Gout medical therapy

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

Clinical treatment guidelines for management of Gout are by American College of Rheumatology. Goal of Gout therapy is to

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

Overview

• The medical therapy of Gout differs for acute flares and maintenance therapy for prevention of acute flares.

• The main stay of therapy is pain managament, ideally achieved with NSAIDS and oral or intra articular Glucocorticoids.

• Colchicine is usually used for maintainance therapy, however; within 24 hours of symptom onset, low dose colchicine can be used.

• For treatment resistant Gout, lesinurad with Xanthine oxidase inhibitors as a combination is used.

• Other, less standard methods of treatment include the use of topical creams, ice packing and increasing mobility for reducing pain.

Medical Therapy

Following medications are used in the management of gout.

Treatment of acute flares

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.
• NSAIDs: They should be initiated at their full dosing at Food and Drug Administration approved anti-inflammatory/ analgesic doses. It should not be tapered with symptomatic improvement; instead full dose should be administered till complete resolution.
• Colchicine: Acute gout can be treated with a loading dose of 1.2 mg, followed by 0.6 mg 1 hour later. This can then be followed by a gout attack prophylaxis dosing beginning 12 hours or later and continued till the attack resolves. 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.
• corticosteroids: Corticosteroids can be given as an initial monotherapy. Prednisolone or prednisone 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. While oral corticosteroid is the preferred route, intra-articular route can be considered for acute gout of 1 or 2 large joints.
• 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 , i.e. do not stop ULT therapy during an acute flare.  

Local ice

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

Medications

Comparison of NSAID and steroids for acute gout

	Patients	Interventions		Results
		Steroid	NSAID
Janssens et al 2008	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	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.

Glucocorticoids

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

Oral glucocorticoids include

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

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:

• Intramuscular - Triamcinolone acetate 40 - 60mg, Betamethasone 7mg
• Intravenous - Methylprednisolone 20mg for 4 - 5 days and then swirch to maintainance dose.

Non-steroidal anti-inflammatory agents

NSAIDs have proven efficacy than placebo according to Randomized controlled trial but proven to be equally efficacious( in particular, indomethacin,) compared to Glucocorticoids . 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 include:

• Indomethacin - 50 mg PO q8h
• naproxen - 500 mg PO q12h
• Sulindac - 200 mg PO q12hr.

COX-2 selective inhibitors are proven to have similar benefits as NSAIDs with an added advantage of protection from NSAIDs induced Gastritis 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.

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

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

Gout prevention with 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

• weight reduction reduces serum uric acid levels.
• Limiting alcohol intake and abstinence from alcohol in acute flares.
• 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
• Prevention and optimal management of chronic diseases and metabolic syndromes, cardiovascular events

Dietary changes

• Decreased levels of meat and sea food consumption and increased intake of low fat or non fat containing dairy products decreases gout attacks, where as foods rich in purine should be limited to moderate amounts.
• Increased dietary consumption of cherries decreases gout attacks.
• Limiting high Fructose corn syrup intake reduces attacks of gout.

Pharmacological urate lowering therapy (ULT)

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.
• Tophus or tophi by clinical exam or imaging study.
• CKD stage 2–5 or end-stage renal disease, which by itself, is an appropriate indication for pharmacologic ULT.
• Past urolithiasis.

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.
  • A nurse-led protocol, "allopurinol, started at 100 mg once per day and titrated upwards in 100 mg increments every 3–4 weeks according to serum urate concentrations, to a maximum of 900 mg once per day" for a goal of uric acid level < 6 mg/dl is effective
  • 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.
• Febuxostat - Start with an oral dosage of 40 mg/day and can be increased to a maximum of 80 mg/day.

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 should not be prescribed Febuxostat.

Uricosuric drugs:

• Probenecid
• Sulfinpyrazone (patient information)
• benzbromarone
• Lesinurad

Probenecid is the drug of choice among uricosuric drugs. It is used as second line therapy because of Creatinine clearance of 50 ml/minute; which warrants monitoring serum Uric acid levels. Probenecid cannot be used as first line Monotherapy in case of Contraindication to at least one Xanthine oxidase inhibitor and when Creatinine clearance is below 50 ml/minute.

mg/dL was beneficial.

Anti cytokines

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

Prophylaxis to prevent acute gout flares during initiation of uric acid lowering therapy

A new trial suggests benefit from colchicine over placebo during the first 6 months of allopurinol therapy.

• 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.
• The first-line for this purpose is oral Colchicine , or low-dose NSAIDs. A randomized controlled trial found that colchicine was more effective than steroids for this purpose.
• 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. 
• The duration of treatment should be greater of at least 6 months, 3 months after achieving target serum urate levels in patient with no tophi on physical exam, or 6 months after achieving desired urate levels appropriate for the patient with one of more tophi. 

Management of chronic gout/chronic tophaceous gouty arthropathy:

Chronic gout can be managed by a combined approach of pharmacological and non pharmacological therapy.The goal is to attain a serum urate level less than 6 mg/dl. Maintaining serum urate levels as low as 5 mg/dl will improve the signs and symptoms of disease including palpable and visible tophi. This includes treatment options of Urate lowering therapy. Doses should be titrated by monitoring serum uric acid levels constantly until the target uric acid levels are achieved. Continued measurements for every 6 months should be obtained once the desired level is achieved. All of the following play a key role in maintaining desired serum uric acid levels.

• 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

• Dietary and lifestyle modification
• Careful review of patients medications and stopping those that elevate serum uric acid levels; for example, Thiazide diuretics, Loop diuretic, Niacin, and Calcineurin inhibitor.
• Evaluating 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.