Table 2 Consensus for 30 revised draft recommendations was reached after two rounds of a Delphi exercise

Who are the targeted patients?

Patients with any of the following: gout flare, recurrent gout flares (> 1 flare), subcutaneous tophi; refractory gout, gout in patients with CKD.

What is the treatment target?

All people with gout should be managed adopting a treat-to-target strategy with dose titration and subsequent dosing adjustment guided by serial serum urate assessments to achieve both:

a. Clinical cure; as well as

b. The targeted serum urate level is achieved with a fixed, standard dose of ULT (urate-lowering therapy).

Clinical cure: gout flares stop, tophi resolved.

Target serum urate <6mg/dL (360 μmol/L); preferable < 5mg/dL (300umol/L) for patients with severe gout (tophi, chronic arthropathy, frequent gout flare).

Serum urate should remain > 3 mg/dL (180 μmol/L) on the long term, as a potent antioxidant [31].

All patients taking ULT should continue taking their therapy lifelong to maintain the serum urate at the targeted level.

A comprehensive management protocol adopting treat to target approach should include patient education, shared decision-making, and a treat-to-target strategy.

What is the best strategy for the treatment of gout flare?

Patient education:

The gout flare should be treated as early as possible.

The patient should be aware of the importance of continuing any established ULT during the gout flare.

The patients should be informed and educated on how to self-medicate at the first warning symptoms.

Affected joints should be rested, elevated, and exposed in a cool environment, e.g., ice-packs.

Treatment Choice:

Should be considered bearing in mind:

1. The presence of contraindications and comorbidities,

2. The patient’s previous experience with treatments,

3. Time of initiation after the onset of the gout flare and the number and type of joint(s) involved.

4. Colchicine and NSAIDs should be avoided in patients with severe renal impairment.

5. Colchicine should not be prescribed for patients receiving strong P-glycoprotein and/or CYP3A4 inhibitors such as cyclosporin or clarithromycin.

Medication choice:

1. Colchicine (within 12 h of flare onset) at a loading dose of 1 mg followed 1 h later by 0.5 mg on day 1 and/or

2. A NSAID (tNSAID or Cox-2 inhibitor) (plus proton pump inhibitors (PPIs) if appropriate)

3. Oral corticosteroid (30–35 mg/day of equivalent prednisolone for 3–5 days) or

4. Intra-articular aspiration and injection of corticosteroids.

Follow up in 4 weeks (2–5 weeks??):

Assess for response to therapy. Assess for comorbidities (CVS factors: hypertension, lipids), diabetes Mellitus, obesity.

Assess for lifestyle factors: exercise, diet, alcohol, sugar intake.

Review current medications: stop thiazide diuretic.

Blood check for serum urate, renal functions.

No ULT is advised if this was the first gout flare.

Advice regarding prophylaxis:

Initiation of ULT is advised close to the time of the first diagnosis in patients presenting at [32]:

- A young age (< 40 years), or

- A very high SUA level (> 8.0 mg/dL; 480 μmol/L) and/or comorbidities (renal impairment (CKD > 3, hypertension, ischaemic heart disease, heart failure).

- Tophi

- Renal stones

What is the recommended duration of treatment of gout flare?

7–14 days (until flare resolves; otherwise, a rebound flare can occur)

What is the approach for the treatment of recurrent gout?

Urate-lowering therapy (ULT):

Initiating ULT is recommended for patients with any of the following: recurrent gout flares (> 1 flare) subcutaneous tophi; evidence of radiographic damage (any modality) attributable to gout. ULT should be considered and discussed with every patient with a definite diagnosis of gout from the first presentation adopting a shared decision-making approach.

ULT is not recommended for patients with asymptomatic hyperuricemia (no prior gout flares or subcutaneous tophi).

ULT is not recommended for patients experiencing their first gout flare.

Allopurinol is the preferred first-line agent, over all other ULTs, including patients with moderate-to-severe CKD (stage ≥ 3).

All ULTs should be started at a low dose and then titrated upwards until the targeted serum urate level is reached.

The targeted serum urate should be maintained lifelong.

What is the advised timing of starting ULT therapy?

Starting ULT treatment is best delayed until inflammation has settled as ULT is better discussed when the patient is not in pain.

Initiation of ULT therapy:

First line ULT: Allopurinol.

Start at a low dose of 50–100 mg/day. Titrate the dose of Allopurinol in 50-100mg every 4-weeks.

Target serum urate < 6 mg/dL (360 μmol/L); preferable < 5mg/dL (300 μmol/L) for patients with severe gout (tophi, chronic arthropathy, frequent gout flares).

Split the allopurinol dose if more than 30 mg dose/day.

Maximum dose 900 mg /day (in patients with normal renal functions).

Consider flare prophylaxis while initiating allopurinol therapy.

Do not stop Allopurinol therapy during gout flare.

When to consider switching ULT treatment?

- Intolerability to Allopurinol or - CKD preventing adequate dose escalation

- Persistently high serum urate concentrations (> 6 mg/dL) despite maximum-tolerated dose as per the guidelines.

- Patients who continue having frequent gout flares (> 2 flares/year) OR

- Patients who have non- resolving subcutaneous tophi.

Switching ULT therapy: - Consider switching to febuxostat 40–80 mg once daily.

- Increase febuxostat dose to 120 mg once daily after 4-weeks if the targeted serum urate level has been achieved.

- For people with gout with a history of CVD or a new CV event, caution should be considered, decision adjusted tailored to the patient’s cardiac status, when febuxostat is advised.

- Intolerability to febuxostat: Consider switching to uricosuric therapy (sulfinpyrazone or probenecid or benzbromarone)

- Titrate dose every 4-weeks according to serum urate

What is the management approach in case of failure to achieve targeted serum urate despite ULT dose escalation?

- Consider Uricosurics either as monotherapy or in combination with allopurinol

- Add-on therapy to partially responsive ULT therapy can result in improved serum urate control,

- Benzbromarone (50–200 mg/day) is a more potent uricosuric as compared with probenecid (1–2 g/day), bearing in mind its hepatotoxicity, so avoid its use in patients with hepatic disease, initiating treatment with low dose regimens, monitoring liver enzymes during treatment, and avoiding the association of benzbromarone with other hepatotoxic medicines [33].

- For patients considered for uricosuric therapy, there is no need to check for urinary urate.

- For patients considered for uricosuric therapy, it is not advised to recommend alkalinisation of the urine (lack of evidence for efficacy).

- Patients with known renal calculi or moderate-to-severe CKD (stage > 3) should not be treated with uricosurics.

- Adequate hydration is highly recommended for patients on uricosuric therapy, at least 1.5 L of fluid daily.

What is the best approach for prophylaxis against gout flare?

- Prophylaxis against flares should be fully explained and discussed with the patient

- Prophylaxis is recommended during the first 3-6 months of ULT [32].

- Medication choices for prophylactic treatment are:- colchicine, 0.5–1 mg/day, (the colchicine dose should be reduced in patients with renal impairment); or

- Prophylaxis with NSAIDs at low dosage (particularly If colchicine is not tolerated or is contraindicated), plus PPIs.

- One-off intramuscular injection of methylprednisolone 120 mg, then small doses of oral prednisolone.

- In cases receiving statin therapy, patients and physicians should be aware of potential neurotoxicity and/or muscular toxicity with prophylactic colchicine.

- Co-prescription of colchicine with strong P-glycoprotein and/or CYP3A4 inhibitors should be avoided.

- Prophylaxis with NSAIDs at low dosage, if not contraindicated, should be considered.

What is the best management approach for refractory gout?

Refractory gout flare: In patients with frequent flares and contraindications to colchicine, NSAIDs, and corticosteroids (oral and injectable), IL-1 blockers should be considered for treating flares. Current infection is a contraindication to the use of IL-1 blockers.

Refractory Chronic gout: Switching to pegloticase is recommended for people with gout for whom ULT treatment, uricosurics, (including combinations) and other interventions have failed to achieve the targeted serum urate, and who continue to have frequent gout flares (≥ 2 flares/year) or who have non-resolving subcutaneous tophi.

What is the strategy for long-term management of gout?

When to consider?

Treatment targets achieved: clinical cure (gout flares stop, tophi resolved); targeted serum urate (< 300 μmol/L).

Action: consider lowering the ULT dose to maintain the targeted serum urate (between 300 and 360 μmol/L).

Check serum urate every 6–12 months to ensure it is maintained within the targeted range (if elevated, adjust the ULT dose accordingly) [34].

Continue ULT lifelong.

What are the main points to be included in the patients’ education program for gout patients?

Information should be given to every person living with gout about the disease pathophysiology, the availability of effective treatments, and the associated comorbidities, and the basis of treating the gout flares and lowering the level of urate crystals through a lifelong treat to target management approach.

Lifestyle advice:

Optimize body weight (adopt a weight loss program) is advised for gout patients who are overweight/ obese, regardless of disease activity.

Significantly limiting alcohol intake (regardless of disease activity).

Limiting purine intake: avoid heavy meals and excessive intake of meat and seafood (regardless of disease activity).

Limiting sugar-sweetened drinks.

Adding vitamin C supplementation is not advised.

Should people with gout be screened for comorbidities?

Every person with gout should be systematically screened for associated comorbidities: -

- Cardiovascular risk factors, coronary heart disease, heart failure

- Hypertension

- Hyperlipidemia

- Diabetes Mellitus

- Renal impairment

- Stroke

- Peripheral arterial disease

- Obesity

- Smoking

What is the best approach for the management of gout in patients with CKD?

Patients with CKD:

- The allopurinol maximum dosage should be adjusted to creatinine clearance. If the SUA target cannot be achieved at this dose, the patient should be switched to febuxostat or given benzbromarone with or without allopurinol.

- Lowering the allopurinol starting dose according to the renal function level reduces the risk of allopurinol hypersensitivity, and the subsequent gradual increase in the dose above the dose based on eGFR is advised as it helps to reduce serum urate levels in most people with gout without any increase in toxicity.

Gout therapy in CKD (grade 3–5): ULT therapy:- Allopurinol is the first option, however, the starting dose and the maintenance doses should be distinguished.

- Starting regime of allopurinol should be adjusted to the individual patient’s eGFR. This will help to reduce the likelihood of developing a gout flare or allopurinol hypersensitivity syndrome (AHS), advised approach is as below:

- gradually increasing the allopurinol dose is advised till the target is achieved.

- Gout sufferers with creatinine clearances less than 30 mL/min typically require lower doses of allopurinol to achieve the same reductions in serum urate levels.

- should monitor for pruritis, rash, elevated hepatic transaminases, and eosinophilia.

There are insufficient data for febuxostat in patients with creatinine clearance <30 Uricosuric therapy:

- Benzbromarone: contraindicated if CrCl <20 mL/min

- Lesinurad: contraindicated if CrCl <45 mL/min

- Probenecid: Not effective if CrCl < 30 mL/min

Prophylaxis:-

- Colchicine: CrCl < 30 mL/min: initial dose: 0.3 mg/day, caution if up-titrated; monitor closely for adverse effects.

- NSAID: avoid

Management of flares:-

- Steroids: Dosage adjustment for CKD not required

- ACTH: Dosage adjustment for CKD not required

Is there a specific management strategy for people with gout on dialysis?

- Allopurinol: Intermittent (hemodialysis) HD: should be administered post-dialysis, start with 100 mg alternate days post-dialysis; daily HD: additional 50% of dose may be required post-dialysis; daily peritoneal dialysis (PD): start with 50 mg/day; all types of renal replacement therapy (RRT): up-titrate dose with 50 mg–increments every 2–5 weeks, measure serum urate pre-dialysis.

- Febuxostat: some successful reports of dialysis patients using febuxostat up to 80mg/day. No fully published trials.

- Uricosuric therapy: contraindicated in dialysis patients.

- Sevelamer: may be the phosphate binder of choice for patients with advanced CKD and gout, based on its urate-lowering effect.

Prophylaxis:-

- Colchicine: Not removed by dialysis; increased risk of myo/neurotoxicity.

- NSAID: may be considered.

Management of flares:

- Steroids: Dosage adjustment for CKD not required

- ACTH: Dosage adjustment for CKD not required

Are there specific recommendations for specific medications used commonly for patients with gout?

- When a gouty patient receiving loop or thiazide diuretics, substitute the diuretic is advised.

- An interaction between allopurinol and furosemide that results in increased serum urate and plasma oxypurinol concentrations has been reported.

- For hypertension consider losartan or calcium channel blockers

- For hyperlipidemia, consider a statin or fenofibrate.

Recommendations for Gout during pregnancy: gout is very uncommon in pre-menopausal women and in pregnancy, apart from patients with familial juvenile hyperuricaemic nephropathy, consequently, data are scarce.

- Conservative measures including ice are safe for managing gout flares.

- NSAIDs can be used in the mid-trimester.

- Steroids are generally safe to use in pregnancy

- The recommendations for lifestyle modifications including dietary changes are also safe.