Evidence reviews for pharmacological and non-pharmacological interventions for managing gout flares

Evidence reviews for pharmacological and non-pharmacological interventions for managing gout flares

Gout: diagnosis and management

Evidence review D

NICE Guideline, No. 219

London: National Institute for Health and Care Excellence (NICE); 2022 Jun.

ISBN-13: 978-1-4731-4603-7

1. Pharmacological and non-pharmacological interventions for managing gout flares

1.1. Review question: What is the clinical and cost effectiveness of pharmacological interventions (including NSAIDs, colchicine, corticosteroids and IL-1 inhibitors) and non-pharmacological interventions for managing gout flares?

1.1.1. Introduction

Recurrent flares are the most characteristic manifestation of gout and present with sudden onset of severe pain, swelling and inflammation, often overnight. Most flares present to and are managed in primary care.

Treatment of gout flares aims to provide rapid relief from joint pain and inflammation. The most commonly used pharmacological interventions to treat flares are non-steroidal anti-inflammatory drugs (NSAIDs), followed by colchicine and corticosteroids. However, many people with gout have contraindications to NSAIDs, such as peptic ulcer disease, chronic kidney disease and severe heart failure. Interleukin-1 inhibitors are a new approach to managing gout flares but are not commonly used in clinical practice. Non-pharmacological interventions such as rest and application of ice-packs to the affected joint are often employed as adjunctive treatment.

This evidence review will examine the clinical and cost effectiveness of pharmacological and non-pharmacological interventions to treat gout flares.

1.1.2. Summary of the protocol

For full details see the review protocol in Appendix A

Table 1

PICO characteristics of review question.

1.1.3. Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A and the methods document

Declarations of interest were recorded according to NICE’s conflicts of interest policy.

1.1.4. Effectiveness evidence

1.1.4.1. Included studies

Eleven randomised controlled studies were included in the review²⁵^,³²^,⁴⁶^,⁵³^,⁵²^,⁵¹^,⁶³^,⁶⁹^,⁸⁰^,⁴⁷^,³⁷ these are summarised in Table 2 below. Evidence from these studies is summarised in the clinical evidence summary below (Table 3 - Table 7).

The eleven randomised controlled studies evaluated pharmacological and non-pharmacological interventions for managing gout flares. One study evaluated the use of colchicine versus placebo. Four studies evaluated corticosteroids versus NSAIDs. Two studies compared NSAIDs versus colchicine. Three studies compared IL-1 inhibitors versus corticosteroids. One study compared ice therapy, corticosteroids and colchicine versus no ice therapy, corticosteroids and colchicine.

See also the study selection flow chart in Appendix C, study evidence tables in Appendix D, forest plots in Appendix E and GRADE tables in Appendix F.

1.1.4.2. Excluded studies

Five Cochrane reviews were excluded.²⁴^,⁶²^,⁷³^,⁷⁴^,⁷⁷ Janssens 2008²⁴ was excluded as two out of three included studies were not relevant, one of them had no pairwise analysis and another one included an inappropriate comparison (adrenocorticotropic hormone compared to triamcinolone). Sivera 2014⁶² was excluded because one of the included studies had an inappropriate intervention (Rilonacept compared to indomethacin) and for other three studies outcomes were extracted at different time points (at 72 hours), whereas we used the last available timepoint across reviews. In this case the last available timepoint was 7 days. Van 2014⁷³ was excluded as only three out of twenty-three included studies were relevant. Studies were excluded due to inappropriate intervention, inappropriate comparison or they were not available. Van Echteld 2014⁷⁴ was excluded because one of two included studies used a very high dose of colchicine [6.7 mg] and common practice is 1 - 2 mg of Colchicine per day. Therefore, this study (Ahern 1987)¹ was excluded from our review. The other study (Terkeltaub 2010)⁶⁹ included high dose colchicine and low dose colchicine. We analysed the low dose and removed the high dose data. Wechalekar 2013⁷⁷ was excluded because this review had no included studies. All included studies in all five Cochrane reviews were checked for inclusion and 6 of them were included in our review

See the excluded studies list in Appendix J.

1.1.5. Summary of studies included in the effectiveness evidence

Table 2

Summary of studies included in the evidence review.

See Appendix D for full evidence tables.

1.1.6. Summary of the effectiveness evidence

Table 3

Clinical evidence summary: Colchicine versus placebo.

Table 4

Clinical evidence summary: Corticosteroids versus NSAIDs.

Table 5

Clinical evidence summary: NSAIDs versus colchicine.

Table 6

Clinical evidence summary: IL-1 inhibitors versus corticosteroids.

Table 7

Clinical evidence summary: ice plus prednisone and colchicine versus prednisone and colchicine.

See Appendix F for full GRADE tables

1.1.7. Economic evidence

1.1.7.1. Included studies

One health economic study comparing naproxen and low-dose colchicine was included in this review⁴⁷. This is summarised in the health economic evidence profile below (Table 8) and the health economic evidence table.

No additional health economic analyses comparing the other relevant comparisons listed in the protocol were identified for this review.

1.1.7.2. Excluded studies

No relevant health economic studies were excluded due to assessment of limited applicability or methodological limitations.

See also the health economic study selection flow chart.

1.1.8. Summary of included economic evidence

Table 8

Health economic evidence profile: naproxen versus low-dose colchicine.

1.1.9. Economic model

This area was not prioritised for new cost-effectiveness analysis.

1.1.10. Unit costs

Relevant unit costs are provided below to aid consideration of cost effectiveness.

Table 9

UK cost of NSAIDs for people without CKD.

Table 10

UK cost of NSAIDs for people with CKD stage 3.

Table 11

UK cost of NSAIDs for people with CKD stage 4-5.

Table 12

UK cost of Colchicine.

Table 13

UK cost of Corticosteroids.

Table 14

UK cost of proton pump inhibitors (PPI’s).

Table 15

UK cost of IL-1 Inhibitors.

1.1.11. Evidence statements

Economic

One cost-utility analysis found that naproxen was cost effective compared to low-dose colchicine for the treatment of gout flares. Naproxen was the dominant strategy (less costly and more effective). This analysis was assessed as partially applicable with minor limitations.

1.1.12. The committee’s discussion and interpretation of the evidence

1.1.12.1. The outcomes that matter most

The committee considered the following outcomes as important for decision-making: health-related quality of life, pain, joint swelling/joint inflammation, joint tenderness, patient global assessment of treatment success, adverse events (cardiovascular, renal and gastrointestinal), admission (hospital and A&E/urgent care) and GP visits.

The committee decided to combine joint swelling and joint inflammation as they agreed that these outcomes are synonymous for people with gout. The committee also agreed to categorise timepoints reported in the included studies by short-term (up to two weeks), medium-term (two to six weeks) and long-term (more than six weeks).

1.1.12.2. The quality of the evidence

Eleven randomised controlled trials (RCTs) evaluating pharmacological therapy and one randomised controlled trial (RCT) evaluating combination therapy (pharmacological and non-pharmacological interventions) for managing gout flares were included in this review.

One RCT evaluated the use of colchicine versus placebo. The evidence was limited as only two outcomes were reported by the study. The outcome data was only available for pain (proportion of joints with 50% or greater decrease in pain score (on VAS) from baseline) and gastrointestinal adverse events (diarrhoea and vomiting). Both were reported as short-term outcomes (up to 2 weeks). The quality of pain (proportion of joints with 50% or greater decrease in pain score (on VAS) from baseline) outcome was graded as moderate due to high risk of selection bias. The quality of the gastrointestinal adverse events outcome was graded very low due to high risk of selection bias and imprecision.

Four studies evaluated the use of corticosteroids versus NSAIDs. The outcome data was reported for pain (VAS, number of patients with clinically significant change in pain score at rest and number of patients with clinically significant change in pain score with activity), joint tenderness, adverse events (gastrointestinal and cardiovascular), number of patients visited ED, number of patients visited outpatient department and GP visits. All outcomes were reported as short-term (up to 2 weeks). The quality of evidence ranged from high to low quality due to lack of blinding, imprecision and inconsistency.

Two studies compared NSAIDs versus colchicine. The outcome data was reported for pain (change score), complete pain resolution, joint swelling scores, patient assessment of global treatment response (completely/much better), adverse events (gastrointestinal), number of patients visited ED and GP visits. Outcomes were reported as short term (up to 2 weeks) and medium-term (2 to 6 weeks). The quality of evidence ranged from high to very low quality due to lack of blinding, attrition bias and imprecision.

Three studies compared IL-1 inhibitors versus corticosteroids. The outcome data was reported for health-related quality of life SF 36 (physical and mental components), pain (VAS and VAS % change), joint swelling, joint tenderness, patient global assessment (OR), patient global assessment (good or excellent) and adverse events (any). Outcomes were reported as short term (up to 2 weeks) and long-term (more than 6 weeks). The quality of evidence ranged from moderate to very low quality due selection bias, lack of blinding and imprecision.

One study compared ice therapy plus corticosteroids and colchicine versus no ice therapy plus corticosteroids and colchicine. The outcome data was only reported for pain (VAS) and joint circumference (joint swelling). Both outcomes were reported as short-term (up to 2 weeks). The quality of evidence ranged from low to very low quality due to selection bias, lack of blinding and imprecision.

1.1.12.3. Benefits and harms

The evidence showed a clinical benefit for colchicine when compared with placebo for reducing pain (50% or greater decrease in pain scores from baseline), however the evidence indicated clinical harm for gastrointestinal adverse events (diarrhoea and vomiting) in the colchicine group in the short-term (up to 2 weeks).

The evidence showed a clinical benefit for corticosteroids when compared to NSAIDs for short-term (up to 2 weeks) gastrointestinal adverse events (abdominal pain, indigestion, nausea, vomiting, diarrhoea and GI haemorrhage). The evidence suggested that there was no clinically important difference for pain, joint tenderness, cardiovascular adverse events, number of patients who visited emergency and outpatient departments, and G.P. visits.

The evidence showed a clinical benefit for NSAIDs when compared to colchicine for short-term (up to 2 weeks) gastrointestinal adverse events (nausea and or vomiting, diarrhoea and constipation). There was no difference for abdominal pain, dyspepsia or vomiting at 2 weeks or any of these outcomes in the medium-term (2 to 6 weeks). The evidence suggested that there was no clinically important difference for pain outcomes (change score, complete pain resolution at short-term (up to 2 weeks) and medium term (2 to 6 weeks), joint swelling scores, patient assessment of global treatment response (completely/much better at short-term (up to 2 weeks) and medium-term (2 to 6 weeks)), number of patients visiting ED (medium-term 2 to 6 weeks) and number of GP visits (medium-term 2 to 6 weeks).

The evidence showed a clinical benefit for IL-1 inhibitors compared to corticosteroids for health related quality of life outcomes: SF36 physical component at short term (up to 2 weeks) and long-term (more than 6 weeks), SF-36 mental component long-term (more than 6 weeks), pain outcomes (VAS and VAS % change both short-term up to 2 weeks) and participant global assessment of response to treatment (good or excellent short up to 2 weeks). The evidence showed clinical benefit for corticosteroids compared to IL-1 inhibitors for any adverse events in the short-term. For joint swelling, joint tenderness and patient global assessment outcomes absolute effects and clinical significance could not be estimated as studies only reported odds ratios and did not report means separately for intervention and control arms, but the results favoured corticosteroids.

The evidence showed a clinical benefit for combination therapy ice and corticosteroid and colchicine compared with no ice therapy and corticosteroid and colchicine for pain (VAS). The evidence suggested no clinical difference for joint circumference (joint swelling).

Treatment options for managing gout flares

Overall, the evidence showed no clinical difference for NSAIDs compared to colchicine and corticosteroids for most of the outcomes. There was some evidence of benefit for colchicine when compared to placebo for pain outcome. However, there was also evidence of harm for colchicine when comparing both to placebo and NSAIDs for gastrointestinal adverse events. The evidence also suggested that there is clinical benefit for corticosteroids when compared to NSAIDs for gastrointestinal adverse events. The committee discussed that in current practice NSAIDs, or colchicine would usually be prescribed first before using corticosteroids. The committee discussed when considering treatments for older patients, colchicine would not be the first choice because of risk of side effects, and when prescribing corticosteroids, the lowest dose would be used. The committee also noted NSAIDs are potentially nephrotoxic, with renal adverse effects including AKI, renal disease progression and hyperkalaemia. The risks are highest in those with more advanced CKD and are increased in older people and those taking inhibitors of the RAS and diuretics. They agreed NSAIDS would be prescribed taking into account patient characteristics, the CKD stage and duration of therapy.

After reviewing the evidence, the committee agreed that the evidence was not strong for any of the drugs and concluded recommendations should reflect current practice of considering either NSAIDs, colchicine or a corticosteroid based on the presence of any comorbidities, other medications being taken and the preference of the patient.

Based on their experience the committee decided to recommend considering co-prescribing proton pump inhibitor (PPI) for people taking an NSAID for a flare. They acknowledged PPI are not always prescribed if NSAIDS were only to be taken for a short period of time.

The committee noted intra-articular and intra-muscular corticosteroids are more commonly used to manage gout flare in secondary care than in GP practices, Oral corticosteroid can be given as a first-line option but corticosteroid by injection could be considered.

IL-1 inhibitors showed clinical benefit when compared to corticosteroids for the vast majority of outcomes, however the committee agreed the cost of IL1-inhibitors is high and there are effective alternative drugs available and therefore this drug would not usually be considered for the vast majority of people with a flare. The committee noted this treatment is used in very few centres in the UK and would only be considered appropriate for a very small population such as people with contraindications or non-response to all NSAIDS, colchicine and corticosteroids. Therefore, the committee decided to make a “do not offer” recommendation for IL-1 inhibitors unless the other drugs had been tried or were contraindicated or not tolerated.

The evidence showed clinical benefit for ice therapy compared to no ice therapy for pain (VAS) outcome. The committee considered evidence from only one small study to be limited, however in their experience applying ice can help to ease pain and inflammation and it is a simple and inexpensive treatment people can try. Therefore, the committee decided to recommend ice therapy as an adjunct to pharmacological treatments.

1.1.12.4. Cost effectiveness and resource use

One economic evaluation was identified for this review. The included health economic study compared naproxen to low-dose colchicine, illustrating that naproxen was the dominant strategy (less costly and more effective). In addition, naproxen had an 80% chance of being cost effective at NICE’s £20,000 threshold. The included health economic evidence only evaluated the cost effectiveness of naproxen and low dose colchicine and did not include other drugs relevant to this review question (NSAIDs other than naproxen, corticosteroids and IL-1 inhibitors), therefore unit costs were also presented to aid committee consideration of cost effectiveness.

The committee discussed the limitations of the included health economic study, noting that the cost of PPIs were not included for the total costs of naproxen. Although, the committee noted the cost of PPIs are relatively cheap, costing £0.06 – £0.98 per unit. The committee also acknowledged that PPIs may not be prescribed to all patients receiving NSAIDs if the duration of treatment is short and not anticipated to be long-term. For example, PPIs may not be required if a person is only anticipated to receive NSAIDs for the treatment of gout flares and they are only expected to experience one or two gout flares per year (where flares last for an average duration of four to five days)..

Considering the costs of PPIs and the costs presented in the included health economic study, the committee concluded the overall results of the cost effectiveness analysis would unlikely be changed if the costs of PPIs had been included in the analysis. The total costs for naproxen and colchicine presented in the health economic study were £17.57 and £23.31 respectively. In the analysis, naproxen was prescribed for a total of seven days, therefore assuming a cost of £0.06 - £0.98 per day for the cost of a PPI, the total cost for naproxen would increase by £0.42 - £6.86 – resulting in a total cost of £17.99 - £24.43. Although £24.43 is more expensive than the total cost of colchicine (£23.31). The committee noted that the range for the cost of PPIs was predominately driven by the cost of Omeprazole 40mg, costing £0.98. Excluding the cost of Omeprazole 40mg, the cost of PPIs ranges from £0.06 - £0.49. When PPIs cost a maximum £0.49 the total cost for naproxen is £19.74 which is cheaper than the total cost of colchicine (£23.31).

The committee noted the use of PPIs would not affect the effectiveness of NSAIDs and so naproxen would still be the dominant strategy (less costly and more effective) when all PPIs, except Omeprazole 40mg, are prescribed. When Omeprazole 40mg is prescribed, naproxen is more costly and more effective and the ICER is £2,800 per QALY gained. However, in general, the committee did note that the time horizon of the analysis (4 weeks) was not sufficiently long enough to capture the long-term adverse events for not prescribing a PPI.

Overall although the included health economic study illustrated that naproxen was the dominant strategy compared to low dose colchicine, due to potential limitations of this study and committee opinion, the committee made an ‘offer’ recommendation for; NSAIDs, low dose colchicine, and prednisolone as a first-line treatment for a gout flare. The committee noted that when prescribing therapeutic treatment for a gout flare – in the form of NSAIDs, low dose colchicine and oral prednisolone – it is important to take account of patient comorbidities, co-prescribing and patient preferences. The committee also considered the costs of NSAIDs, low dose colchicine, and prednisolone and concluded that all interventions would be cost effective at NICE’s £20,000 threshold, whereby the most cost-effective intervention would be patient specific. For example, in people where NSAIDs or low dose colchicine are contraindicated or not tolerated, oral prednisolone would be the most cost-effective drug for managing gout flares. This recommendation is not expected to result in a substantial resource impact as the recommendation is reflective of current practice in England.

The committee discussed that in instances where NSAIDs, low dose colchicine or oral prednisolone are contraindicated, not tolerated or not effective, intra-articular or intra-muscular corticosteroid injection may also be appropriate. The committee acknowledged that, if clinically appropriate, oral prednisolone should be prescribed as a first-line corticosteroid because oral prednisolone is cheaper than intra-articular or intra-muscular corticosteroid injections. Oral prednisolone costs £0.18 per day and is typically prescribed for five days, costing £0.90. Intra-articular or intra-muscular injections cost £1.49 - £12.00 per injection but will also have additional costs in terms of nurse administration time. Overall, the committee made a ‘consider’ recommendation for the use of, intra-articular or intra-muscular corticosteroid injections. This recommendation is not expected to have a substantial resource impact as it is reflective of current practice.

The committee also discussed the use of IL-1 inhibitors, noting that less than 1% of gout patients would be prescribed an IL-1 inhibitor for treatment of a gout flare. Clinical evidence was presented comparing canakinumab and intramuscular corticosteroids (triamcinolone). However, the cost of canakinumab is much greater than triamcinolone (£9,927 and £0.89 - £12.00 per injection respectively) therefore the committee concluded it was highly unlikely Canakinumab would be an effective use of NHS resources.

The committee also discussed the use of anakinra, which is the additional IL-1 inhibitor included in the clinical protocol. No clinical evidence was presented for anakinra, but the committee noted Anakinra is substantially cheaper than canakinumab. Anakinra costs £26.23 per unit and typically three to five doses of anakinra will be given to people for management of a gout flare, costing £78.69 - £131.15. Conversely, canakinumab costs £9,928 per unit, with one injection given for the treatment of a gout flare.

Overall, IL-1 inhibitors are substantially more expensive than NSAIDs, low dose colchicine, and corticosteroids. Therefore, the committee made a ‘do not offer’ recommendation for the use of IL-1 inhibitors. The committee did however acknowledge that in clinical practice IL-1 inhibitors are sometimes prescribed for patients with the most severe gout where all other treatment options have failed, noting people should be referred to rheumatology services before prescribing an IL-1 inhibitor. Based on clinical experience, the committee concluded that IL-1 inhibitors could be cost effective for patients where NSAIDs, low dose colchicine, and corticosteroids are contraindicated or not tolerated because gout flares can be extremely painful. This recommendation is not expected to have a substantial resource impact as it is reflective of current practice.

Non-pharmacological interventions for managing gout flares are typically recommended in conjunction with pharmacological interventions. The cost of ice is borne by patients themselves and so will not have a substantial resource impact.

1.1.13. Recommendations supported by this evidence review

This evidence review supports recommendations 1.3.1 to 1.3.5 and the research recommendation on the clinical and cost effectiveness of colchicine compared with corticosteroids for managing gout flares?

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Appendices

Appendix A. Review protocols

Review protocol for pharmacological and non -pharmacological interventions for managing gout flares (PDF, 194K)

Health economic review protocol (PDF, 139K)

Appendix B. Literature search strategies

What is the clinical and cost effectiveness of pharmacological interventions (including NSAIDs, colchicine, corticosteroids and IL-1 inhibitors) and non-pharmacological interventions for managing gout flares?

The literature searches for this review are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual.⁴¹

For more information, please see the Methodology review published as part of the accompanying documents for this guideline.

B.1. Clinical search literature search strategy (PDF, 214K)

B.2. Health Economics literature search strategy (PDF, 171K)

Appendix I. Health economic model

No original health economic modelling was undertaken for this review question.

Appendix J. Excluded studies

Clinical studies

Download PDF (140K)

Health Economic studies

None.

Appendix K. Research recommendation – full details

F.1.1. Research recommendation

In people with gout (including people with gout and chronic kidney disease), what is the clinical and cost effectiveness of colchicine compared with corticosteroids for managing gout flares?

F.1.2. Why this is important

Gout flares are excruciatingly painful and require rapid treatment with non-steroidal anti-inflammatory drugs (NSAIDs), colchicine or corticosteroids. Flares are most frequently treated with NSAIDs, although many people with gout have contraindications to NSAIDs, e.g. chronic kidney disease or cardiovascular disease. RCTs show that NSAIDs have similar effectiveness for flares to colchicine and corticosteroids, however, there has never been a direct comparison of the effectiveness and safety of colchicine and corticosteroids.

F.1.3. Rationale for research recommendation

Download PDF (149K)

F.1.4. Modified PICO table

Download PDF (135K)

Final

Evidence reviews underpinning recommendations 1.3.1 to 1.3.5 and research recommendations in the NICE guideline

National Institute for Health and Care Excellence

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK583527PMID: 36063467

Table 1PICO characteristics of review question

Population	Inclusion: Adults (18 years and older) with gout flares Strata: People with chronic kidney disease (stage 3) People with chronic kidney disease (stage 4-5) People without chronic kidney disease or people with CKD stages 1-2 Mixed population (people with CKD and people without CKD) Exclusion: People with calcium pyrophosphate crystal deposition, including pseudogout
Intervention(s)	NSAIDs (commonly used in clinical practice in the UK) Celecoxib Diclofenac sodium Etoricoxib Ibuprofen Indomethacin Meloxicam Naproxen Colchicine Corticosteroids (commonly used in clinical practice in the UK) Methylprednisolone Prednisolone Triamcinolone IL-1 inhibitors (commonly used in clinical practice in the UK) Anakinra Canakinumab Non-pharmacological interventions - rest, elevation, bed cages and ice Combinations (pharmacological + non-pharmacological) Combine all doses (doses much higher than standard doses will be excluded) Within drug class comparisons will not be made, e.g. IL-1 inhibitors will be combined in analyses
Comparison(s)	Compared to each other Standard care/usual care Control/no intervention Placebo
Outcomes	All outcomes are considered equally important for decision making and therefore have all been rated as critical: health-related quality of life (e.g. as described by SF-36, Gout Assessment Questionnaire (GAQ) and the Gout Impact Scale (GIS) or other validated gout-specific HRQoL measures pain (measured on a visual analogue scale (VAS) or numerical rating scale such as the five-point Likert scale, or reported as pain relief of 50% or greater) joint swelling/ joint inflammation joint tenderness patient global assessment of treatment success (response to treatment) (e.g. Likert scales, visual analogue scales (VAS), numerical ratings scales (NRS)) adverse events – (1) cardiovascular, (2) renal and (3) gastrointestinal (e.g. diarrhoea) admissions (hospital and A&E/urgent care) GP visits Timepoints: short-term (up to two weeks), medium-term (two to six weeks) and long-term (> six weeks)
Study design	RCT Systematic reviews of RCTs If insufficient RCT evidence is available (no or little evidence for interventions/comparisons), search for non-randomised studies (prospective and retrospective cohort studies will be considered if they adjust for key confounders: Age Gender Previous treatment (non-pharmacological and pharmacological use) Published NMAs will be considered for inclusion.

Table 2Summary of studies included in the evidence review

Study

Intervention and comparison

Population

Outcomes

Comments

Janssens 2008²⁵

RCT

Intervention (n=60)

Corticosteroids - Prednisolone 35mg once a day and look alike placebo naproxen twice a day for 5 days.

Concurrent medication/care: no NSAIDs or other analgesics (including colchicine) within 24 h before baseline assessments or for the duration of the trial.

Comparison (n=60)

NSAIDs - Naproxen 500 mg twice a day and placebo capsule prednisolone for 5 days.

n=120

Participants were patients with monoarticular gout arthritis confirmed by identification of monosodium urate crystals in the synovial fluid of the affected joint

Age - mean years (SD): Prednisolone group 57.3 (12.2), naproxen group 57.7 (13.4).

Gender (M:F): Prednisolone group 54/6, naproxen group 53/7.

Ethnicity: not reported

Netherlands

Pain (VAS) at 90 hours

Adverse events - gastrointestinal at 90 hours

Liu 2019³²

RCT

Intervention (n=61)

Colchicine. Patients in the colchicine group received colchicine 0.5 mg orally, 3 times daily, for 5 days, later changed to once daily (“later” was not specified)

Comparison (n=61)

NSAIDs - Etoricoxib. Patients in the etoricoxib group received etoricoxib 120mg orally (Hangzhou MSD Pharmaceutical Co., Ltd), once daily, for 5 days, later changed to 60 mg orally once daily. (“Later” was not specified)

n=122

Patients from 18 to 70 years old with newly diagnosed acute gouty arthritis; an onset of acute gouty arthritis duration of less than 48 h and no administration of colchicine, NSAID or glucocorticoids; no administration of medications affecting uric acid metabolism over the last 3 months; without diseases affecting uric acid metabolism.

Age - mean years (SD): Etoricoxib group 44(9); Colchicine 43(9)

Gender (M:F): Etoricoxib group 49/4; Colchicine 47/5

Ethnicity: not reported

China

Joint pain scores at 10 days

Adverse events – gastrointestinal at 10 days

Gastrointestinal events included: diarrhoea, vomiting

Man 2007³⁷

RCT

Intervention (n=46)

NSAIDs - Indomethacin. In the indomethacin group, each patient initially received diclofenac (3 mL; 75mg) intramuscularly, indomethacin 50 mg orally, acetaminophen 1 g orally, and 6 tablets of prednisolone like placebo orally and was observed for 120 minutes. The patient was then given a 5-day prescription of indomethacin (50 mg orally every 8 hours for 2 days, followed by indomethacin 25 mg every 8 hours for another 3 days), 6 tablets of prednisolone-like placebo once a day, and acetaminophen 1 g every 6 hours as required. Duration 5 days.

Comparisons (n=44)

Corticosteroids - Prednisolone. In the prednisolone group, each patient initially received an intramuscular placebo injection (3 mL), prednisolone 30 mg (6 times 5 mg) orally, acetaminophen 1g (2 tablets) orally, and indomethacin-like placebo (2 tablets) orally and was then observed for 120 minutes. The patient was then given a 5-day prescription of indomethacin-like placebo, prednisolone 30 mg orally once per day, and acetaminophen 1g every 6 hours as required.

n=90

Patients were included if they had a clinical diagnosis of acute arthritis suggestive of gout.

Age - mean years (SD): Indomethacin 66 (16) Prednisolone 64 (15)

Gender (M/F): Indomethacin 39/7, Prednisolone 35/9

Ethnicity: not reported

Australia

Adverse events – gastrointestinal events at 14 days

Adverse events – cardiovascular events at 14 days

Gastrointestinal events included: epigastric pain, other abdominal pain, indigestion, vomiting, diarrhoea, gastrointestinal haemorrhage and nausea.

Cardiovascular events included: chest pain

Rainer 2016⁴⁶

RCT

Intervention (n=208)

NSAIDs - Indomethacin. In the indomethacin group, patients initially received 50 mg (two 25-mg tablets) of oral indomethacin 3 times a day and 6 tablets of oral placebo prednisolone once a day for 2 days, followed by 25 mg of indomethacin 3 times a day and 6 tablets of placebo prednisolone once a day for 3 days.

Comparison (n=208)

Corticosteroids - Prednisolone. In the prednisolone group, patients initially received 30 mg (three 10-mg tablets) of oral prednisolone once a day and 2 tablets of placebo indomethacin 3 times a day for 2 days, followed by 30 mg (three 10-mg tablets) of prednisolone once a day and 1 tablet of placebo indomethacin 3 times a day for 3 days. Patients took the first dose in the presence of one of the investigators.

n=416

Patients with the diagnosis of acute gout

Age - mean years (SD): Indomethacin group 64.37(16.01); Prednisolone group 65.91(14.95)

Gender (M/F): Indomethacin group 164/44; Prednisolone group 145/63

Ethnicity: not reported

Hong Kong (China)

Patients with clinically significant change in pain score (13 mm on a 100-mm VAS) - at rest at 14 days

Patients with clinically significant change in pain score (13 mm on a 100-mm VAS) - with activity at 14 days

Joint tenderness (mean change from baseline to day 14) at 14 days

Adverse events - gastrointestinal

Visited ED at 14 days

Visited Outpatient department at 14 days

GP visits at 14 days

Gastrointestinal events included: nausea, vomiting, abdominal pain, indigestion.

Roddy 2020⁴⁷

RCT

Intervention (n=200)

NSAIDs – Naproxen - Single initial dose of oral naproxen 750 mg (three 250 mg tablets) followed by 250 mg (one tablet) every 8 hours for up to 7 days. Co-prescription of a proton-pump inhibitor was at the GP’s discretion.

Comparison (n=199)

Oral colchicine 500 mg (one tablet) every 8 hours for 4 days. Participants prescribed a statin were advised to omit the statin during colchicine treatment

n=399

Participants consulting for a current gout flare

Age mean- years (SD): Naproxen group - 58.7(14.4), Colchicine 60 (13.4)

Gender (M/F): Naproxen group - 173/27; Colchicine group - 174/25

Ethnicity: not reported

Complete pain resolution at 7 days

Complete pain resolution at 4 weeks

Patient assessment of global treatment response (completely/much better) at 7 days

Patient assessment of global treatment response (completely/much better) at 4 weeks

Adverse events – gastrointestinal events at 7 days

Adverse events – gastrointestinal events at 4 weeks

Consultation re-attendance for gout during 4-week follow-up - emergency department

Consultation Re-attendance for gout during 4-week follow-up - GP at 4 weeks

Gastrointestinal events included: nausea and vomiting, diarrhoea, dyspepsia, constipation, abdominal pain

Saag, 2021⁵⁰

Intervention (n=56)

IL-1 inhibitors - Anakinra 100 mg by subcutaneous injection

Comparison (n=55):

Corticosteroids - Triamcinolone 40mg single injection on day 1

N= 165 (111 used in this analysis as anakinra 200mg group was not relevant to this review)

Patients having a gout flare and who have had ≥1 episode of intolerance or non-responsiveness to NSAIDs and colchicine.

Age (median, range): Anakinra 100mg group: 53.5 (25-79), Triamcinolone group: 56.0 (30-83)

Gender: Anakinra 100mg group: 48 males (85.7%)

Triamcinolone group: 48 males (87.3%)

Ethnicity: Anakinra 100mg group: White 38 (67.9%), Black 15 (26.8%), Asian 3 (5,4%)

Triamcinolone group: White 39 (70.9%), Black 15 (27.3%), Asian 1 (1.8%)

Pain - VAS change from baseline at 24-72 hours from the start of flares 1, 2 and 3 (during the 5 days treatment period)

Any adverse event during the study period, including the extension period (up to 2 years)

There were two anakinra groups, only the 100mg group was relevant to the protocol and was included.

Previous non-response to NSAIDs/colchicine

Schlesinger 2002⁵³

RCT

Intervention (n=10)

Combination interventions - Pharmacological plus non-pharmacological. received topical ice therapy, oral corticosteroids (prednisone tapered from 30 mg to 0 over 6 days (30 mg 2 days, 20 mg × 2 days, 10 mg × 2 days) and colchicine 0.6 mg/day. Ice therapy, by application of ice packs with self-ties on the inflamed target joint for 30 min 4 times/day, was given to all patients in Group A. The patients were followed for one week.

Comparison (n=9)

No Ice therapy + oral corticosteroids (prednisone tapered from 30 mg to 0 over 6 days (30 mg 2 days, 20 mg × 2 days, 10 mg × 2 days) and colchicine 0.6 mg/day. No ice therapy. Duration 6 days.

n=19

Patients with acute gouty attacks

Age - mean (SD): age not reported

Gender (M/F): age not reported

Ethnicity: not reported

USA

Pain at 1 week

Joint swelling/joint inflammation - joint circumference (cm) at 1 week

Schlesinger 2012⁵¹: β-RELIEVED trial and β-RELIEVED II trial RCT

β-RELIEVED trial: Intervention - (n=115):

IL-1 inhibitors - Canakinumab. canakinumab single dose 150 mg by subcutaneous injection

Comparison (n=115):

Corticosteroids - Triamcinolone acetonide single dose 40 mg intramuscular injection.

β-RELIEVED-II trial:

Intervention (n=112):

IL-1 inhibitors - Canakinumab. canakinumab single doses 150 mg by subcutaneous injection

Comparison (n=114):

Corticosteroids - Triamcinolone. Triamcinolone acetonide 40 mg intramuscular injection (B-RELIEVED-II sub-study). Duration single dose.

n=456

Patients with acute arthritis of primary gout, with a history of ≥ three self-reported flares in the previous 12 months, having an acute flare for ≤five days characterised by baseline pain intensity ≥50 mm on a 0–100 mm visual analogue scale (VAS)

Age - mean years (SD): Canakinumab group - 52.3 (11.8), triamcinolone group 53.6(11.5)

Gender (M/F): 414/40

Ethnicity (%): Canakinumab group - Caucasian 74.2 %, Black – 11.6%; Asian −5.8%; Other – 8.419 Triamcinolone group - Caucasian – 76.9%; Black – 10.5%; Asian −5.2%; Other 7.4%

USA

Physician assessment of swelling (OR) - β-RELIEVED at 7 days

Pain 100-mm visual analogue scale at 72 hours (B-Relieved)

Physician assessment of tenderness (OR) - β-RELIEVED at 7 days

Patient global assessment (OR) - β-RELIEVED at 7 days

Any adverse event - β-RELIEVED - long term at 24 weeks

Physician assessment of swelling (OR) - β-RELIEVED-II at 7 days

Pain 100-mm visual analogue scale at 72 hours (B-Relieved-II)

Physician assessment of tenderness (OR) - β-RELIEVED at 7 days

Patient global assessment (OR) - β-RELIEVED-II at 7 days

Any adverse event - β-RELIEVED-II - long term at 24 weeks

The study also reported all outcomes at 72 hours

So 2010⁶³ (Schlesinger 2011⁵²)

RCT

Intervention (n=28):

IL-1 inhibitors - Canakinumab. Canakinumab 150 mg by subcutaneous injection and saline by intramuscular injection

Comparison (n=57):

Corticosteroids - Triamcinolone. triamcinolone acetonide (40 mg) intramuscularly and a subcutaneous placebo injection on day 1

n=85

Patients with a history of at least 1 previous gout flare, also required to have had an acute gout flare for ≤5 days, have a baseline pain intensity of ≥50 mm on a visual analogue scale (VAS) ranging from no pain (0 mm) to unbearable pain (100 mm),

Age - mean years (SD): Canakinumab 50.6(15.38); Triamcinolone acetonide 52.4(11.55)

Gender (M:F): Canakinumab 28/0; Triamcinolone acetonide 55/2

Ethnicity:

Canakinumab vs triamcinolone acetonide

White 85.7% vs 94.7%

Black 3.6% vs 5.3%

Asian 7.1% vs 0%

Other 3.6% vs 0%

USA

SF 36 - physical component at 7 days

Pain - VAS change from baseline at 7 days

Patient global assessment - Excellent at 7 days

Patient global assessment - Good at 7 days

Any adverse events at 7 days

Dose ranging study 150 mg single dose of Canakinumab was used for this review

Other doses (not relevant): 10 mg, 25 mg, 50 mg or 90mg as a single dose;

Terkeltaub 2010⁶⁹

RCT

Intervention (n=74)

Colchicine - (1.2 mg followed by 0.6 mg in 1 hour followed by placebo doses every hour for 5 hours [1.8 mg total])

Comparison (n=59)

Placebo - (2 placebo capsules initially, followed by 1 placebo capsule every hour for 6 hours).

n=185

Male and postmenopausal female patients ≥18 years of age with a confirmed past diagnosis of gout (according to the American College of Rheumatology [ACR] classification criteria and having had ≥2 gout flares within the prior 12 months were eligible for randomization.

Age - mean years (SD): 51.5 (11.12)

Gender (M/F): 176/9

Ethnicity:

Colchicine vs placebo

American Indian/Alaska Native – 1.4% vs 0%

Asian – 1.4% vs 1.7%

Black/African American – 5.4% vs 18.6%

White/Caucasian – 89.2% vs 79.7%

Other – 2.7% vs 0%

USA

Pain - treatment response based on target joint pain score 32 hours after first dose - ≥ 50% pain reduction (number of patients) at 32 hours

Adverse events Gastrointestinal

Low dose of Colchicine was used for this review

Another dose was reported (not relevant) - high dose - (1.2 mg followed by 0.6 mg every hour for 6 hours [4.8 mg total]))

Adverse events included: diarrhoea, nausea, vomiting

Xu 2016⁸⁰

RCT

Intervention (n=41)

Corticosteroids - Prednisolone (35 mg daily,

Comparison 1 (n=46)

NSAIDs - Etoricoxib (120 mg qd, Duration 4 days.

Comparison 2 (n=45)

NSAIDs - Indomethacin. Etoricoxib (120 mg daily, Duration 4 days

n=132

Inclusion criteria were: 1) gout attacks within 72 hours of screening; 2) The degree of pain in the index joint was at least moderate (2 on a 5-point Likert scale) at baseline; and 3) the index joint was defined as the joint that was the most painful at the time of randomization.

Age - mean (SD): prednisolone group - 44.03 (15.37), Etoricoxib 44.43 (15.08), indomethacin 43.81 (12.29).

Gender (M:F): male (%) prednisolone group - 100%, Etoricoxib 100%, indomethacin 97.2%.

Ethnicity: not reported

China

Pain at 4 days

Swelling at 4 days

Joint tenderness at 4 days

Adverse events - gastrointestinal at 4 days

Adverse events included: gastric or abdominal pain

Table 3Clinical evidence summary: Colchicine versus placebo

Outcomes

No of participants (studies) Follow up

Certainty of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with placebo

Risk difference with Colchicine

Pain - Proportion with 50% or greater decrease in pain score (VAS) from baseline – Short-term (up to 2 weeks)

132

(1 RCT)

MODERATE^a

RR 2.43 (1.30 to 4.54)

172 per 1,000

247 more per 1,000 (52 more to 610 more)

Adverse events - gastrointestinal (diarrhoea and vomiting) - Short-term (up to 2 weeks)

133

(1 RCT)

VERY LOW^a^,^b

RR 1.26 (0.67 to 2.39)

203 per 1,000

53 more per 1,000 (67 fewer to 283 more)

a: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.

b: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs.. GRADE default MIDs used for all outcomes, for dichotomous outcomes MIDs were taken to be RRs of 0.8 and 1.25.

Table 4Clinical evidence summary: Corticosteroids versus NSAIDs

Outcomes	No of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	No of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with NSAIDs	Risk difference with Corticosteroids
Pain (VAS 0-100) at 90 hours - Short-term (up to 2 weeks)	118 (1 RCT)	LOW^a^,^b	-	mean 12.9 (SD 18.1)	MD 3.9 higher (3.77 lower to 11.57 higher)
Pain - Number of patients with clinically significant change in pain score (13 mm on a 100-mm VAS) - at rest - Short-term (up to 2 weeks)	416 (1 RCT)	MODERATE^b	RR 0.91 (0.75 to 1.10)	534 per 1,000	48 fewer per 1,000 (133 fewer to 53 more)
Pain - Number of patients with clinically significant change in pain score (13 mm on a 100-mm VAS) - with activity - Short-term (up to 2 weeks)	416 (1 RCT)	HIGH	RR 1.06 (0.95 to 1.19)	726 per 1,000	44 more per 1,000 (36 fewer to 138 more)
Joint tenderness - Short-term (up to 2 weeks)	416 (1 RCT)	HIGH	-	The mean joint tendernesswas 0	MD 0.05 lower (0.33 lower to 0.23 higher)
Adverse events- gastrointestinal (abdominal pain) - Short-term (up to 2 weeks)	737 (4 RCTs)	LOW^c	RR 0.60 (0.22 to 1.67)	132 per 1000	53 fewer (103 fewer to 89 more)
Adverse events- gastrointestinal indigestion)- Short-term (up to 2 weeks)	506 (2 RCTs)	MODERATE^b	RR 0.52 (0.30 to 0.91)	130 per 1000	62 fewer per 1000 (91 fewer to 12 fewer)
Adverse events- gastrointestinal (nausea)- Short-term (up to 2 weeks)	506 (2 RCTs)	HIGH	RR 0.26 (0.12 to 0.59)	106 per 1000	79 fewer per 1000 (94 fewer to 44 fewer)
Adverse events- gastrointestinal (vomiting)- Short-term (up to 2 weeks)	506 (2 RCTs)	HIGH	RR 0.10 (0.02 to 0.56)	55 per 1000	50 fewer per 1000 (54 fewer to 24 fewer)
Adverse events- gastrointestinal (diarrhoea) - Short-term (up to 2 weeks)	90 (1 RCT)	LOW^b	Peto OR 0.14 (0.01 to 1.33)	65 per 1000	70 fewer per 1000 (from 150 fewer to 20 more)
Adverse events- gastrointestinal (GI haemorrhage) - Short-term (up to 2 weeks)	90 (1 RCT)	HIGH	Peto OR 0.13 (0.02 to 0.78)	109 per 1000	110 fewer per 1000 (from 210 fewer to 10 fewer)
Adverse events - cardiovascular - Short-term (up to 2 weeks)	90 (1 RCT)	LOW^b	Peto OR 0.14 (0.00 to 7.13)	22 per 1000	19 fewer per 1000 (22 fewer to 115 more)
Number of patients visited ED - Short-term (up to 2 weeks)	416 (1 RCT)	LOW^b	RR 1.22 (0.73 to 2.04)	111 per 1000	24 more per 1000 (30 fewer to 115 more)
Number of patients visited outpatient department - Short-term (up to 2 weeks)	416 (1 RCT)	MODERATE^b	Peto OR 0.13 (0.02 to 0.95)	19 per 1000	17 fewer per 1000 (19 fewer to 1 fewer)
GP visits - Short-term (up to 2 weeks)	416 (1 RCT)	MODERATE^b	RR 0.58 (0.28 to 1.19)	91 per 1000	38 fewer per 1000 (66 fewer to 17 more)

a: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias

b: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs. Established MIDs used for VAS continuous scale - improvements of ≥ 10 points on a 1-100 scale; GRADE default MIDs used for all other outcomes. For dichotomous outcomes MIDs were taken to be RRs of 0.8 and 1.25. For continuous outcomes 0.5 × baseline SD was calculated: joint tenderness (0.5 × baseline SD of control group as baseline values were not reported in the paper): 0.74.

c: Downgraded by 1 or 2 increments because: The point estimate varies widely across studies, subgroup analysis could not be performed. I^{2 =} 65%, therefore a random effects model was used.

Table 5Clinical evidence summary: NSAIDs versus colchicine

Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with Colchicine subgroup	Risk difference with NSAIDs
Joint pain scores (change score) - Short-term (up to 2 weeks)	105 (1 RCT)	HIGH	-	mean 0.96	MD 0.06 higher (0.28 lower to 0.4 higher)
Complete pain resolution - Short-term (up to 2 weeks)	344 (1 RCT)	LOW^a	RR 1.01 (0.88 to 1.18)	667 per 1,000	7 more per 1,000 (80 fewer to 120 more)
Complete pain resolution – Medium-term (2 to 6 weeks)	344 (1 RCT)	LOW^a	RR 1.02 (0.91 to 1.15)	747 per 1,000	15 more per 1000 (67 fewer to 112 more)
Joint swelling scores - Short-term (up to 2 weeks)	105 (1 RCT)	HIGH	-	mean 0.73	MD 0.04 higher (0.19 lower to 0.27 higher)
Patient assessment of global treatment response (completely/much better) n - Short-term (up to 2 weeks)	344 (1 RCT)	VERY LOW^a^,^b	RR 1.06 (0.91 to 1.24)	632 per 1,000	38 more per 1,000 (57 fewer to 152 more)
Patient assessment of global treatment response (completely/much better) n – Medium-term (2 to 6 weeks)	344 (1 RCT)	VERY LOW^a^,^b	RR 1.00 (0.91 to 1.11)	822 per 1,000	0 fewer per 1,000 (74 fewer to 90 more)
Adverse events-gastrointestinal (vomiting) - Short-term (up to 2 weeks)	105 (1 RCT)	VERY LOW^a^,^b	RR 1.96(0.18 to 20.99)	19 per 1000	18 more per 1000 (from 16 fewer to 384 more)
Adverse events-gastrointestinal (nausea and/or vomiting) - Short-term (up to 2 weeks)	344 (1 RCT)	MODERATE^b	RR 0.72 (0.43 to 1.20)	172 per 1000	48 fewer per 1000 (98 fewer to 34 more)
Adverse events-gastrointestinal (diarrhoea) - Short-term (up to 2 weeks)	449 (2 RCTs)	HIGH	RR 0.47 (0.33 to 0.68)	305 per 1000	162 fewer per 1000 (205 fewer to 98 fewer)
Adverse events-gastrointestinal (dyspepsia) - Short-term (up to 2 weeks)	344 (1 RCT)	LOW^b	RR 1.02 (0.57 to 1.83)	115 per 1,000	2 more per 1000 (49 fewer to 95 more)
Adverse events-gastrointestinal (abdominal pain) - Short-term (up to 2 weeks)	344 (1 RCT)	LOW^b	RR 1.02 (0.53 to 1.98)	92 per 1000	2 more per 1000 (43 fewer to 90 more)
Adverse events-gastrointestinal (constipation) - Short-term (up to 2 weeks)	344 (1 RCT)	HIGH	RR 0.46 (0.31 to 0.67)	385 per 1000	208 fewer per 1000 (266 fewer to 127 fewer)
Adverse events-gastrointestinal (nausea and/or vomiting) - Medium-term (2 to 6 weeks)	344 (1 RCT)	LOW^b	RR 1.43 (0.46 to 4.43)	29 per 1,000	12 more per 1000 (16 fewer to 99 more)
Adverse events-gastrointestinal (dyspepsia) - Medium-term (2 to 6 weeks)	344 (1 RCT)	LOW^b	RR 1.66 (0.71 to 3.91)	46 per 1000	30 more per 1000 (13 fewer to 134 more)
Adverse events-gastrointestinal (abdominal pain) - Medium-term (2 to 6 weeks)	344 (1 RCT)	LOW^b	RR 0.51 (0.16 to 1.67)	46 per 1000	23 fewer per 1000 (39 fewer to 31 more)
Adverse events-gastrointestinal (constipation) - Medium-term (2 to 6 weeks)	344 (1 RCT)	LOW^b	RR 1.54 (0.56 to 4.22)	34 per 1,000	19 more per 1000 (15 fewer to 111 more)
Adverse events-gastrointestinal (diarrhoea) - Medium-term (2 to 6 weeks)	344 (1 RCT)	LOW^b	RR 0.51 (0.18 to 1.47)	57 per 1,000	28 fewer per 1000 (47 fewer to 27 more)
Consultation re-attendance for gout during 4-week follow-up - Emergency department – Medium-term (2 to 6 weeks)	344 (1 RCT)	VERY LOW^a^,^b	Peto OR 1.02 (0.06 to 16.23)	6 per 1000	0 fewer per 1,000 (5 fewer to 80 more)
Consultation re-attendance for gout during 4-week follow-up - GP – Medium-term (2 to 6 weeks)	344 (1 RCT)	LOW^a^,^b	RR 0.68 (0.44 to 1.07)	224 per 1000	72 fewer per 1000 (126 fewer to 16 more)

a: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias

b: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs. Established MIDs used for VAS continuous scale - improvements of ≥ 10 points on a 1-100 scale; For dichotomous outcomes MIDs were taken to be RRs of 0.8 and 1.25. For continuous outcomes 0.5 × baseline SD was calculated: joint pain scores: 0.435; joint swelling: 0.98.

Table 6Clinical evidence summary: IL-1 inhibitors versus corticosteroids

Outcomes	No of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	No of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with corticosteroids	Risk difference with Il-1 inhibitors
Health related quality of life SF-36 - Physical Component - Short-term (up to 2 weeks)	85 (1 RCT)	VERY LOW^a^,^b	-	mean 41.9	MD 6.4 higher (2.37 higher to 10.43 higher)
SF-36 Physical component – long-term (more than 6 weeks)	85 (1 RCT)	VERY LOW^a^,^b	-	The mean SF-36 Physical component - long more than 6 weeks was 47.1	MD 5.7 higher (1.88 higher to 9.52 higher)
SF-36 - Mental component – long-term (more than 6 weeks)	85 (1 RCT)	VERY LOW^a^,^b	-	mean 49.1	MD 4.2 higher (0.22 higher to 8.18 higher)
Pain: 100-mm visual analogue scale - Short-term (up to 2 weeks)	454 (2 RCTs)	LOW^a^,^b	-	mean 35.7	MD 10.56 lower (15.26 lower to 5.87 lower)
Pain 100-mm VAS % change Scale from: 0 to 100 follow up: mean 2 weeks	194 (2 RCTs)	VERY LOW^a^,^b^,^d	-	mean −57.1	MD 10.32 lower (17.25 lower to 3.38 lower)
Joint swelling - Short-term (up to 2 weeks)	454 (2 RCTs)	LOW^a^,^b	OR 1.58 (1.09 to 2.31)	Not provided	Could not be estimated^c
Joint tenderness - Short-term (up to 2 weeks)	454 (2 RCTs)	MODERATE^a	OR 2.16 (1.47 to 3.18)	Not provided	Could not be estimated^c
Patient global assessment - Short-term (up to 2 weeks)	454 (2 RCTs)	MODERATE^a	OR 1.98 (1.39 to 2.83)	Not provided	Could not be estimated^c
Participant global assessment of response to treatment: good or excellent - Short-term (up to 2 weeks)	83 (1 RCT)	LOW^a	RR 1.67 (1.29 to 2.17)	554 per 1000	371 more per 1000 (161 more to 648 more)
Any adverse event-short -term (up to 2 weeks)	539 (3 RCTs)	LOW^a^,^b	RR 1.20 (1.03 to 1.39)	507 per 1000	101 more per 1000 (15 more to 198 more)
Any adverse event-long-term >6 weeks	109 (1 RCT)	LOW^b	RR 0.94 (0.59 to 1.49)	407 per 1000	24 fewer per 1000 (167 fewer to 200 more)

a: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias

b: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs.Established MIDs for SF-36 physical/mental- 3.75; for VAS continuous scale - improvements of ≥ 10 points on a 1-100 scale; GRADE default MIDs used for all other outcomes. For dichotomous outcomes MIDs were taken to be RRs of 0.8 and 1.25.. Calculated MIDs for gout flares: 1, 2 and 3 were: 9.1, 10.3 and 5.9;

c: Absolute effect could not be estimated because studies only reported OR and did not report means separately for intervention and control arms. Inverse variance analysis method was used.

d: I²= 79%, p=0.03

Table 7Clinical evidence summary: ice plus prednisone and colchicine versus prednisone and colchicine

Outcomes

No of participants (studies) Follow up

Certainty of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with corticosteroids and colchicine

Risk difference with Ice and corticosteroids and colchicine

Pain (VAS 0-10) - Short-term (up to 2 weeks)

(1 RCT)

LOW^a^,^b

mean 4.74

MD 3.94 lower (6.02 lower to 1.86 lower)

Joint circumference (joint swelling) (cm) - Short-term (up to 2 weeks)

(1 RCT)

VERY LOW^a^,^b

mean 33.4 (cm)

MD 0.9 lower (9.45 lower to 7.65 higher)

a: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.

b: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs. Established MIDs VAS continuous scale - improvements of ≥ 10 points on a 1-100 scale; GRADE default MIDs used for all other outcomes. For dichotomous outcomes MIDs were taken to be RRs of 0.8 and 1.25. For continuous outcomes 0.5 × baseline SD was calculated, joint circumference: no baseline values reported so the control group SD was used:5.13.

Table 8Health economic evidence profile: naproxen versus low-dose colchicine

Study	Applicability	Limitations	Other comments	Incremental cost	Incremental effects	Cost effectiveness	Uncertainty
Roddy 2020⁴⁷ (England)	Partially applicable^(a)	Minor limitations^(b)	Within-RCT analysis (Open-label randomised pragramtic trial [CONTACT] comparing naproxen and low-dose colchicine for the treatment of gout flares in primary care, Roddy 2020⁴⁷) Cost-utility analysis (QALYs) Population: People 18 years and over consulting for a current gout flare. Comparators: Naproxen versus low-dose colchicine Time horizon: 4 weeks	Saves £5.74^(c)	0.0004 QALYs^(d)	Naproxen dominates (less costly and more effective)	Probability naproxen cost effective (£20K threshold): 80%

: Abbreviations: ICER= incremental cost-effectiveness ratio; QALY= quality-adjusted life years; RCT= randomised controlled trial

(a): The analysis uses EQ-5D-5L and so is not in line with the NICE reference case with preference for the EQ-5D-3L.

(b): Unit costs taken from ‘standard UK sources’ but no references provided, cost of PPIs not included for naproxen, short time horizon.

(c): 2015/16 costs. Cost components incorporated: Drug costs, GP costs, nurse costs, Emergency GP costs, A&E costs, intervention costs.

(d): QALYs adjusted for baseline values (both ‘QALYs’ and ‘QALYs adjusted for baseline values’ were reported in the study)

Table 9UK cost of NSAIDs for people without CKD

Drug^(a)	Cost per unit	Daily dose	Cost per day	Cost per flare^(b)
Celecoxib
Celecoxib 100mg capsules	£0.03	200mg – 400mg	£0.07 - £0.13	£0.21 - £1.30
Diclofenac sodium
Diclofenac sodium 50mg gastro-resistant tablets / Misoprostol 200microgram tablets	£0.20	150mg daily	£0.60	£1.80 - £6.00
Diclofenac sodium 50mg gastro-resistant tablets	£0.05	150mg daily	£0.15	£0.45 - £1.50
Etoricoxib
Etoricoxib 60mg tablets	£0.10	120mg daily	£0.20	£0.60 - £2.00
Ibuprofen
Ibuprofen 400mg tablets	£0.07	1.2g daily	£0.21	£0.63 - £2.10
Ibuprofen 600mg tablets	£0.06	1.8g daily	£0.17	£0.51 - £1.70
Indomethacin
Indomethacin 50mg capsules	£0.06	150mg – 200mg daily	£0.18 - £0.24	£0.54 - £2.90
Meloxicam
Meloxicam 15mg orodispersible tablets sugar free	£0.85	7.5mg – 15mg daily	£0.85	£2.55 - £8.50
Meloxicam 15mg tablets	£0.16		£0.16	£0.48 - £1.60
Meloxicam 7.5mg orodispersible tablets sugar free	£0.85		£0.85	£2.55 - £8.50
Meloxicam 7.5mg tablets	£0.11		£0.11	£0.33 - £1.10
Naproxen
Naproxen 250mg effervescent tablets sugar free	£2.89	750mg – 1500mg daily	£8.66	£25.98 - £28.90
Naproxen 250mg gastro-resistant tablets	£0.14		£0.41	£1.23 - £4.10
Naproxen 250mg tablets	£0.05		£0.16	£0.48 - £1.60
Naproxen 250mg/5ml oral suspension	£0.45		£1.35	£4.05 - £13.50
Naproxen 500mg gastro-resistant tablets	£0.17		£0.51	£1.53 - £5.10
Naproxen 500mg tablets	£0.06		£0.19	£0.57 - £1.90

: Sources:

(a): British National Formulary, Accessed October 2021⁹

: Dosing:

(b): Assuming people receive medication for 3 – 10 days

Table 10UK cost of NSAIDs for people with CKD stage 3

Drug^(a)	Cost per unit	Daily dose	Cost per day	Cost per flare^(b)
Celecoxib
Celecoxib 100mg capsules	£0.03	100mg – 400mg	£0.03 - £0.13	£0.09 - £1.30
Diclofenac sodium
Diclofenac sodium 25mg gastro-resistant tablets	£0.06	75 – 150mg daily	£0.18	£0.54 - £1.80
Diclofenac sodium 75mg gastro-resistant / Misoprostol 200microgram tablets	£0.26		£0.79	£2.37 - £7.90
Diclofenac sodium 75mg gastro-resistant modified-release capsules	£0.14		£0.43	£1.29 - £4.30
Diclofenac sodium 75mg modified-release capsules	£0.20		£0.61	£1.83 - £6.10
Diclofenac sodium 75mg modified-release tablets	£0.31		£0.94	£2.82 - £9.40
Etoricoxib
Etoricoxib 60mg tablets	£0.10	60mg – 120mg daily	£0.10 – £0.20	£0.30 - £2.00
Etoricoxib 90mg tablets	£0.09	90mg daily	£0.09	£0.27 - £0.90
Ibuprofen
Ibuprofen 200mg tablets	£0.04	600mg daily	£0.15	£0.44 - £1.50
Ibuprofen 400mg tablets	£0.07	1.2g daily	£0.21	£0.63 - £2.10
Ibuprofen 600mg tablets	£0.06	1.8g daily	£0.17	£0.51 - £1.70
Indomethacin
Indomethacin 50mg capsules	£0.06	150mg – 200mg daily	£0.18 - £0.24	£0.54 - £2.40
Meloxicam
Meloxicam 15mg orodispersible tablets sugar free	£0.85	7.5mg – 15mg daily	£0.85	£2.55 - £8.50
Meloxicam 15mg tablets	£0.16		£0.16	£0.48 - £1.60
Meloxicam 7.5mg orodispersible tablets sugar free	£0.85		£0.85	£2.55 - £8.50
Meloxicam 7.5mg tablets	£0.11		£0.11	£0.33 - £1.10
Naproxen
Naproxen 250mg effervescent tablets sugar free	£2.89	500mg – 1000mg daily	£5.78 – £11.56	£17.34 - £115.60
Naproxen 250mg gastro-resistant tablets	£0.08		£0.16 – £0.32	£0.48 - £3.20
Naproxen 250mg tablets	£0.05		£0.10 – £0.20	£0.20 - £2.00
Naproxen 250mg/5ml oral suspension	£0.45		£0.90 – £1.80	£2.70 - £18.00
Naproxen 500mg gastro-resistant tablets	£0.17		£0.17 - £0.34	£0.51 - £3.40
Naproxen 500mg tablets	£0.06		£0.06 - £0.12	£0.18 - £1.20

: Sources:

(a): British National Formulary, Accessed October 2021⁹

: Dosing:

(b): Assuming people receive medication for 3 – 10 days

Table 11UK cost of NSAIDs for people with CKD stage 4-5

Drug^(a)	Cost per unit	Daily dose	Cost per day	Cost per flare^(b)
Celecoxib
Celecoxib 100mg capsules	£0.03	100mg – 200mg	£0.03 - £0.06	£0.09 - £0.60
Diclofenac sodium
Diclofenac sodium 25mg gastro-resistant tablets	£0.06	75mg daily	£0.18	£0.54 - £1.80
Etoricoxib
Etoricoxib 30mg tablets	£0.22	30mg daily	£0.22	£0.66 - £2.20
Etoricoxib 60mg tablets	£0.10	60mg daily	£0.10	£0.30 - £1.00
Ibuprofen
Ibuprofen 200mg tablets	£0.04	600mg daily	£0.15	£0.44 - £1.50
Ibuprofen 400mg tablets	£0.07	1.2g daily	£0.21	£0.63 - £2.10
Indomethacin
Indomethacin 25mg capsules	£0.05	75mg – 100mg daily	£0.15 - £0.20	£0.45 - £2.00
Meloxicam
Meloxicam 7.5mg orodispersible tablets sugar free	£0.85	7.5mg daily	£0.85	£2.55 - £8.50
Meloxicam 7.5mg tablets	£0.11	7.5mg daily	£0.11	£0.33 - £1.10
Naproxen
Naproxen 250mg effervescent tablets sugar free	£2.89	250mg – 750mg daily	£2.89 – £8.67	£8.67 - £86.70
Naproxen 250mg gastro-resistant tablets	£0.08		£0.08 – £0.24	£0.24 - £2.40
Naproxen 250mg tablets	£0.05		£0.05 – £0.15	£0.15 - £1.50
Naproxen 250mg/5ml oral suspension	£0.45		£0.45 – £1.35	£1.35 - £13.50
Naproxen 500mg gastro-resistant tablets	£0.17		£0.17	£0.36 - £1.20
Naproxen 500mg tablets	£0.06		£0.06	£0.18 - £0.60

: Sources:

(a): British National Formulary, Accessed October 2021⁹

: Dosing:

(c): Assuming people receive medication for 3 – 10 days

Table 12UK cost of Colchicine

Drug	Cost per unit	Daily dose	Cost per day	Cost per flare^(a)
Colchicine 500microgram tablets	£0.05	1mg – 2mg daily	£0.10 - £0.20	£0.30 - £2.00

: Source: NHS Drug Tariff, Accessed October 2021⁴³

(a): Assuming people receive medication for 3 days

Table 13UK cost of Corticosteroids

Drug	Cost per unit	Dosage
Methylprednisolone
Methylprednisolone 40mg/1ml / Lidocaine 10mg/1ml (1%) suspension for injection vials	£3.94	1 injection per gout flare
Methylprednisolone 80mg/2ml / Lidocaine 20mg/2ml (1%) suspension for injection vials	£7.06	1 injection per gout flare
Methylprednisolone acetate 120mg/3ml suspension for injection vials	£8.96	1 injection per gout flare
Methylprednisolone acetate 40mg/1ml suspension for injection vials	£3.44	1 injection per gout flare
Methylprednisolone acetate 80mg/2ml suspension for injection vials	£6.18	1 injection per gout flare
Prednisolone
Prednisolone 5mg tablets	£0.03	30mg daily (costing £0.18 per day)
Triamcinolone
Triamcinolone acetonide 40mg/1ml suspension for injection vials	£1.49	1 injection on initiation or titration of ULT
Triamcinolone acetonide 50mg/5ml suspension for injection vials	£3.63	1 injection per gout flare
Triamcinolone hexacetonide 20 mg/1ml suspension for injection ampules	£12.00	1 injection per gout flare

: Source: NHS Drug Tariff, Accessed October 2021⁴³

Table 14UK cost of proton pump inhibitors (PPI’s)

Drug	Cost per unit	Dosage
Omeprazole
Omeprazole 10mg tablets	£0.33	1 tablet per day
Omeprazole 20mg tablets	£0.49	1 tablet per day
Omeprazole 40mg tablets	£0.98	1 tablet per day
Esomeprazole
Esomeprazole 20mg tablets	£0.15	1 tablet per day
Esomeprazole 40mg tablets	£0.15	1 tablet per day
Lansoprazole
Lansoprazole 15mg tablets	£0.13	1 tablet per day
Lansoprazole 30mg tablets	£0.18	1 tablet per day
Rabeprazole
Rabeprazole 10mg tablets	£0.05	1 tablet per day
Rabeprazole 20mg tablets	£0.06	1 tablet per day
Pantoprazole
Pantoprazole 20mg tablets	£0.06	1 tablet per day
Pantoprazole 40mg tablets	£0.06	1 tablet per day

: Source: British National Formulary, Accessed October 2021⁹

: Note: PPI’s are a gastro-resistant tablet which can be prescribed in conjunction with NSAIDs and oral corticosteroids.

Table 15UK cost of IL-1 Inhibitors

Drug	Cost per unit	Dosage
Anakinra
Anakinra 100mg /0.67ml solution for injection pre-filled syringes	£26.23	3-5 injections per gout flare
Canakinumab
Canakinumab 150mg per 1ml solution for injection vials	£9,928	1 injection per gout flare

: Source: British National Formulary, Accessed October 2021⁹

Evidence reviews for pharmacological and non-pharmacological interventions for managing gout flares

1. Pharmacological and non-pharmacological interventions for managing gout flares

1.1. Review question: What is the clinical and cost effectiveness of pharmacological interventions (including NSAIDs, colchicine, corticosteroids and IL-1 inhibitors) and non-pharmacological interventions for managing gout flares?

1.1.1. Introduction

1.1.2. Summary of the protocol

1.1.3. Methods and process

1.1.4. Effectiveness evidence

1.1.4.1. Included studies

1.1.4.2. Excluded studies

1.1.5. Summary of studies included in the effectiveness evidence

1.1.6. Summary of the effectiveness evidence

1.1.7. Economic evidence

1.1.7.1. Included studies

1.1.7.2. Excluded studies

1.1.8. Summary of included economic evidence

1.1.9. Economic model

1.1.10. Unit costs

1.1.11. Evidence statements

Economic

1.1.12. The committee’s discussion and interpretation of the evidence

1.1.12.1. The outcomes that matter most

1.1.12.2. The quality of the evidence

1.1.12.3. Benefits and harms

Treatment options for managing gout flares

1.1.12.4. Cost effectiveness and resource use

1.1.13. Recommendations supported by this evidence review

1.1.14. References

Appendices

Appendix A. Review protocols

Appendix B. Literature search strategies

Appendix C. Effectiveness evidence study selection

Appendix D. Effectiveness evidence

Appendix E. Forest plots

Appendix F. GRADE tables

Appendix G. Economic evidence study selection

Appendix H. Economic evidence tables

Appendix I. Health economic model

Appendix J. Excluded studies

Clinical studies

Health Economic studies

Appendix K. Research recommendation – full details

F.1.1. Research recommendation

F.1.2. Why this is important

F.1.3. Rationale for research recommendation

F.1.4. Modified PICO table

Table 1PICO characteristics of review question

Table 2Summary of studies included in the evidence review

Table 3Clinical evidence summary: Colchicine versus placebo

Table 4Clinical evidence summary: Corticosteroids versus NSAIDs

Table 5Clinical evidence summary: NSAIDs versus colchicine

Table 6Clinical evidence summary: IL-1 inhibitors versus corticosteroids

Table 7Clinical evidence summary: ice plus prednisone and colchicine versus prednisone and colchicine

Table 8Health economic evidence profile: naproxen versus low-dose colchicine

Table 9UK cost of NSAIDs for people without CKD

Table 10UK cost of NSAIDs for people with CKD stage 3

Table 11UK cost of NSAIDs for people with CKD stage 4-5

Table 12UK cost of Colchicine

Table 13UK cost of Corticosteroids

Table 14UK cost of proton pump inhibitors (PPI’s)

Table 15UK cost of IL-1 Inhibitors