TRIPASS XR تري باس

 

CORONARY HEART DISEASE

Hyperuricemia is noted to be an independent risk factor for CHD, although it is

unlikely to be a primary cause of disease. Several observational studies have shown

a link between hyperuricemia and an increase in CHD (e.g., HTN, stroke, heart

failure, and ischemic heart disease).

18-21 Researchers continue to study the causality

and note that despite the apparent strong relationship, the subject remains

controversial. Impaired glucose utilization also has a relationship with

hyperuricemia. Because of these close linkages, patients who present with gout

and/or hyperuricemia should be monitored closely for the development of CHD and

diabetes.

RENAL DYSFUNCTION

Uric acid excretion is decreased in patients with renal dysfunction owing to

decreased glomerular filtration, and as a consequence, hyperuricemia is a common

finding. The use of xanthine oxidase (XO) in patients with hyperuricemia and chronic

kidney disease has been examined in low-quality studies with mixed results.

Currently, treating hyperuricemia in patients with renal dysfunction is not

recommended unless patients manifest gouty arthritis.

19,22 Appropriate monitoring of

renal function in M.D. by obtaining blood urea nitrogen (BUN), serum creatinine

(SCr), and electrolytes is important for evaluating her risk factors as well as

determining drug doses for treating gout.

CASE 45-1, QUESTION 3: During the medication management clinic visit, M.D. mentions that her doctor

said her gout attack could have been caused by drinking too much beer, and she asks you whether this is really

true.

ETHANOL CONSUMPTION

Overindulgence of alcohol has been linked to acute gout attacks. Alcohol intake was

examined in a prospective cohort of men with new diagnoses of gout from the Health

Professionals Follow-Up Study and found that the risk of gout is 2.5-fold in patients

who drink two or more beers/day.

23 Ethanol-induced gout or hyperuricemia has been

attributed to several mechanisms. M.D.’s episode of overindulgence of beer,

possible dehydration from vigorous exercise, and lactic acidemia from muscle

energy expenditure made the diagnosis of an acute gout attack the most likely cause of

her toe pain and inflammation.

Diagnosis

CASE 45-2

QUESTION 1: E.J., a 52-year-old male school bus driver, reports to the emergency department with the

primary complaint of extreme pain in his right elbow. He admits to playing several games of basketball

yesterday followed by a few beers with friends. He awoke in the early hours of the morning with a sore and

stiff elbow, which he self-medicated with acetaminophen before trying to get back to sleep. He sought medical

attention when his pain escalated to the point where he was unable to apply pressure to the area and struggled

to move his arm. Pertinent medical history includes the recent diagnosis of HTN and obesity. At visit with his

primary-care physician 1 month ago, E.J. was prescribed hydrochlorothiazide 12.5 mg once daily, which is his

only medication. He was also encouraged to go on a diet and to increase his exercise. He states that he has no

drug or food allergies and is tolerating the antihypertensive well. On physical examination, the right elbow is

exquisitely tender and erythematous, and his vital signs are all within normal limits. The elbow is warm to the

touch and has moderate swelling. What objective data would be of value in assisting in the diagnosis of E.J.’s

elbow pain and inflammation?

JOINT FLUID ASPIRATION

A definitive diagnosis of gout can be established by finding MSU crystals in the

aspirated synovial fluid of the affected joint. The absence of MSU crystals in the

synovial fluid, however, does not rule out the diagnosis of gout. Although joint fluid

aspiration is considered the gold standard for diagnosis of acute gout, it is rarely

done in clinical practice. If synovial fluid is aspirated from an inflamed joint, it

should also be analyzed for bacteria and a WBC count should be obtained. In gouty

arthritis, the WBC count is likely to range from 5,000 to 50,000/L.

3

In septic arthritis,

the WBC count of the synovial fluid is usually greater than 50,000/L. E.J.’s physician

may consider fluid joint aspiration as a diagnostic measure if E.J. is agreeable and

the physician is equipped to conduct the procedure.

LABORATORY TESTS

Because uric acid primarily is excreted renally and renal impairment is a risk factor

for gout, the serum concentrations of E.J.’s BUN and SCr should be measured along

with an SUA concentration, especially in light of his history of HTN and

hydrochlorothiazide therapy. Although infection, in particular septic arthritis, could

also present as sudden onset of joint pain and inflammation, it is not likely in this

case. An elevated systemic white blood cell (WBC) count may be consistent with

infection or gout. If joint infection is of genuine concern, synovial fluid aspiration

could differentiate between infection and gout.

RADIOGRAPHY

Radiographic findings of the affected joint are nonspecific and generally

characterized by asymmetric soft tissue swelling overlying the involved joint. When

gout has been long-standing, bony changes can be noticed on a radiograph, along with

calcium deposition and increased density in the areas of soft tissue swelling.

24

Ultrasound and computed tomography are also used for diagnosis with the latter

showing early changes compared to a traditional radiography. (See

http://www.healthinplainenglish.com/health/musculoskeletal/gout/forexamples.)

A radiograph of E.J.’s elbow should be obtained if other musculoskeletal disorders

(e.g., bone fracture) are being considered.

PSEUDOGOUT

Deposition of microcrystals (i.e., calcium pyrophosphate, calcium oxalate, calcium

hydroxyapatite) into joints can cause

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acute or chronic arthritis in a manner similar to that caused by MSU deposition.

25 The

role of these microcrystals in causing acute synovitis has been greater than

previously expected because improved crystallographic technology (e.g., electron

microscopy, radiograph diffraction) can differentiate these diagnoses from that of

acute gout. Crystal-induced diseases tend to occur in older patients as a result of

prior joint disease, especially osteoarthritis (which is generally a disease of the

elderly), predisposing them to crystal deposition and acute episodes of joint

inflammation. Older adults are also more prone to microcrystal-induced arthritis

because these crystals generally accumulate for a long period and must attain a

sufficient concentration and size before they precipitate into the synovial fluid and

cause inflammation.

26

CRITERIA FOR DIAGNOSIS

The American College of Rheumatology (ACR) first suggested classification criteria

for gout in 1977, which until recently have been commonly used for diagnosis.

27

In

2015, new criteria for the classification of gout were published via a collaboration

between ACR and European League Against Rheumatism (EULAR).

28 The new

criteria represent the best available evidence and incorporate a multifaceted,

objective approach to making a diagnosis. The ACR/EULAR criteria are streamlined

into 3 steps. The updated criteria now separate individuals with symptoms of gout

undergoing evaluation of joint fluid aspiration from those not undergoing this

procedure (Table 45-1).

In order for gout to be considered, a patient must meet the entry criterion (Step 1),

which is described as one or more episodes of pain, swelling, or tenderness in a

peripheral joint or bursa. If the entry criterion is met, the clinician moves to Step 2.

The sufficient criterion described in Step 2 evaluates the presence of MSU crystals

from fluid aspiration of the symptomatic joint, bursa, or tophus. If the patient meets

the criteria described in Steps 1 and 2, a diagnosis of gout is made. If fluid aspiration

is not performed or the results are negative, the clinician moves to the next step. Step

3 examines three different areas consistent with gout: clinical characteristics (i.e.,

symptoms, timing, clinical evidence of disease), laboratory findings (i.e., SU

synovial fluid analysis), and imaging findings (i.e., results consistent with urate

disposition, evidence of joint damage). Step 3 utilizes a scoring method for the

different characteristics associated with gout, and a diagnosis is made with a score of

8 or greater. A classification calculator can be found at:

http://goutclassificationcalculator.auckland.ac.nz/

CASE 45-2, QUESTION 2: Laboratory tests were ordered for E.J., and the results are as follows:

SUA, 10.1 mg/dL

BUN, 10 mg/dL

SCr, 1.0 mg/dL

WBC count, 10.2 × 10

3

/μL

A radiograph of his elbow shows soft tissue swelling with no evidence of tophi. Does E.J. have gout?

Additionally, Table 45-2 discusses the EULAR propositions for the diagnosis of

gout.

13

E.J.’s objective and clinical presentation fulfills the ACR/EULAR criteria for

diagnosis, highlighted in Table 45-1. He presents with symptoms meeting the entry

criterion, however, and does not meet the sufficient criterion because he did not

undergo joint aspiration. When using the classification calculator, the final criteria

score is 8 [e.g., pattern of joint involvement (1), characteristics of symptoms (3), and

serum urate (4)]. A score of 8 is consistent with a gout classification.

Management Guidelines

Gout is one of few rheumatologic diseases that can be treated successfully and even

cured in many patients.

29 However, despite the availability of adequate

pharmacologic interventions, a survey of rheumatologists and internists in the United

States (US) found that drug therapy is often not used based on scientific evidence for

both acute and chronic gout.

30 Another survey of US primary-care physicians found

that evidence-based treatment recommendations were made in only 52.8% of cases

of acute gout and 16.7% of cases of chronic gout.

31 Because these common practices

are contrary to current scientific data, the ACR Guidelines for Management of Gout

were developed to provide evidence-based recommendations for treatment.

32 Other

European guidelines include EULAR and British Society of Rheumatology and

British Health Professionals in Rheumatology (BSR/BHPR) Guidelines for the

Management of Gout.

33,34 A comparison of recommendations from these guidelines is

found in Table 45-3.

Treatment of Acute Gout

GOALS OF THERAPY

CASE 45-2, QUESTION 3: What is the primary goal in the treatment of E.J.’s acute gout attack?

The primary goal in the treatment of an acute attack of gout for E.J. is to relieve his

pain and inflammation. Treatment within 24 hours of symptom onset is recommended

to rapidly improve patient symptoms. The immediate goal of therapy should not be

aimed at decreasing the SUA concentration with urate-lowering therapy (ULT). Gout

sufferers are most likely to have been hyperuricemic for several months or years, and

it is not necessary to treat the hyperuricemia immediately. Furthermore, a decrease in

the SUA concentration at this time might mobilize urate stores and precipitate yet

another acute gout attack. However, if the patient is already receiving ULT, it is not

necessary to discontinue therapy during an acute attack.

32–34

DRUG THERAPY OVERVIEW

CASE 45-2, QUESTION 4: What are the pharmacologic options for the treatment of E.J.’s acute pain?

Acute gouty arthritis can be effectively treated in most instances by using

monotherapy with one of the following: nonsteroidal anti-inflammatory drug

(NSAID), colchicine, or corticosteroids.

32–34 Each therapy has been proven

efficacious when compared to placebo; however, to date, there are limited head-tohead comparisons between agents. Treatment should be based on patient preference,

previous response or experience with an agent, and patient-specific factors (e.g.,

comorbidities, current medications, renal or hepatic impairment). Switching to an

alternative agent or add-on therapy may be considered in refractory cases.

Combination therapy is recommended in severe cases especially those involving

multiple joints. Treatment should be continued until patient is asymptomatic (usually

7–10 days).

Nonsteroidal Anti-Inflammatory Drugs

NSAIDs are the preferred first-line therapy for the treatment of acute gout according

to the ACR, EULAR, and BSR/BHPR guidelines because of their effectiveness and

tolerability.

32–34 Although only a few NSAIDs (i.e., naproxen, indomethacin,

sulindac) are US Food and Drug Administration (FDA)-approved for the treatment of

pain associated with acute gout attacks, most have been studied and experts consider

them equally efficacious.

32,34 The choice of NSAID should be determined based on

patient-specific factors, and dosing should be consistent with the FDA-approved

recommendations for the treatment of acute pain and/or acute gout. GI bleeding or

ulceration and inhibition of platelet aggregation are two of the most common serious

adverse effects of nonselective NSAIDs. Both compound the risk of bleeding when

given concomitantly with anticoagulants (e.g., warfarin). Among the nonselective

NSAIDs, ibuprofen is the least likely to cause GI adverse effects and is perhaps the

safest nonselective NSAID for use in patients at risk for GI bleeding, whereas

piroxicam and indomethacin are among the worst offenders.

35 The selective

cyclooxygenase-2 (COX-2) inhibitor NSAIDs are another option in patients at risk

for GI bleeding or when taking chronic anticoagulants because they do not inhibit

platelets at normal doses. Published data to support efficacy in acute gouty arthritis

exist for etoricoxib and lumiracoxib (withdrawn in most countries due to

hepatotoxicity), but these drugs are not available in the United States. Despite limited

evidence for use, celecoxib and meloxicam are available in the United States with

FDA-approved indications for the treatment of acute gout. A Cochrane systematic

review compared nonselective NSAIDs to COX-2 inhibitors for the treatment of

acute gout pain and found no significant differences in efficacy. However, the review

demonstrated increased cardiovascular risk and GI adverse effects with nonselective

NSAID use.

36

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Table 45-1

The ACR/EULAR Gout Classification Criteria

Categories Score

Step 1: Entry criterion (only apply criteria below

to those meeting this entry criterion)

At least 1 episode of swelling, pain, or tenderness

in a peripheral joint or bursa

Step 2: Sufficient criterion (if met, can classify

as gout without applying criteria below)

Presence of MSU crystals in a symptomatic joint

or bursa (i.e., in synovial fluid) or tophus

Step 3: Criteria (to be used if sufficient criterion

not met)

Clinical

Pattern of joint/bursa involvement during

symptomatic episode(s) ever

a

Ankle or mid-foot (as part of monoarticular or

oligoarticular episode without involvement of the

first metatarsophalangeal joint)

1

Involvement of the first metatarsophalangeal joint

(as part of monoarticular or oligoarticular

episode)

2

Characteristics of symptomatic episode(s) ever

Erythema overlying affected joint (patientreported or physician-observed)

One characteristic 1

Can’t bear touch or pressure to affected joint Two characteristics 2

Great difficulty with walking or inability to use

affected joint

Three characteristics 3

Time course of episode(s) ever

Presence (ever) of ≥2, irrespective of antiinflammatory treatment:

Time to maximal pain <24 hours One typical episode 1

Resolution of symptoms in ≤14 days Recurrent typical episodes 2

Complete resolution (to baseline level) between

symptomatic episodes

Clinical evidence of tophus

Draining or chalklike subcutaneous nodule under

transparent skin, often with overlying vascularity,

located in typical locations: joints, ears, olecranon

bursae, finger pads, tendons (e.g., Achilles)

Present 4

Laboratory

Serum urate: measured by uricase method

Ideally should be scored at a time when the

patient was not receiving urate-lowering

treatment, and it was >4 weeks from the start of

an episode (i.e., during intercritical period); if

practicable, retest under those conditions

<4 mg/dL (<0.24 mmol/L)

b −4

6−8 mg/dL (0.36−<0.48 mmol/L) 2

8−<10 mg/dL (0.48−<0.60 mmol/L) 3

≥10 mg/dL (≥0.60 mmol/L) 4

The highest value irrespective of timing should be

scored

Synovial fluid analysis of a symptomatic (ever)

joint or bursa (should be assessed by a trained

observer)

c

MSU negative −2

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Imaging

d

Imaging evidence of urate deposition in

symptomatic (ever) joint or bursa: ultrasound

evidence of double-contour sign

e or DECT

demonstrating urate deposition

f

Present (either modality) 4

Imaging evidence of gout-related joint damage:

conventional radiography of the hands and/or feet

demonstrates at least 1 erosion

g

Present 4

A web-based calculator can be accessed at: http://goutclassificationcalculator.auckland.ac.nz, and through the

American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) websites.

aSymptomatic episodes are periods of symptoms that include any swelling, pain, and/or tenderness in a peripheral

joint or bursa.

b

If serum urate level is <4 mg/dL (<0.24 mmol/L), subtract 4 points; if serum urate level is ≥4−<6 mg/dL

(≥0.24−<0.36 mmol/L), score this item as 0.

c

If polarizing microscopy of synovial fluid from a symptomatic (ever) joint or bursa by a trained examiner fails to

show MSU monohydrate crystals, subtract 2 points. If synovial fluid was not assessed, score this item as 0.

d

If imaging is not available, score these items as 0.

eHyperechoic irregular enhancement over the surface of the hyaline cartilage that is independent of the insonation

angle of the ultrasound beam (note: false-positive double-contour sign [artifact] may appear at the cartilage surface

but should disappear with a change in the insonation angle of the probe).

31,32

fPresence of color-coded urate at articular or periarticular sites. Images should be acquired using a dual-energy

computed tomography (DECT) scanner, with data acquired at 80 kV and 140 kV and analyzed using gout-specific

software with a 2-material decomposition algorithm that color-codes urate (33). A positive scan is defined as the

presence of color-coded urate at articular or periarticular sites. Nail bed, submillimeter, skin, motion, beam

hardening, and vascular artifacts should not be interpreted as DECT evidence of urate deposition (34).

gErosion is defined as a cortical break with sclerotic margin and overhanging edge, excluding distal interphalangeal

joints and gull wing appearance.

Reprinted from Neogi T. 2015 Gout Classification Criteria. Arthritis Rheum. 2015;67(10):2564, with permission.

Table 45-2

EULAR Propositions for Diagnosis of Gout 2006

Proposition A + B (%)

a

1 In acute attacks, the rapid development of acute pain, swelling, and tenderness

that reaches peak intensity within 6–12 hours, especially with overlying

erythema, highly suggests crystal inflammation (although not specific for gout).

93

2 For typical presentations of gout (e.g., recurrent podagra with hyperuricemia),

a clinical diagnosis alone is reasonably accurate, but not definitive without

crystal confirmation.

100

3 Demonstration of MSU crystals in synovial fluid or a tophus permits a

definitive diagnosis of gout.

100

4 A routine search for MSU crystals is recommended in allsynovial fluid

samples obtained from undiagnosed joints.

87

5 Identification of MSU crystals from asymptomatic joints may allow for definite

diagnosis in intercritical gout.

93

6 Gout and sepsis can coexist. When septic arthritis is suspected, synovial fluid

should be Gram stained and cultured for bacteria even if MSU crystals are

identified.

93

7 Serum uric acid concentrations, although the most important risk factor for

gout, do not confirm or exclude gout. Many with hyperuricemia do not develop

gout, and SUA concentrations during acute attacks can be normal.

93

8 Renal uric acid excretion should be assessed in selected gout patients,

especially those with a family history of young-onset gout, onset of gout at

younger than 25 years, or those with renal calculi.

60

9 Although radiographs can be useful for differential diagnosis and can show

typical features of chronic gout, they are not useful in confirming the diagnosis

of early or acute gout.

93

10 Risk factors for gout and comorbidity should be assessed, including features of

the metabolic syndrome (obesity, hyperglycemia, hyperlipidemia,

hypertension).

100

aA + B (%) is the percentage of fully (A) and strongly (B) recommended, based on EULAR ordinalscale.

EULAR, European League Against Rheumatism; MSU, monosodium urate; SUA, serum uric acid.

Adapted with permission from Zhang W et al. EULAR evidence-based recommendations for gout. Part I:

Diagnosis. Report of a task force of the Standing Committee for International Clinical Studies Including

Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65:1301.

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Table 45-3

Comparison of ACR, EULAR, and BSR/BHPR Guidelines for Gout

ACR Management of Gout Part

1

17 and Part 2

32

EULAR Propositions for Gout

Management

33

BSR/BHPR Guidelines for

Management of Gout

34

:

Summary of Selected

Recommendations

Treatment of Acute Gout

Treat an acute attack within 24

hours of attack with any of the

following: oral NSAIDs, colchicine

Treat as soon as possible with oral

NSAIDs or colchicine. In the

absence of contraindications, an

NSAID is a convenient and wellaccepted treatment

Treat acute gout with an NSAID,

colchicine, or corticosteroid and

continue until attack is terminated

(1–2 weeks)

NSAIDs or COX-2 is effective at

FDA-approved doses for 1 week

NSAIDs are effective at

maximum doses

NSAIDs are drug of choice provided

no contraindications for use

Use colchicine 1.2 mg, then 0.6 mg

1 hour later. The 0.6 mg once to

twice daily until attack subsides

High doses of colchicine cause side

effects, and low doses (e.g., 0.5 mg

TID) can be sufficient

Use colchicine in doses of 0.5 mg 2–

4 times daily

Recommend prednisone 0.5 mg/kg

per day for 5–10 days. Intraarticular recommended for acute

gout of 1–2 joints

Intra-articular aspiration and

injection of a long-acting steroid are

effective and safe treatments for an

acute attack

Corticosteroids are effective for

acute gout in patients who cannot

tolerate NSAIDs or are refractory to

other therapy: may use

intramuscularly, intravenously, or

intra-articularly; the latter is highly

effective in monoarticular gout

Treatment of Hyperuricemia to Prevent Recurrent Gout

ULT is indicated in patients with

established gouty arthritis and >2

acute attacks per year, tophi, a

history of urolithiasis, and CKD

(Stage 2 and higher)

ULT is indicated in patients with

recurrent acute attacks,

arthropathy, tophi, or radiographic

changes of gout

Start long-term ULT in

uncomplicated gout only if two or

more attacks occur per year

Treat to a minimum SUA of <6 The therapeutic goal of ULT (i.e., Plasma urate goal is <300 mmol/L

mg/dL, may consider a goal of <5

mg/dL in patients without

symptomatic relief at <6 mg/dL.

Begin ULT once attack is

controlled

SUA less than or equal to the

saturation point for MSU of 6

mg/dL) is to promote crystal

dissolution and prevent crystal

formation

(<5 mg/dL). Start ULT 1–2 weeks

after inflammation has resolved

Recommend ULT with a XO

inhibitor (allopurinol or febuxostat).

Allopurinolshould be initiated at 100

mg/d and titrated every 2–5 weeks

until target dose reached.

May use doses of >300 mg in renal

impairment if it is proper education

and monitoring

Allopurinol, an appropriate longterm urate-lowering agent, should

be initiated at 100 mg/d and

increased by 100 mg every 2–4

weeks, if required. The dose must

be adjusted in patients with renal

impairment. If toxicity occurs,

options include other xanthine

oxidase (XO) inhibitors, a uricosuric

agent, or allopurinol desensitization

(if mild rash)

Initial ULT should be allopurinol

starting with 50–100 mg/d and

increasing by 50–100 mg every few

weeks until therapeutic goal of SUA

<300 mmol/L to a maximum of 900

mg/d allopurinol (adjust as necessary

for renal dysfunction)

Probenecid may be used as a firstline alternative in patients unable to

use or intolerant to at least 1 XO

inhibitor. Avoid use in patients with

a CrCl <50 mL/min

Probenecid can be an alternative to

allopurinol in patients with normal

renal function, but is relatively

contraindicated in patients with

urolithiasis

Uricosuric agents should be used

only as a second-line drug in those

underexcreting urate and in those

resistant to or intolerant of allopurinol

Prophylaxis for acute gout is

recommended for 6 months. The

first-line agent for prophylaxis

against acute gout is colchicine or

low-dose NSAIDs. Oral

corticosteroids are recommended as

a second-line agent

Prophylaxis against acute attacks

for up to 6 months of initiation of

ULT with colchicine (0.5–1 mg/d)

or NSAID (with gastroprotection, if

indicated)

Prevent gout attacks by giving

colchicine 0.5 mg twice daily for up

to 6 months; if patient cannot

tolerate colchicine, NSAIDs or

COX-2 inhibitors can be substituted

but limited to 6 weeks

Adjunctive Therapy to Prevent Recurrent Gout

Patient education on general health,

diet, and lifestyle modifications

includes limiting daily alcoholic

beverages, purine-rich meats, and

fructose-containing

beverages/foods. Specifically, beer

and, to a smaller extent, spirits are

associated with increased gout

attacks; wine is less likely to be a

risk factor. Increasing low-fat dairy

protein has a favorable effect on

SUA

Optimal treatment of gout requires

nonpharmacologic and

pharmacologic modalities tailored to

specific risk factors (SUA levels,

prior attacks); clinical phase of

gout; and general risk factors (age,

comorbidity, drug interactions)

Dietary management: includes skim

milk and yogurt; favors soybeans

and vegetable proteins; restricts

intake of high-purine food (<200

mg/d); avoids liver, kidneys, shellfish,

and yeast extracts; reduces intake of

red meat; favors cherries, fresh or

preserved

Patient education and lifestyle

modifications (e.g., weight loss if

obese, reduced beer, and other

alcohol consumption) are important

Alcohol consumption

a

: restrict to <21

units/wk (men) and <14 units/week

(women); two 125-mL glasses of

wine per day are usually safe; two

25-mL glasses of spirits per day are

safer than 1/2 pint of many beers

a1 unit equals 10 mL of pure alcohol, so the number of units per drink depends on its alcohol content; generally, 6

ounces of wine is about 2 units, a 12-ounce beer is 1.5 units, and a 2-ounce shot is about 1.2 units.

BSR/BHPR, British Society for Rheumatology/British Health Professionals in Rheumatology; COX-2,

cyclooxygenase-2; CrCl, creatinine clearance; EULAR, European League Against Rheumatism; GI,

gastrointestinal; HTN, hypertension; MSU, monosodium urate; NSAID, nonsteroidal anti-inflammatory drug; SUA,

serum uric acid; TID, three times daily; ULT, urate-lowering therapy.

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The potential adverse cardiovascular effects of NSAIDs are of concern.

Cardiovascular risk associated with NSAID therapy has been known for some

time (e.g., myocardial infarction, stroke); however, newer literature highlights the

significance of this risk. Two separate cohort trials indicate increased risk of

cardiovascular morbidity and mortality in patients using NSAIDs after an acute

myocardial infarction. This risk was increased in patients receiving antithrombotic

therapy and was observed even with short-term use (0–3 days).

37

In patients with a

history of myocardial infarction, proceed with caution when considering NSAID use.

NSAIDs can also aggravate HTN, cause renal failure, inhibit diuretic-induced

increases in renal sodium excretion,

38–41 and decrease the hypotensive effect of

diuretics and other antihypertensive drugs.

42,43 Patients with CHD and renal

insufficiency can be treated for a short duration with nonselective NSAIDs, albeit

with much caution. The nonselective NSAIDs are safe for patients with stable,

controlled HTN when given for only a few days and with close monitoring of blood

pressure.

Colchicine

Colchicine has been successfully used to treat acute gout for more than 2,000 years

despite little published research supporting its efficacy.

44 By inhibiting microtubule

polymerization, it decreases the action of inflammatory mediators such as cytokines

and chemokines. Traditionally, colchicine has been dosed as one or two 0.5- to 0.6-

mg tablets initially followed by 0.5 to 0.6 mg hourly or every other hour, until joint

pain was relieved or GI effects (i.e., diarrhea, nausea, vomiting) intervened. To

minimize these significant adverse effects, the EULAR and BSR/BHPR guidelines

33,34

recommend lower doses of 0.5 mg twice to four times daily. However, the AGREE

trial

45 compared a lower-dose regimen (1.2 mg to start followed by 0.6 mg in 1 hour)

with the traditional dosing and found significantly fewer adverse effects with the

lower-dose regimen and similar efficacy. A 2014 systematic review, combining the

AGREE trial with a separate randomized trial, found similar results.

46 Although

colchicine has been marketed in the United States since 1961, it was never approved

by the FDA as safe and effective. The AGREE trial was the basis of the FDA

approval of a new registered colchicine product in the United States. The FDA

granted brand exclusivity to this product. Consequently, there are no approved

generic alternatives available in the United States.

47,48 The approved dosage is 1.2

mg to start followed by 0.6 mg in 1 hour for the treatment of acute gout and 0.6 mg

once to twice daily for gout prophylaxis with a maximal dose of 1.2 mg per day for

chronic dosing, which is also consistent with the ACR recommendations. Colchicine

should be used cautiously in patients with creatinine clearance (CrCl) less than 30

mL/minute and with hepatic impairment.

32 Colchicine has a number of significant

drug interactions that inhibit either cytochrome P-450 (CYP) 3A4 or P-

glycoprotein.

49 A thorough medication history is essential to assure safe prescribing.

Some common medications that interact with colchicine include digoxin, fibric acids,

statins, nondihydropyridine calcium channel blockers, erythromycin, and antifungals.

A table detailing significant colchicine drug interactions can be found online in Table

45-4. Common adverse effects include nausea, vomiting, and diarrhea.

Corticosteroids

Historically, corticosteroids have been considered second-line therapy due to the

potential for serious adverse effects and adrenal suppression when used long-term as

well as the risk of rebound pain when abruptly discontinued.

3,50 However, a recent

systematic review found prednisolone to be as effective as NSAIDs for reducing pain

from acute gout, and no differences in serious adverse events were observed.

36,51

Corticosteroids may be particularly useful for elderly patients or those with renal

disease or CHD who cannot tolerate NSAIDs.

3,34,50,51 Corticosteroid adverse effects

(e.g., osteoporosis, myopathy, peptic ulcer disease, central nervous system effects,

HTN, predisposition to infections) are not likely with short courses of treatment for

gout attacks. Glucose intolerance, however, can occur with short-term therapy. If the

acute gout episode involves only one or two large joints, intra-articular

corticosteroid administration is recommended by the ACR

32

, EULAR

33

, and

BSR/BHPR

34 guidelines, despite limited evidence. There is also evidence to support

the use of intramuscular corticosteroids especially for patients unable to take oral

medications.

32

Analgesics

When an occasional patient requires more pain control, a dose or two of nonopioid

or opioid analgesics can be a reasonable adjunctive therapy to blunt the pain of acute

gouty arthritis while awaiting the apparent benefits of NSAIDs, colchicine, or

corticosteroids.

6 Most patients, however, generally experience benefits from

NSAIDs, colchicine, and corticosteroids soon after a dose is administered.

Other Agents

Alternative regimens include the use of adrenocorticotropic hormone (ACTH) and

interleukin-1 inhibitors (IL-1). The ACR guidelines recommend the use of ACTH

drugs, such as corticotropin, as an alternative to IM/IV corticosteroids in patients

unable to take oral medications; however, the significant expense may outweigh the

benefits of this medication.

32

Interlukin-1 agents (e.g., anakinra, rilonacept,

canakinumab) have not been approved by the FDA for the treatment of acute gout. A

systematic review comparing canakinumab to intramuscular triamcinolone indicated

that canakinumab was more effective in pain reduction during an acute flare;

however, it had significantly higher serious and nonserious adverse effects.

52 The

ACR guidelines recommend reserving these agents for situations where traditional

medications are contraindicated to ineffective until there is a clearer idea of the risk

and benefit profile.

32 As with the ACTH medications, the cost of IL-agents may

prohibit use.

CHOICE OF AGENT

CASE 45-2, QUESTION 5: What therapeutic intervention would be most appropriate for E.J. at this time?

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Table 45-4

Colchicine Drug Interaction

Interacting Drugs Description

Cobicistat May increase the return concentration of colchicine. Management: Colchicine

is contraindicated in patients with impaired renal or hepatic function who are

also receiving a strong CYP3A4 inhibiter like cobicistat. In those with normal

renal and hepatic function, reduce colchicine dose as directed. Consider

therapy modification.

Conivaptan May increase the serum concentration of CYP3A4 substrates. Avoid

combination.

Cyanocobalamin Colchicine may decrease the serum concentration of cyanocobalamin. Monitor

therapy.

CYP3A4 inhibitors (moderate) May increase the serum concentration of colchicine. Management: Reduce

colchicine dose as directed when using with a moderate CYP3A4 inhibitor,

and increase monitoring for colchicine-related iconicity. Use extra caution in

patients with impaired renal and/or hepatic function.

Consider therapy modification.

CYP3A4 inhibitors (strong) May increase the serum concentration of colchicine. Management: Colchicine

is contraindicated in patients with impaired renal or hepatic function who are

also receiving a strong CYP3A4 inhibitor. In those with normal renal and

hepatic function, reduce colchicine dose as directed.

Consider therapy modification.

Dasatinib May increase the serum concentration of CYP3A4 substrates. Monitor

therapy.

Digoxin May increase the serum concentration of colchicine. Monitor therapy.

Fibric acid derivatives May enhance the myopathic (rhabdomyolysis) effect of colchicine. Monitor

therapy.

Fosamprenavir May increase the serum concentration of colchicine. Management: Colchicine

is contraindicated in patients with impaired renal or hepatic function who are

receiving ritonavir-boosted fosamprenavir. In those with normal renal and

hepatic function, reduce colchicine dose as directed.

Consider therapy modification.

Fusidic acid (systemic) May increase the serum concentration of CYP3A4 substrates. Avoid

combination.

HMG-CoA reductase inhibitors Colchicine may enhance the myopathic (rhabdomyolysis) effect of HMG-CoA

reductase inhibitors. Colchicine may increase the serum concentration of

HMG-CoA reductase inhibitors. Consider therapy modification.

Idelalisib May increase the serum concentration of CYP3A4 substrates. Avoid

combination.

Luliconazole May increase the serum concentration of CYP3A4 substrates. Monitor

therapy.

Mifepristone May increase the serum concentration of CYP3A4 substrates. Management:

Minimize doses of CYP3A4 substrates, and monitor for increased

concentrations/toxicity during and 2 weeks following treatment with

mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl,

pinacide, quinidine, sirolimus, and tacrolimus. Consider therapy modification.

Multivitamins/fluoride (with

ADE)

Colchicine may decrease the serum concentration of multivitamins/fluoride

(with ADE). Specifically, colchicine may decrease absorption of

cyanocobalamin (vitamin B12). Monitor therapy.

Multivitamins/minerals (with

ADEK, folate, iron)

Colchicine may decrease the serum concentration of multivitamins/minerals

(with ADEK, folate, iron). Specifically, colchicine may decrease the serum

concentration of cyanocobalamin. Monitor therapy.

Multivitamins/minerals (with

AE, no iron)

Colchicine may decrease the serum concentration of multivitamins/minerals

(with AE, no iron). Specifically, colchicine may decrease absorption of

cyanocobalamin (vitamin B12). Monitor therapy.

P-glycoprotein/ABCBI inducers May decrease the serum concentration of P-glycoprotein/ABCBI substrates.

P-glycoprotein inducers may also further limit the distribution of P-glycoprotein

substrates to specific cells/issues/organs where P-glycoprotein is present in

large amounts (e.g., brain, T-lymphocytes, testes).

Monitor therapy.

P-glycoprotein/ABCBI inhibitors May increase the serum concentration of colchicine. Colchicine distribution

into certain issues (e.g., brain) may also be increased. Management:

Colchicine is contraindicated in patients with impaired renal or hepatic function

who are also receiving a P-glycoprotein inhibitor. In those with normal renal

and hepatic function, reduce colchicine dose as directed. Consider therapy

modification.

Stiripentol May increase the serum concentration of CYP3A4 substrates. Management:

Use of stiripentol with CYP3A4 substrates that are considered to have a

narrow therapeutic index should be avoided because of the increased risk for

adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol

requires closer monitoring. Consider therapy modification.

Telaprevir May increase the serum concentration of colchicine. Management: Colchicine

should not be used with telaprevir in patients with impaired renal or hepatic

function. In those with normal renal and hepatic function, reduced colchicine

doses (as directed) are required if used with telaprevir.

Consider therapy modification.

Tipranavir May increase the serum concentration of colchicine. Management: Colchicine

should not be used with tipranavir in patients with impaired renal or hepatic

function. In those with normal renal and hepatic function, reduced colchicine

doses (as directed) are required if used with tipranavir.

Consider therapy modification.

Source: Facts & Comparisons eAnswers; http://online.factsandcomparisons.com/MonoDisp.aspx?

monoID=fandcp. 914

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