, especially when allopurinol (or febuxostat) was not
used concurrently. These reversible episodes of AKI might be owing to acute urate
tubular nephropathy.
8 El-Zawawy & Mandell

Allopurinol (100- and 300-mg tablets) is the most widely used xanthine oxidase in-
hibitor. Most physicians prescribe no greater than 300 mg/d. However, this dosage
has been demonstrated to reduce the serum urate to less than 6 mg/dL in fewer
than 30% of patients.26 Allopurinol has been approved by the FDA for doses up to
800 mg/d. Guidelines from the British Society of Rheumatology advocate a maximum
dose of 900 mg/d. It should be noted that these maximum doses are based on limited
data, and not on documented toxicity. Slow upward titration, starting with 50 to
100 mg/d at the initiation of therapy, is the commonly recommended regimen.
Although gastrointestinal intolerance is a common problem, it is more likely that
concern over the rare, but extremely severe, hypersensitivity reaction (approximately
25% mortality), has contributed to its underuse and underdosing, particularly in the
setting of chronic kidney disease. This rare complication happens approximately 3
to 9 times in 1000 patients (the higher estimate likely occurring in patients with chronic
kidney disease). It has not been demonstrated that reduction of the target dose will
decrease the frequency of hypersensitivity, but the initiation at a low dose, with a
very slow dose escalation, may reduce the hypersensitivity reaction risk.5
Febuxostat (40- and 80-mg tablets) is a newer oral nonpurine selective inhibitor of
xanthine oxidase. In the FACT trial (Febuxostat versus Allopurinol Controlled Trial), a
52-week randomized, double-blind study in hyperuricemic patients with gout, serum
urate levels were reduced to less than 6.0 mg/dL in more than 50% of patients
receiving febuxostat 80 mg or 120 mg once daily, as compared with only 21% of pa-
tients receiving a 300-mg fixed dose of allopurinol who were observed to achieve this
goal.27 This does not imply that allopurinol at higher doses would not be equally effec-
tive (no allopurinol dose escalation was done in the trial). Indeed, dose escalation of
allopurinol is successful in lowering the SUA to a target of less than 6 mg/dL in almost
all patients.28
Because allopurinol and febuxostat are not similar in chemical structure, febuxostat
is an attractive alternative in patients allergic to allopurinol. This has been studied in a
limited number of patients. In 12 of 13 patients with gout (92%) with previously docu-
mented severe allopurinol adverse effect, the use of febuxostat was safe.29 Febuxo-
stat remains far more expensive in the United States than allopurinol. Lesinurad (or
probenecid) can be added to either of these medications to significantly improve their
efficacy. But even with the combination of a uricosuric and a xanthine oxidase inhibitor
it may be difficult to profoundly lower the SUA in select individuals.
Uricase metabolizes urate to the more soluble molecule allantoin, which is excreted
readily in the urine. Humans (and great apes) evolutionarily deactivated uricase cen-
turies ago, and thus have higher SUA than most other species. Pegloticase is a recom-
binant polyethylene glycol conjugated uricase that is FDA approved for intravenous
therapy for gout in patients who have failed other ULT. It rapidly and profoundly re-
duces serum urate to less than 0.5 mg/dL in the majority of patients and can lead to
resolution of tophi over months.30 A predictable side effect of rapidly and dramatically
reducing SUA is the occurrence of severe gout flares, despite using prophylactic ther-
apy. Pegloticase is administered by intravenous infusion every 2 weeks; this can be
decreased to every 3 weeks in many responder patients. However, most patients
develop some antimedication antibodies, most to the polyethylene glycol “coating.”
Those patients with high titer antibody levels rapidly become drug resistant and expe-
rience the overwhelming majority of the infusion reactions, which are usually mild.31 By
checking the SUA before each infusion, most infusion reactions can be predicted and
prevented. In essence, discontinuing therapy when a diminished hypouricemic
response to the drug is noted is the recommended strategy. Patients who develop
high titer drug antibodies and clear the drug from the circulation rapidly are also the
 Update on Crystal-Induced Arthritides 9

patients who experience allergic reactions, despite receiving steroid and antihistamine
pretreatment. In the remaining patients who experience an ongoing dramatic lowering
of SUA, therapy can be continued until visible tophi are resolved and attacks cease. At
that point (or even before) the pegloticase can be stopped and the patient switched
back to an oral agent targeting the SUA to a level approximately 6 mg/dL.

SUMMARY

Gout is a chronic disease of deposition of MSU in multiple anatomic locations.

Although the major attributed manifestation is the acute gout flare, which must be
treated promptly, ideal long-term management requires dissolution of the urate depo-
sition by lowering the serum urate to less than 6.0 mg/dL to ultimately stop flares and
prevent the development of a chronic arthropathy and likely worsening/progression of
other urate associated metabolic conditions including chronic kidney disease. The de-
cisions surrounding the initiation or intensification of ULT must be individualized, espe-
cially in elderly patients. The decision process must include evaluation of the patient’s
life expectancy, frequency and impact of gout flares, daily function, comorbidities,
baseline medications, and the ability to tolerate ULT, gout flare prophylaxis, and the
treatment of the acute flares.

REFERENCES

1. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US gen-
eral population: the National Health and Nutrition Examination Survey 2007-2008.
Arthritis Rheum 2011;63:3136–41.
2. Mikuls TR, Farrar JT, Bilker WB, et al. Suboptimal physician adherence to quality
indicators for the management of gout and Rheumatology asymptomatic hyper-
uricemia: results from the UK General Practice Research Database (GPRD).
Rheumatology (Oxford) 2005;44(8):1038–42.
3. Nicholls A, Snaith ML, Scott JT. Effect of oestrogen therapy on plasma and urinary
levels of uric acid. Br Med J 1973;1:449–51.
4. Duskin-Bitan H, Cohen E, Goldberg E, et al. The degree of asymptomatic hyper-
uricemia and the risk of gout. A retrospective analysis of a large cohort. Clin
Rheumatol 2014;33:549–53.
5. Stamp LK, O’Donnell JL, Zhang M, et al. Using allopurinol above the dose based
on creatinine clearance is effective and safe in patients with chronic gout,
including those with renal impairment. Arthritis Rheum 2011;63(2):412–21.
6. Rainer TH, Cheng CH, Janssens HJEM, et al. Oral prednisolone in the treatment
of acute gout. Ann Intern Med 2016;164:464–71.
7. Fam AG. Gout in the elderly. Clinical presentation and treatment. Drugs Aging
1998;13:229–43.
8. Meyers OL, Monteagudo FSE. A comparison of gout in men and women: a 10-
year experience. S Afr Med J 1986;70:721–3.
9. Saketkoo LA, Robertson HJ, Dyer HR, et al. Axial gouty arthropathy. Am J Med
Sci 2009;338:140–6.
10. Konatalapalli RM, Lumezanu E, Jelinek JS, et al. Correlates of axial gout: a cross-
sectional study. J Rheumatol 2012;39:1445–9.
11. Schumacher HR, Berger MF, Li-Yu J, et al. Efficacy and tolerability of celecoxib in
the treatment of acute gouty arthritis: a randomized controlled trial. J Rheumatol
2012;39:1859–66.
12. Groff GD, Franck WA, Raddatz DA. Systemic steroid therapy for acute gout: a
clinical trial and review of the literature. Semin Arthritis Rheum 1990;19:329–36.
10 El-Zawawy & Mandell

13. Terkeltaub RA, Furst DE, Bennett K, et al. High versus low dosing of oral colchi-
cine for early acute gout flare: twenty-four-hour outcome of the first multicenter,
randomized, double-blind, placebo controlled, parallel-group, dose-comparison
colchicine study. Arthritis Rheum 2010;62:1060–8.
14. Ghosh P, Cho M, Rawat G, et al. Treatment of acute gouty arthritis in complex hos-
pitalized patients with anakinra. Arthritis Care Res 2013;65(8):1381–4.
15. Thueringer JT, Doll NK, Gertner E. Anakinra for the treatment of acute severe gout
in critically ill patients. Semin Arthritis Rheum 2015;45(1):81–5.
16. Kuncl RW, Duncan G, Watson D, et al. Colchicine myopathy and neuropathy.
N Engl J Med 1987;316:1562–8.
17. Hung IF, Wu AK, Cheng VC, et al. Fatal interaction between clarithromycin and
colchicine in patients with renal insufficiency: a retrospective study. Clin Infect
Dis 2005;41:291–300.
18. Terkeltaub RA, Furst DE, DiGiacinto JL, et al. Novel evidence based colchicine
dose reduction algorithm to predict and prevent colchicine toxicity in the pres-
ence of cytochrome P450 3A4/P glycoprotein inhibitors. Arthritis Rheum 2011;
63:2226–37.
19. Clive DM. Renal transplant-associated hyperuricemia and gout. J Am Soc Neph-
rol 2000;11:974–9.
20. Zykova SN, Storhaug HM, Toft I. Cross-sectional analysis of nutrition and serum
uric acid in two Caucasian cohorts: The AusDiab Study and the Tromsø study.
Nutr J 2015;14:49.
21. Choi HK, Atkinson K, Karlson EW, et al. Purine-rich foods, dairy and protein
intake, and the risk of gout in men. N Engl J Med 2004;350:1093–103.
22. Hong JY, Lan TY, Tang GJ, et al. Gout and the risk of dementia: a nationwide
population-based cohort study. Arthritis Res Ther 2015;17:139–46.
23. Perez-Ruiz F, Herrero-Beites AM, Carmona L. A two staged approach to the treat-
ment of hyperuricemia in gout: the “dirty dish” hypothesis. Arthritis Rheum 2011;
63:4002–6.
24. Levy G, Cheetham TC. Is it time to start treating asymptomatic hyperuricemia?
Am J Kidney Dis 2015;66:933–5.
25. Hoy S. Lesinurad: first global approval. Drugs 2016;76:509–16.
26. Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, et al. Efficacy of allopurinol and benz-
bromarone for the control of hyperuricaemia. A pathogenic approach to the treat-
ment of primary chronic gout. Ann Rheum Dis 1998;57:545–9.
27. Becker MA, Schumacher HR Jr, Wortmann RL, et al. Febuxostat compared with
allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005;353:
2450–61.
28. Reinders MK, Haagsma C, Jansen TL, et al. A randomised controlled trial on the
efficacy and tolerability with dose escalation of allopurinol 300–600 mg/day
versus benzbromarone 100–200 mg/day in patients with gout. Ann Rheum Dis
2009;68:892–7.
29. Chohan S. Safety and efficacy of febuxostat treatment in subjects with gout and
severe allopurinol adverse reactions. J Rheumatol 2011;38(9):1957–9.
30. Baraf H, Becker M, Gutierrez-Urena S, et al. Tophus burden reduction with peglo-
ticase: results from phase 3 randomized trials and open-label extension in pa-
tients with chronic gout refractory to conventional therapy. Arthritis Res Ther
2013;15:R137.
31. Lipsky P, Calabrese L, Kavanaugh A, et al. Pegloticase immunogenicity: the rela-
tionship between efficacy and antibody development in patients treated for re-
fractory chronic gout. Arthritis Res Ther 2014;16:R60.