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*[[Allopurinol]] -  start with dosage of 100 mg/day can be escalated at the rate of 100 mg/2 - 5 weeks, maximum recommended dosage is 800 mg and should be continued indefinitely, once the target serum uric acid levels are achieved.<ref name="pmid23024028">{{cite journal| author=Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T | display-authors=etal| title=2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. | journal=Arthritis Care Res (Hoboken) | year= 2012 | volume= 64 | issue= 10 | pages= 1431-46 | pmid=23024028 | doi=10.1002/acr.21772 | pmc=3683400 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23024028  }}</ref>
*[[Allopurinol]] -  start with dosage of 100 mg/day can be escalated at the rate of 100 mg/2 - 5 weeks, maximum recommended dosage is 800 mg and should be continued indefinitely, once the target serum uric acid levels are achieved.<ref name="pmid23024028">{{cite journal| author=Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T | display-authors=etal| title=2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. | journal=Arthritis Care Res (Hoboken) | year= 2012 | volume= 64 | issue= 10 | pages= 1431-46 | pmid=23024028 | doi=10.1002/acr.21772 | pmc=3683400 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23024028  }}</ref>
**In patients with  [[CKD]] (stage 4 and 5), dosage started with 50 mg/ day and can be increased at the rate of 50 mg/ 2- 5 weeks.<ref name="pmid21279998">{{cite journal| author=Stamp LK, O'Donnell JL, Zhang M, James J, Frampton C, Barclay ML | display-authors=etal| title=Using allopurinol above the dose based on creatinine clearance is effective and safe in patients with chronic gout, including those with renal impairment. | journal=Arthritis Rheum | year= 2011 | volume= 63 | issue= 2 | pages= 412-21 | pmid=21279998 | doi=10.1002/art.30119 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21279998  }}</ref>
**In patients with  [[CKD]] (stage 4 and 5), dosage started with 50 mg/ day and can be increased at the rate of 50 mg/ 2- 5 weeks.<ref name="pmid21279998">{{cite journal| author=Stamp LK, O'Donnell JL, Zhang M, James J, Frampton C, Barclay ML | display-authors=etal| title=Using allopurinol above the dose based on creatinine clearance is effective and safe in patients with chronic gout, including those with renal impairment. | journal=Arthritis Rheum | year= 2011 | volume= 63 | issue= 2 | pages= 412-21 | pmid=21279998 | doi=10.1002/art.30119 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21279998  }}</ref>
*[[Febuxostat]] - Start with an oral dosage of 40 mg/day<ref name="pmid21330679">{{cite journal| author=Gray CL, Walters-Smith NE| title=Febuxostat for treatment of chronic gout. | journal=Am J Health Syst Pharm | year= 2011 | volume= 68 | issue= 5 | pages= 389-98 | pmid=21330679 | doi=10.2146/ajhp100394 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21330679  }}</ref> and can be increased to a maximum of 80 mg/day.<ref name="pmid16339094">{{cite journal| author=Becker MA, Schumacher HR, Wortmann RL, MacDonald PA, Eustace D, Palo WA | display-authors=etal| title=Febuxostat compared with allopurinol in patients with hyperuricemia and gout. | journal=N Engl J Med | year= 2005 | volume= 353 | issue= 23 | pages= 2450-61 | pmid=16339094 | doi=10.1056/NEJMoa050373 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16339094  }}</ref>
*[[Febuxostat]] - Start with an oral dosage of 40 mg/day<ref name="pmid21330679">{{cite journal| author=Gray CL, Walters-Smith NE| title=Febuxostat for treatment of chronic gout. | journal=Am J Health Syst Pharm | year= 2011 | volume= 68 | issue= 5 | pages= 389-98 | pmid=21330679 | doi=10.2146/ajhp100394 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21330679  }}</ref> and can be increased to a maximum of 80 mg/day.<ref name="pmid16339094">{{cite journal| author=Becker MA, Schumacher HR, Wortmann RL, MacDonald PA, Eustace D, Palo WA | display-authors=etal| title=Febuxostat compared with allopurinol in patients with hyperuricemia and gout. | journal=N Engl J Med | year= 2005 | volume= 353 | issue= 23 | pages= 2450-61 | pmid=16339094 | doi=10.1056/NEJMoa050373 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16339094 }}</ref><ref name="pmid20370912">{{cite journal| author=Becker MA, Schumacher HR, Espinoza LR, Wells AF, MacDonald P, Lloyd E | display-authors=etal| title=The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. | journal=Arthritis Res Ther | year= 2010 | volume= 12 | issue= 2 | pages= R63 | pmid=20370912 | doi=10.1186/ar2978 | pmc=2888216 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20370912 }}</ref>


Allopurinol is superior to Febuxostat in that all cause mortality rate is higher with Febuxostat and hence people who show little or no response and severe [[Adverse effect (medicine)]] to Allopurinol  
Allopurinol is superior to Febuxostat in that all cause mortality rate is higher with Febuxostat and hence people who show little or no response and severe [[Adverse effect (medicine)]] to Allopurinol  

Revision as of 00:16, 9 June 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Overview

  • The medical therapy of Gout differs for acute flares, chronic condition and maintenance therapy for prevention of acute flares.
  • Colchicine is usually used for maintainance therapy, however; within 24 hours of symptom onset, low dose colchicine can be used.[3]
  • Other, less standard methods of treatment include the use of topical creams, ice packing[5] and increasing mobility for reducing pain.

Medical Therapy

Following medications are used in management of gout.

Glucocorticoids

Oral glucocorticoids are always preferred over parental glucocorticoids due to benefit/risk profile. Glucocorticoids are proven to be equally effective as NSAIDs [6] and associated with fewer adverse side effects[7][8]

Oral glucocorticoids include

  • Prednisone - 40mg for 4-5 days and then gradually tapered off over 7-10 days[9][10]

Intra articular Glucocorticoids: Septic arthritis should be ruled out before initiating intra articluar glucocorticoids.

  • Triamcinolone acetate - dosage varies depending on the size of joint. Usually used in monoartiular or oligoarticular(1 or 2-3 joints) involvement.
    • 40 - 60 mg(large joints), 30 mg(medium joints), 10 mg(small joints)

Parental glucocorticoids include:

Comparison of NSAID and steroids for acute gout
  Patients Interventions Results
Steroid NSAID
Janssens et al 2008[13] 120 total patients with uric acid crystals on arthrocentesis Prednisolone 35 mg once daily for 5 days Naproxen 500 mg twice daily for 5 days NSAID trended better (88% versus 80% response; p=0.3)
No differences in rates of drug toxicity.
Man et al 2007[6] 90 total patients with clinical diagnosis of gout† Initially prednisolone 30 mg
Followed by prednisolone 30 mg daily for 5 days and as needed acetaminophen
Initially diclofenac 75 mg with indomethacin 50 mg
Followed by indomethacin 50 mg every 8 hrs for 2 days then 25 mg every 8 hrs for 3 days and as needed acetaminophen.
Steroids faster reduction in pain.
Steroids used more acetaminophen.
More adverse effects from indomethacin.

Indomethacin trended to more relapses at 2 weeks (11% vs 17%).

Notes:

† Clinical diagnosis of gout was "pain and warmth in a joint, and presented within 3 days of the onset of pain and also had 1 or more of the following: metatarsal-phalangeal joint involvement; knee or ankle joint involvement and aspirate containing crystals; or typical gouty arthritis, with either gouty tophi present or previous joint aspiration confirming the diagnosis of gout." Seven patients allowed arthrocentesis and all were positive for gout.

Non-steroidal anti-inflammatory agents

NSAIDs have proven efficacy than placebo according to Randomized controlled trial[14] but proven to be equally efficacious( in particular, indomethacin[13],) compared to Glucocorticoids [6] . Can be given within 48hrs in patients age less than 60 with no Comorbidity and used as an alternative to glucocorticoids. Current FDA approved NSAIDS[15] include:

COX-2 selective inhibitors are proven to have similar benefits as NSAIDs with an added advantage of protection from NSAIDs induced Gastritis[16] [17] but yet to be approved by FDA.

Colchicine

Colchicine is usually used as maintainance theray to prevent flares; can be used as an alternate to NSAIDs and glucocorticoids in acute gout attack but effective when started within 24 hours[18][19].

  • Dosage - 1.2 mg followed by 0.6 mg in 1 hour followed by consequent dosages depending upon the response.[20]
    • 0.6 mg q8h followed by tapering doses
    • 0.5 mg q12h to q6h[21]

To avoid drug toxicity, lower doses of colchicine (0.6 per day) have been used in combination with glucocorticoids.[5]

Urate lowering therapy

Can be further divided into non - pharmacological( dietary and life style modifications) and pharmacological(xanthine oxidase inhibitors and Uricosuric drugs).

Non - Pharmacological urate lowering therapy
life style modifications[22]
  • weight reduction reduces serum uric acid levels[23].
  • Limiting alcohol intake and abstinence from alcohol in acute flares[24].
  • All general lifestyle changes( like smoking cessation, increased physical activity, limiting telivision watching, eating healthy, etc.) that play role in control of chronic diseases are found to be more beneficial in gout[25]
  • Prevention and optimal management of chronic diseases and metabolic syndromes, cardiovascular events[26]
Dietary changes
  • Decreased levels of meat and sea food consumption[27] [28]and increased intake of low fat or non fat containing dairy products[29] decreases gout attacks, where as foods rich in purine should be limited to moderate amounts.[30]
  • Increased dietary consumption of cherries decreases gout attacks.[31]
  • Limiting high Fructose corn syrup intake reduces attacks of gout.[32]

Pharmacological urate lowering therapy (ULT)

These include:

Xanthine oxidase inhibitors:

  • Allopurinol - start with dosage of 100 mg/day can be escalated at the rate of 100 mg/2 - 5 weeks, maximum recommended dosage is 800 mg and should be continued indefinitely, once the target serum uric acid levels are achieved.[33]
    • In patients with CKD (stage 4 and 5), dosage started with 50 mg/ day and can be increased at the rate of 50 mg/ 2- 5 weeks.[34]
  • Febuxostat - Start with an oral dosage of 40 mg/day[35] and can be increased to a maximum of 80 mg/day.[36][37]

Allopurinol is superior to Febuxostat in that all cause mortality rate is higher with Febuxostat and hence people who show little or no response and severe Adverse effect (medicine) to Allopurinol

Pharmacological therapy to lower serum uric acid levels is indicated in any patient with established diagnosis of gout with

·      Prior gout attacks (2 or more per year) and current hyperuricemia (evidence A )

·      Tophus or tophi by clinical exam or imaging study (evidence A)

·      CKD stage 2–5 or end-stage renal disease, which by itself, is an appropriate indication for pharmacologic ULT (evidence C)

·      Past urolithiasis (evidence C) 

The goal is to attain a serum urate level at a minimum of less than 6 mg/dl (evidence A). Serum urate level should be lowered sufficiently so to have a dependable improve in signs and symptoms of the disease, including palpable and visible tophi detected by physical examination, and that this may involve therapeutic serum urate level lowering to below 5 mg/dl (evidence B). 

The recommended first line is xanthine oxidase inhibitor therapy with either allopurinol or febuxostat (evidence A). There is no preference of either XOI over the other XOI drug. ULT can be started during an acute gout attack, provided an effective anti-inflammatory therapy has already been initiated (evidence C)

·    

·      Probenecid is the first choice among uricosuric agents (evidence B). It is recommended to monitor urinary uric acid levels during its therapy (evidence C). With a creatinine clearance of 50 ml/minute, it is not recommended as first-line ULT monotherapy (evidence C). History of urolithiasis and elevated uric acid level in urine also contraindicates its use (evidence C). Monitor urinary pH and consider urine alkalinization (e.g., with potassium citrate), in addition to increased fluid intake, as a risk management strategy for urolithiasis (evidence C).  

Probenecid was recommended as an alternative first-line option in case of contraindication or intolerance to at least 1 xanthine oxidase inhibitor (evidence B). However, probenecid should not be used as a first-line monotherapy when creatinine clearance is below 50 ml/minute. 


It is recommended that regular monitoring of serum urate levels be done every 2–5 weeks during drug titration; including continued measurements every 6 months once the desired level is achieved (evidence C).

Clinical practice guidelines address treatment. However, trials comparing glucocorticoids (steroids) and non-steroidal anti-inflammatory agents (NSAIDs) were not published till after the guidelines.

A nurse-led protocol with treatment goal of 6 mg/dL was beneficial.

Regarding medications, if there are no mitigating factors in choosing a drug, glucocorticoids, non-steroidal anti-inflammatory agents (NSAIDs), and colchicine all work; however, colchicine consistently causes drug toxicity.

A combination treatment is ice four times a day with oral prednisone 30 mg orally tapered over 6 days (30 mg for two days, 20 mg for two days, 10 mg for two days) and colchicine 0.6 mg/day. An advantage of this regimen is the reduced toxicity from the low dose of colchicine and that the colchicine helps prevent flares if allopurinol is later started. Colchicine has been combined with NSAIDs that are not metabolized by the CYP3A4 isoenzyme of cytochrome P-450 (naproxen is not metabolized by CYP3A4). Combining glucocorticoids with NSAIDs increased the risk for gastrointestinal drug toxicity

Anti-cytokines

The monoclonal antibody against interleukin-1 beta, canakinumab[38] and Anakinra[39] can be used in treatment resistant cases.

Local ice

Ice packs, applied for 30 minutes 4 times per day, can help when used as in conjunction with pharmacological treatment.[5][40]

Clinical treatment guidelines for management of Gout is set up by American College of Rheumatology.[41] Goal of Gout therapy is to

  • Treat Gout flares.
  • Provide maintenance therapy to prevent flares and, dietary and life style modifications.

Management of acute gout attack:

Acute gout attacks are self limited, hence only symptomatic treatment is indicated. Appropriate choice of medications should be made based on the general condition of the patient, assessment of Comorbidities and duration of the symptom onset. Initiation of treatment with exact dosage of Medication within the earliest possible time frame i.e., preferentially within first 12- 24 hours of onset may result in complete resolution of symptoms. It is important to note that there is no isolated best medication for gout and, depending on patients, choice between single and combination therapy may vary.




·      Access the intensity of the attack based on severity of pain and the number of joints involved.

·      For a mild/moderate gout severity (6 of 10 on a 0 –10 pain visual analog scale) involving 1 or a few small joints or 1 or 2 large joints, initiating monotherapy with options being oral nonsteroidal anti-inflammatory drugs (NSAIDs), systemic corticosteroids, or oral colchicine (evidence A for all drug categories).

o  NSAIDs: Approved medications are naproxen, indomethacin (both evidence A), and sulindac (evidence B). They should be initiated at their full dosing at either the Food and Drug Administration (FDA)– or European Medical Agency–approved anti-inflammatory/ analgesic doses. It should not be tapered with symptomatic improvement; instead full dose should be administered till complete resolution.

o  Colchicine: Acute gout can be treated with a loading dose of 1.2 mg, followed by 0.6 mg 1 hour later (evidence B). This can then be followed by a gout attack prophylaxis dosing beginning 12 hours or later and continued till the attack resolves (evidence C). If the patient was already on prophylactic colchicine and received acute gout regimen in the last 2 weeks, then consider other therapeutic options i.e. corticosteroid, NSAID.

o  Corticosteroids: Corticosteroids can be given as an initial monotherapy. Prednisone, or prednisolone at a starting dosage of at least 0.5 mg/kg per day for 5–10 days and then discontinued (evidence A). Alternatively, a full dose for 2–5 days can be given, followed by tapering for 7–10 days, and then discontinued (evidence C). While oral corticosteroid is the preferred route, intra-articular route can be considered for acute gout of 1 or 2 large joints (evidence B).

·      For a severe acute gout attack (7 of 10 on a 0 –10 pain visual analog scale) and in patients with an acute polyarthritis or involvement of more than 1 large joint, combination therapy should be considered. Recommendation is to initiate simultaneous use of full doses (or, where appropriate, a full dose of 1 agent and prophylaxis dosing of the other) of 2 of the pharmacologic modalities as recommended above.

·      If the patient was previously on an established pharmacologic uric acid lowering therapy (ULT), it is recommended to be continued without interruption during an acute attack (evidence C), i.e. do not stop ULT therapy during an acute flare.  

Prophylaxis to prevent acute gout flares 16339094, 21846852, 20370912, 21353107, 15570646

It is recommended that for all cases of gout, where urate lowering therapy is started, a prophylaxis for acute flares should be started as well, given that gout attacks are common in early ULT (evidence A). 16339094, 21846852, 20370912, 21353107 

The first-line for this purpose is oral colchicine (evidence A) 21353107, 15570646, or low-dose NSAIDs (evidence C). 

A low-dose of colchicine as 0.5 mg or 0.6 mg taken orally once or twice a day is the recommendation, with dosing further adjusted downward for moderate to severe renal function impairment and potential drug–drug interactions) 21480191. 

The duration of treatment should be greater of at least 6 months (evidence A) 16339094 20370912, 21353107, 3 months after achieving target serum urate levels in patient with no tophi on physical exam (evidence B), or 6 months after achieving desired urate levels appropriate for the patient with one of more tophi (evidence C). 

Management of chronic gout/chronic tophaceous gouty arthropathy:

 

Once the diagnosis of gout is established, a systematic pharmacologic as well as non-pharmacologic management approach should be initiated. A set of baseline recommendations for all patients are: 

·      Patient education on the disease, its treatment options and their objectives, including the particular role of uric acid excess in gout and as the key long-term treatment target (evidence B) 22679303.

·      Consider diet and lifestyle modification

·      Always consider elimination of serum urate– elevating prescription medications e.g. thiazide and loop diuretics, niacin, and calcineurin inhibitors (evidence C)

·      Always consider secondary causes of hyperuricemia for all gout patients

·      A clinical evaluation of gout disease activity and its burden should be done for each patient by history and a thorough physical examination for symptoms of arthritis and signs such as tophi and acute and chronic synovitis (evidence C).  


References

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  20. Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW (2010). "High versus low dosing of oral colchicine 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. 62 (4): 1060–8. doi:10.1002/art.27327. PMID 20131255.
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