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Gout is a joint disease caused by monosodium urate deposition, directly related to hyperuricemia caused by disturbance of purine metabolism or decreased uric acid excretion, and other risk factors include genetic factors, male sex, older adults, diet and lifestyle, obesity, etc
.
Patients with gout attacks present with red, swollen, severe pain, and limited
mobility.
Treatment options mainly include relieving and preventing gout attacks, lowering uric acid, and adjusting diet and lifestyle
.
On November 17, 2022, the New England Journal of Medicine (NEJM) published "Gout" in the "Clinical Practice" column, which described the pathogenesis, risk factors, symptoms, examination, diagnosis, and treatment
of gout.
The article emphasizes that treatment of gout should be individualized, and although cheap and effective treatments for gout exist, patients are often undertreated
.
The authors also note that there are few studies on the effects of diet and lifestyle interventions in gout management, and that the available data suggest little benefit
.
We introduce its main contents
here.
To read the full translation, please visit the NEJM Medical Frontiers official website, APP or click on the WeChat mini program image
.
Clinical PointsClinical
Questions
Gout is a chronic disease caused by monosodium urate deposition and is characterized by the onset and disabling
of arthritis.
If left untreated, gout attacks that are inflammatory can last for days to weeks, often causing severe pain and debilitating
.
Intermittent asymptomatic gout attacks can become more frequent and symptoms worse
over time.
Approximately 15% of patients develop advanced gout, which is characterized by subcutaneous nodules forming monosodium urate (tophi), persistent joint inflammation, and potential joint erosion and deformation
.
Hyperuricemia is a necessary but not sufficient risk factor
.
The prevalence of this disease (defined as uric acid levels in the circulatory system exceeding the threshold for the solubility of monosodium urate [>6.
8 mg/dL]) is 3~5 times
that of gout.
Serum urate concentration heritability can be as high as 60%; Other risk factors for hyperuricemia and gout include male sex, older adults, dietary and lifestyle factors, obesity, renal impairment, and use of drugs that increase urate concentrations (e.
g.
, diuretics).
Strategy and evidence
assessment Patients usually present with an acute attack of gout
.
Typical features of a gout attack include monoarticular involvement of the foot, particularly the first metatarsophalangeal joint (Figure 1A) or ankle, and a history of similar attacks, rapid onset or worsening of pain or swelling (or both), redness, associated comorbidities, and hyperuricemia (Table 1).
Patients with long-standing, undiagnosed and untreated gout may have tophi, most commonly on the extensor surface of the elbow or other
joints.
Figure 2 The clinical manifestations of gout are shown in the picture of gout, including pictures of gouty arthritis in the first metatarsophalangeal joint (foot gout) and interphalangeal joints (figure A); Monosodium urate crystals observed under a high-power polarized light microscope (Figure B); Ultrasound image of the first metatarsophalangeal joint musculoskeletal (figure C) shows the typical double-track sign (arrow-shaped) due to monosodium urate deposition on hyaline cartilage; Dual-energy computed tomography of the elbow joint (panel D) shows monosodium urate deposition (tophi).
Table 1 Typical clinical presentation suggestive of a gout attack
The patient evaluation framework developed by the European League against Rheumatism (EULAR) calls for evaluation methods to focus on the detection of monosodium urate crystals from synovial fluid or tophi aspirates (Figure 1B).
A positive polarizing microscope result is 100% specific and diagnostic in patients with suggestive symptoms and signs
.
Joint aspiration and other targeted tests are essential to rule out other disorders that present like this, either alone or in combination with gout, such as septic arthritis or pseudogout (Table 2).
Table 2 Unique clinical manifestations of common diseases similar to gout*
* CCP stands for cyclic citrullinated peptide, CPPD for calcium pyrophosphate deposition, CRP for C-reactive protein, and ESR for erythrocyte sedimentation rate.
† These disorders may coexist
with hyperuricemia and gout.
In cases where the necessary equipment or skills are lacking, the diagnosis
can be made based on the suggestive clinical presentation (Table 1) and diagnostic process.
If uncertainty persists in the diagnosis, imaging may be helpful
.
Routine x-rays (most commonly on symptomatic joints of the foot or hand) may show advanced gout bone erosion, characterized by overhanging edges and sclerotic
margins.
Advanced imaging with musculoskeletal ultrasonography and dual-energy computed tomography can be used as a noninvasive technique to detect monosodium urate deposition, but both methods require specialized skills and lack sensitivity
in patients with early-stage gout.
Although hyperuricemia is a risk factor for gout, serum urate measurement has a limited
role in the diagnosis of gout due to its low specificity.
Similarly, normal serum urate concentrations have a limited negative predictive value during gout attacks, possibly due to the urate-lowering effect
of inflammation.
Although a single measurement is of limited significance, serial measurement of consistently normal serum urate concentrations in the absence of urate-lowering therapy strongly suggests a diagnosis
other than gout.
Other evaluation principles include systematic assessment
of comorbidities and modifiable risk factors for hyperuricemia.
High blood pressure, obesity, cardiovascular disease, diabetes, and CKD are all more common in people with gout, and they help explain the increased
mortality in people with gout.
Treatment of gout attacks: The goal of gout
attack treatment is to quickly relieve pain and restore function
.
Currently recommended first-line therapy should be individualized according to comorbidities, including colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), and glucocorticoids, which can be given orally, non-gastrointestinally, or intra-articularly (Table 3).
For prompt treatment, subspecialty guidelines recommend that patients carry medication with them (the "pocket-in-pocket" approach) and take it as
soon as initial symptoms appear.
Table 3 also lists the drugs
that are less commonly used in the treatment of gout attacks.
Table 3 Gout treatment methods ** eGFR means estimated glomerular filtration rate, NSAID means NSAID.
† For severe attacks of gout, colchicine may be combined with NSAIDs or corticosteroids; Corticosteroids can also be given by intra-articular injection; The appropriate prophylactic dose of interleukin-1 inhibitors or adrenocorticotropic hormone is unclear; One network meta-analysis suggests that acetic acid derivatives NSAIDs (such as indomethacin or diclofenac) may be more effective than propionic acid derivatives (such as ibuprofen or naproxen)
for gout attacks.
‡ The Food and Drug Administration has not approved the use of the interleukin-1 inhibitors anakinra and canakimab for gout, but the European Medicines Agency has approved it
.
§ Allopurinol and febuxostat inhibit xanthine oxidase; Pegloticase is a recombinant uricase that metabolizes uric acid to allantoin (approved for the treatment of refractory gout).
Urate-expelling agents may not be effective
in patients with advanced renal impairment.
The American College of Rheumatology conditionally recommends that patients of Southeast Asian descent and black African descent undergo HLA:5801 testing before initiating allopurinol therapy, regardless of
renal function.
Based on the key role of NLRP3 in gout-related inflammation, including the activation and release of interleukin-1, colchicine has been used to block NLRP3 oligomerization
.
Of the currently recommended first-line regimens, non-gastrointestinal corticosteroids provide the most rapid pain
relief.
Although adrenocorticotropic hormone and interleukin-1 inhibitors are potentially effective regimens, cost and accessibility limit their use
.
Urate-lowering therapy
Allopurinol is a xanthine oxidase inhibitor marketed in the 60s of the 20th century and is still the first-line urate-lowering therapy (Table 3).
Other treatments include febuxostat (a xanthine oxidase inhibitor), probenecid (a urate-reducer), benzbromarone (a urate-removing drug not yet available in the United States), and, less commonly, pegloticase
.
If treatment fails with allopurinol and febuxostat at recommended doses, other treatment options include uricotics alone or with xanthine oxidase inhibitors
.
Subspecialty Society guidelines recommend a standard approach characterized by initial low-dose urate-lowering therapy followed by a gradual dose titration to achieve and maintain serum urate concentrations of <6.
0 mg/dL<b10>.
The American College of Physicians advocates a treat-to-avoid-symptoms strategy
, citing a lack of robust evidence to support the approach.
However, there is a lack of guidelines on how best to avoid symptoms, so the above advice is difficult
to apply.
Treatment to avoid symptoms may include treatment strategies that do not target the major problem of monosodium urate deposition, such as long-term use of colchicine, NSAIDs, or glucocorticoids
without urate-lowering therapy.
Since the American College of Physicians issued guidelines for symptom avoidance through treatment, there has also been more evidence in favor of standard treatments, including the results of a trial evaluating nurse-led interventions that showed that standard urate-lowering therapy reduced gout attack frequency and tophi (Table S2).
At 2 years, only 8% of patients receiving eligible urate-lowering therapy had more than 2 gout attacks per year, compared with 24%
of patients receiving usual care.
Indications for urate-lowering therapy in patients with gout include recurrent episodes of gout (eg, ≥ twice a year), tophi, and evidence of gout-related joint injury and erosive changes
on x-rays.
Although these indications are common in patients with established gout, several studies and resulting guidelines suggest that there is potential for earlier intervention, particularly in patients
with significant hyperuricemia, nephrolithiasis, or CKD.
Therefore, European guidelines recommend that all patients with gout should be considered and discussed with urate-lowering therapy
at the patient's first presentation with gout.
Because rapidly decreasing urate levels can lead to the physiological consequence of gout attacks, best practices include prophylactic anti-inflammatory therapy during initiation and adjustment of urate-lowering therapy
.
Another approach is to initiate urate-lowering therapy
in a stepwise fashion.
Gout therapy and comorbidities
Comorbidities complicate
gout treatment.
Gout therapy can affect comorbidities or may interact with
comorbidity medications.
For example, studies have observed that about 75% of gout patients have high blood pressure, and NSAIDs or glucocorticoids can worsen high blood pressure (Figure 2).
In contrast, long-term use of colchicine and kanakimab (interleukin-1β inhibitors) may have cardioprotective effects
in gout-free patients.
It is unclear
whether recurrent, limited, or long-term medication in the treatment of gout attacks confers similar protective effects with prophylactic medication in people with gout.
Urate-expelling agents may not be effective
in patients with advanced renal impairment.
The American College of Rheumatology conditionally recommends that patients of Southeast Asian descent and black African descent undergo HLA:5801 testing before initiating allopurinol therapy, regardless of
renal function.
Previous guidelines recommended fixed low-dose allopurinol for patients with CKD, while recent reports support the use of allopurinol compliant therapy for this population
.
Allopurinol and febuxostat were similar in the efficacy and safety profile of patients with CKD included in the STOP Gout trial
.
In patients with gout and moderate to severe CKD, initiation and escalation of allopurinol and the resulting goal of serum urate are not
associated with worsening renal function or shortened survival.
Allopurinol hypersensitivity syndrome is a rare but potentially life-threatening complication characterized by severe rash, eosinophilia, and acute liver and kidney injury
.
Patients with CKD are at increased risk of allopurinol hypersensitivity syndrome
.
Detection of the HLA-B*5801 risk allele stratifies risk and appears to be cost-effective
in Asian and African-American black patients (regardless of CKD status) who inherit the gene more commonly.
Effects of comorbid therapy on gout
Just as gout therapy can affect comorbidities in patients, comorbid therapies can affect gout (Figure 2).
A well-known example is that diuretics increase serum urate concentrations
.
Patients receiving β receptor blockers, ACE inhibitors, or angiotensin receptor blockers (other than losartan) are at
increased risk of gout.
In contrast, losartan, calcium channel blockers, fenofibrate, and sodium-SGLT2 inhibitors promote uriuria and reduce serum urate concentrations
.
Metformin, commonly used to treat type 2 diabetes, reduces cellular inflammation caused by monosodium urate crystals and may reduce the burden
of gout attacks.
Overall, data suggest that some therapies for comorbidities have a pleiotropic effect and may improve outcomes
in patients with gout.
Adjust diet and lifestyle
Changeable lifestyle or dietary factors that negatively affect serum urate levels and the risk of gout attacks include alcohol consumption (especially beer), dehydration, obesity, consumption of high-fructose sweeteners (such as sugary carbonated beverages) and high-purine foods (such as meat and shellfish).
Although epidemiological studies have established an association between dietary factors and obesity and gout risk, the effects of dietary and lifestyle interventions in gout management have only been evaluated in a few studies, and the available data suggest little benefit
.
A 2019 review of 18 clinical trials of dietary interventions (e.
g.
low-calorie, low-purine diet) showed that urate-lowering effects were generally small (<1 mg/dL).
<b10> Pooled studies were generally at moderate or high
risk of bias.
Study heterogeneity precludes formal meta-analyses
.
Patient education and motivation
The common misconception that gout is self-inflicted and not seriously ill has become obstacles
for both doctors and patients in the treatment process.
Although there are already inexpensive and effective treatments, medical gaps remain.
Gout is a lifelong disease, but more than half of patients discontinue the drug
within 1 year of initiating urate-lowering therapy.
However, low adherence to treatment can be addressed
with patient education and close follow-up.
The updated guidelines contain conditional recommendations that patients should be treated with urate lowering by medical personnel other than physicians as part of a healthcare model that includes patient education and shared
decision-making.
Areas of uncertainty
There is still uncertainty
about the treatment of gout.
These uncertainties include appropriate serum urate thresholds in patients with advanced gout; Potential adverse effects of long-term, potent urate-lowering therapy (e.
g.
, serum urate, <3 mg/dL), as epidemiological studies have found an inverse association between serum urate concentration and risk of neurodegenerative disease; After initiation of urate-lowering therapy, prophylactic anti-inflammatory therapy is of appropriate duration; and appropriate measures<b11> to increase acceptance and adherence to urate-lowering therapy.
There is no conclusive evidence to support the pathogenic role
of serum urate in conditions other than gout and kidney stones.
Results from one randomized controlled trial suggest that allopurinol improves endothelial function, so urate-lowering therapy may protect against cardiovascular disease through a mechanism that is not currently well defined and independent of urate-lowering properties
.
On the other hand, the CARES trial, conducted after the FDA required evaluation of febuxostat in patients with gout and cardiovascular disease, raised concerns about
the safety of urate-lowering therapy.
The 2018 trial showed that patients randomized to febuxostat had higher cardiovascular-related mortality and all-cause mortality than patients assigned to allopurinol, prompting the FDA to add boxed warnings to febuxostat; However, subsequent FAST trials showed no difference
in the incidence of cardiovascular events, including death from cardiovascular causes or death from all causes, between the two therapies.
The two studies differed in methods in the following areas: blinding of use, proportion of participants with cardiovascular disease, composite outcomes assessed, follow-up strategies, etc
.
Problems with the CARES trial, including a nearly 50 percent loss to follow-up rate, and the reassuring results of FAST (a 5.
8 percent loss to follow-up rate) prompted experts to call on the FDA to reconsider its warning
about febuxostat.
Cases and recommendations
A 64-year-old man presents with pain in his left foot
.
The patient's left foot is red and swollen and unable to bear weight
.
He had similar attacks on the right toe and right elbow, which were relieved
by naproxen.
The patient has high blood pressure, type 2 diabetes, and moderate chronic kidney disease (CKD).
Physical examination reveals warmth, redness, and tenderness in the first metatarsophalangeal joint of the left foot
.
There are tubercles
in both elbows.
Patients in the case summary have typical manifestations
of gout.
If feasible, especially if it has not been done before, the diagnosis of gout should be made
.
In this case, the diagnosis can be confirmed by the first metatarsophalangeal joint or suspected tophi aspiration (monosodium urate crystals observed under polarized microscopy).
A detailed history is essential
to identify other conditions and medications that may affect treatment.
Options that can reduce symptoms of gout attacks include low-dose colchicine (≤ 1.
8 mg/day for 7~10 days) or intra-articular glucocorticoids; NSAIDs and systemic corticosteroids
should be avoided due to comorbidities.
Depending on recurrent episodes of gout and indications for tophi, low-dose allopurinol should be used, which can be initiated simultaneously during treatment of gout attacks with anti-inflammatory drugs or after symptoms have resolved
.
During the initiation and dose adjustment of urate-lowering therapy, prophylactic anti-inflammatory therapy (colchicine of 0.
5~0.
6 mg/d)
should be used.
The dose level of allopurinol should be gradually increased according to the serum urate concentration measured regularly (such as increasing every 3~6 weeks) to avoid treatment inertia, and to make the serum urate concentration reach and maintain < 6.
0 mg/dL<b13>.
Prophylactic anti-inflammatory therapy should be discontinued
after serum urate targets have been achieved and the patient has been gout-free for at least 1 month.
Patient education and motivation (which can be performed by medical personnel other than physicians) should be performed during clinical care, focusing on gout attack triggers and the role of urate-lowering therapy in reducing the risk of
gout attacks.
Patients should also be educated about lifestyle and dietary interventions, although these are generally ineffective
.
Mikuls TR.
Gout.
N Engl J Med 2022; 387:1877-1887.
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.
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.
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