Idiopathic Gout: Clinical Guidelines

List of Abbreviations

BP — blood pressure

AH — arterial hypertension

ACR — American College of Rheumatology

ALT — alanine aminotransferase

AST — aspartate aminotransferase

VAS — visual analogue scale

WHO — World Health Organization

bDMARDs — biologic disease-modifying antirheumatic drugs

GC — glucocorticoids

HU — hyperuricemia

CI — confidence interval

DECT — dual-energy computed tomography

EULAR — European Alliance of Associations for Rheumatology

GI – gastrointestinal tract

IHD — ischemic heart disease

IL — interleukin

BMI — body mass index

CT — computed tomography

XO — xanthine oxidase

UA — uric acid

Urolithiasis – urolithiasis

MRI — magnetic resonance imaging

MS — metabolic syndrome

MSU — monosodium urate

NSAIDs — non-steroidal anti-inflammatory and antirheumatic drugs

SGLT2 — sodium-glucose cotransporter 2

ADR — adverse drug reaction

ADR – adverse drug reaction

OA — osteoarthritis

HR — hazard ratio

RA — rheumatoid arthritis

RCTs — randomized controlled trials

RF — Russian Federation

DM — diabetes mellitus

SF — synovial fluid

eGFR — estimated glomerular filtration rate

eGFR — estimated glomerular filtration rate

HF — heart failure

CRP – C-reactive protein

CVD — cardiovascular diseases

TG — triglycerides

US — ultrasound

ULT – urate-lowering therapy

TNF-α — tumor necrosis factor-α

RF — risk factors

CKD – chronic kidney disease

Chol – cholesterol

HDL-C – high-density lipoprotein cholesterol

LDL-C – low-density lipoprotein cholesterol

COX – cyclooxygenase

ECG – electrocardiography (recording of the electrocardiogram; interpretation, description, and analysis of electrocardiographic data)

EchoCG – echocardiography

Terms and Definitions

Arthritis — inflammation of joint tissues, the symptoms of which include pain, redness, hyperthermia, swelling, limited mobility, and stiffness.

Asymptomatic hyperuricemia — hyperuricemia (HU) in the absence of any prior clinical symptoms of gout (arthritis).

Hyperuricemia (HU) — serum uric acid (UA) level above threshold values determined by clinical and epidemiological studies demonstrating an association with an increased risk of urate crystallization and the development of gout, as well as the advisability and benefit of therapy aimed at reducing levels below these thresholds.

Genetically engineered biologic drugs (GEBDs) — a group of medicinal products of biological origin, including monoclonal antibodies (chimeric, humanized, fully human) and recombinant proteins (usually including the Fc fragment of human IgG) produced using genetic engineering methods, which specifically suppress the immuno-inflammatory process and slow down the progression of joint destruction.

Glucocorticoids (GCs) — synthetic steroid hormones possessing intrinsic anti-inflammatory activity.

Evidence-based medicine — the conscientious, explicit, and judicious use of current best evidence (clinical research results) in combination with individual clinical expertise, taking into account patient values and preferences in making decisions about the patient's health and care [1].

Disease — a condition arising from exposure to pathogenic factors, characterized by impaired functioning of the organism, working capacity, and ability to adapt to changing conditions of the external and internal environment, accompanied by concurrent changes in the protective-compensatory and protective-adaptive reactions and mechanisms of the organism [2].

Lifestyle modification — measures aimed at the normalization of weight and dietary patterns, physical activity, and the restriction of alcohol consumption, with the goal of reducing serum UA levels.

Outcome — any potential result arising from exposure to a causal factor, preventive or therapeutic intervention, or any ascertained change in health status resulting from an intervention [3].

Clinical trial — any investigation conducted in human subjects to discover or verify the clinical and/or pharmacological effects of investigational products, to identify any adverse reactions to investigational products, and/or to study their absorption, distribution, metabolism, and excretion with the object of ascertaining their safety and/or efficacy [4].

Conflict of interest — a situation in which a medical or pharmaceutical worker, in the exercise of their professional activities, has a personal interest, whether acting personally or through a representative, in obtaining material gain or other advantage that influences or may influence the proper performance of their professional duties due to a contradiction between the personal interest of the medical or pharmaceutical worker and the interests of the patient [2].

Monosodium urate (MSU) crystals — the sodium salt of UA, the pathogenic crystals in gout (chemical formula C5H4N4NaO3).

Xanthine oxidase (XO) — an enzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to UA.

Medicinal products — pharmacological agents in the form of dosage forms used for the prevention, diagnosis, and treatment of disease, rehabilitation, and for the maintenance, prevention, or termination of pregnancy [5].

Medical intervention — types of medical examinations and/or medical manipulations performed by a medical worker or other employee authorized to provide medical care to a patient, affecting the physical or mental state of a person and having a preventive, diagnostic, therapeutic, rehabilitative, or research-related focus, as well as artificial termination of pregnancy [2].

Intercritical period — the asymptomatic period following or between attacks of gouty arthritis, despite the presence of MSU crystals.

Uric acid (UA) — the end product of nucleic acid and purine base metabolism in humans (chemical formula C5H4N4O3) under the action of the enzyme xanthine oxidase.

Nonsteroidal anti-inflammatory and antirheumatic drugs (NSAIDs) — a group of synthetic medicinal products possessing symptomatic analgesic, antipyretic, and anti-inflammatory effects associated primarily with the inhibition of cyclooxygenase activity, an enzyme that regulates prostaglandin synthesis.

Oligoarthritis — arthritis involving 1–4 joints.

Acute arthritis — arthritis developing over the course of several hours or days.

Patient — an individual to whom medical care is being provided or who has applied for medical care, regardless of the presence of a disease and their condition [2].

Gout — a chronic auto-inflammatory disease developing due to inflammation at sites of monosodium urate (MSU) crystal deposition in individuals with hyperuricemia (HU) caused by environmental and/or genetic factors.

Gouty arthritis — a clinically overt episode of acute inflammation in a joint caused by MSU crystals.

Subcutaneous tophus — a tophus detectable upon physical examination.

Polyarthritis — arthritis involving >4 joints.

Polarized light microscopy — a method for studying the properties of histological structures possessing the ability to exhibit double refraction (anisotropy), including crystals, under polarized light.

Working group for the development/updating of clinical guidelines — a team of specialists working together and in coordination to develop/update clinical guidelines and bearing joint responsibility for the results of this work.

Syndrome — a stable set of multiple symptoms sharing a common pathogenesis [6].

Synovial fluid (SF) — a viscous fluid found in joint cavities, produced by the cells lining the synovial joints.

Glomerular filtration rate (GFR) — the volume of blood plasma filtered in all renal glomeruli per minute. The GFR value is expressed in ml/min, is determined by renal plasma flow, filtration pressure, and filtration surface area, and depends on the mass of functioning nephrons. It is used as an integral indicator of renal functional status and is standardized to body surface area (the average body surface area is 1.73 m2).

Condition — alterations in the organism arising from exposure to pathogenic and/or physiological factors and requiring the provision of medical care [2].

Tophus — a focal accumulation of MSU crystals in the tissues of a patient with gout.

Urate-lowering drugs — a group of medicinal products whose action is aimed at preventing the formation of and dissolving existing MSU crystals.

Urates — circulating salts of UA in the body.

Level of evidence — the degree of certainty that the observed effect of a medical intervention is true [7].

Grade of recommendation — the degree of certainty regarding the validity of the intervention's effect and that following the recommendation will do more good than harm in a specific situation [7].

Chronic kidney disease (CKD) — persistent kidney damage lasting for at least three months due to various etiological factors, the anatomical basis of which is the replacement of normal anatomical structures by fibrosis, leading to their dysfunction.

Chronic gouty arthritis — persistent inflammation in the joint(s) caused by MSU crystals.

Target serum UA level — a serum UA level, varying for different groups of patients with gout, the achievement of which through treatment leads to the dissolution of existing MSU crystals and the prevention of new crystal formation.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Gout is a chronic auto-inflammatory disease developing due to inflammation at sites of monosodium urate (MSU) crystal deposition in individuals with hyperuricemia (HU) caused by environmental and/or genetic factors [8].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

An obligate risk factor (RF) for the development of gout is the presence of HU. The latter is defined as an elevated serum UA level > 6.8 mg/dl (> 404 µmol/l) at which MSU crystals form under physiological conditions (temperature 37^oC) [9]. The formation of MSU crystals is also possible at lower index levels (> 6.0 mg/dl (> 360 µmol/l) at a temperature of 35^oC) [10].

The higher the serum UA level, the higher the risk of developing gout. There is a direct, but non-linear relationship: with a serum UA level of < 6 mg/dL (<360 µmol/L), the 15-year cumulative risk of developing gout is 1.12%; at a level within 6.0–6.9 mg/dL, it is 3.7%; and at a level ≥ 10 mg/dL (> 600 µmol/L), it is 48.57% [11].

Of all patients with asymptomatic hyperuricemia, only 10–15% ultimately develop gout [12].

The causes of the selective transformation of asymptomatic hyperuricemia into gout are unknown; however, a number of factors associated with hyperuricemia are closely and independently linked to an increased risk of developing gout.

- Age — increasing age is associated with an increased risk of developing gout, starting from adulthood in men and postmenopausal age in women [13].

- Male sex — the prevalence of women with gout is much lower than that of men, and the main reason for this is considered to be the effect of estrogens, which exert a pronounced uricosuric action that is lost after the onset of menopause [14, 15].

- Genetic factors — their presence is associated with serum urate levels and includes hundreds of described genetic variants [16, 17].

- Overweight and obesity — there is a direct, independent relationship between body mass index (BMI) and the risk of developing gout [13].

- Elevated blood pressure (BP) — the incidence rate of gout is three times higher in patients with arterial hypertension (AH) than in patients with normal BP [13].

- Alcohol consumption — serum UA levels and the risk of developing gout increase in proportion to an increase in the consumption of beer or hard liquor, independently of other factors, including dietary ones [18, 19].

- Consumption of large amounts of purine-rich foods — serum UA levels and the risk of developing gout increase in parallel with an increase in total meat or seafood consumption [19].

- Consumption of fructose-containing beverages — the consumption of sugary soft drinks is dose-dependently associated with an increased risk of developing gout [20].

- Use of diuretic drugs — the use of any diuretics, especially thiazide and loop diuretics, is independently associated with an increased risk of developing gout [21].

- Chronic kidney disease (CKD) — a decrease in renal function, independently of other factors including the use of diuretics, repeatedly increases the risk of gout incidence, especially in patients with end-stage renal disease, including those receiving hemodialysis [22, 23].

The most important pathogenetic mechanism underlying the clinical manifestations of gout is associated with the induction of acute inflammation by MSU crystals at the sites of their formation [24, 25]. In gout, MSU crystals forming in the synovial fluid (SF) and surrounding tissues act as a trigger for acute arthritis, initiating a cascade of immune reactions. Initially, phagocytosis of crystals occurs, which induces the activation of intracellular structures, inflammasomes—intracellular cytosolic multiprotein oligomeric complexes responsible for activating the immune response—resulting in the synthesis of a wide range of pro-inflammatory cytokines, chemokines (primarily IL-1 [IL-1], as well as IL-6, IL-8, IL-18, tumor necrosis factor-α [TNF-α], etc.). Their production promotes the development of an acute massive inflammatory reaction, vasodilation, and rapid migration of immune cells, predominantly neutrophils, to the site of inflammation. This manifests as an acute attack of arthritis, the primary clinical manifestation of gout.

1.3 Epidemiology of the Disease or Condition

The age-standardized global incidence rate of gout averages 91.1 (95% CI: 81.3, 104.1) cases per 100,000 population per year, varying across different regions from 48.2 to 190 cases. Prevalence is 510.6 (95% CI: 455.6, 570.3) cases per 100,000 population, ranging from 231.4 to 1,394 cases, and increased by 7.2% (95% CI: 6.4, 8.1) between 1990 and 2017. In developed countries, the prevalence of gout ranges from < 1% to 6.8%. The peak incidence occurs at ages 40–50 in men and after 60 years in women (postmenopausal period). The prevalence of gout increases with age; it is 3–7 times more common among men, but in old age, the difference decreases to a 2–3-fold male predominance [26, 27].

Gout is the most common inflammatory arthritis in the world. According to estimates, as of 2017, there were approximately 41.2 million adults with gout worldwide, which is more than double the number of people suffering from rheumatoid arthritis [28].

Gout is associated with an increased risk of death from cardiovascular disease (CVD) [29], as well as non-cardiac causes [30]. The overall high risk of premature mortality in gout has not improved for more than two decades [31]. The burden of gout is exacerbated by its frequent combination with comorbidities, including arterial hypertension (AH) (75%), CKD (70%), obesity (53%), and CVD (10–14%), each of which is also associated with an increased risk of morbidity and mortality [32].

1.4 Features of Coding the Disease or Condition

M10.0 — Idiopathic gout

Gouty bursitis

Primary gout

Gouty tophi [urate tophi] of heart † (I43.8*)

1.5 Classification of the disease or condition

There are 4 stages distinguished in the development and progression of gout [33]:

1. Asymptomatic hyperuricemia with the absence of MSU crystal deposits (the patient has an elevated serum UA level, but no MSU crystals are present).

2. Asymptomatic hyperuricemia with the presence of MSU crystal deposits, but without symptoms or a history of gout (no episodes of arthritis and no tophi).

3. MSU deposits with a current (acute gouty arthritis) or previous episode of gouty arthritis (intercritical period with no arthritis at present).

4. Chronic tophaceous gout (patients with tophi, chronic arthritis, erosions according to imaging methods, functional impairments).

1.6 Clinical presentation of the disease or condition

In the vast majority of cases, gout presents with typical symptoms characterized by short-term (from a few days to 2 weeks), self-resolving acute attacks of mono- or oligoarthritis, which are accompanied by severe pain, swelling, hyperemia, hyperthermia of the joint or synovial bursa, as well as limited function of the affected joint. There are no complaints in the intercritical period. In some cases, mostly with a prolonged course, the disease manifests as chronic arthritis or polyarthritis.

Another late clinical sign of gout is focal accumulation of urate crystals with the formation of subcutaneous tophi, detectable upon physical examination.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria — American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria (Appendix G1).

The diagnosis of gout is established either by visual detection of MSU crystals in SF or tophus contents, or by the presence of a combination of clinical, laboratory, and instrumental signs of the disease scored in points. According to the criteria, if the score is 8 or more, the disease can be classified as gout.

2.1 Complaints and Anamnesis

Reliability of Evidence Grade C, Consensus Level of Evidence 5

Comments. The relative risk of developing gout in patients with chronic kidney disease, obesity, elevated blood pressure, and lipid metabolism disorders is much higher than the population average, which is one of the reasons for the high mortality rate in patients with gout [36–40]. In the presence of gout and hyperuricemia, cases of end-stage renal disease are registered more frequently, and mortality in patients with chronic kidney disease in the presence of gout increases fourfold [41, 42]. The presence of obesity is equated with an earlier age of gout onset and involvement of a larger number of joints [43]. Data collection includes information on the presence of a family history of gout, a history of obesity, CVD, CKD, AH, lifestyle, and medication use (Table P3, Appendix A3.1).

GPP B, LoE 2

Comments. Dietary habits should be analyzed, including the consumption of fructose-containing beverages, purine-containing foods (red meat, fish, seafood), and alcohol intake, the contribution of which to the development of gout has been demonstrated in several population studies and meta-analyses [18, 20, 47–54] (Table P3, Appendix A3.1).

• In every patient with gout, it is recommended to determine the risk factors for the development of this disease associated with the use of the following medicinal products: diuretics, low-dose acetylsalicylic acid**, cyclosporine**, tacrolimus**, and anti-tuberculosis drugs [34, 44, 55].

LeveL of Evidence C, Grade of Recommendation 5

Comments. Loop and thiazide diuretics increase renal uric acid reabsorption and lead to hyperuricemia and an increased risk of gout, which persists for a long time even after their withdrawal, and promote the rapid growth of tophi [56]. According to prospective studies, the use of certain immunosuppressants (cytostatic drugs) (tacrolimus** and cyclosporine**) leads to the rapid development of gout [57]. The use of antituberculosis drugs (primarily pyrazinamide** and ethambutol**, or a combination of pyrazinamide, rifampicin, and isoniazid (isoniazid + pyrazinamide + rifampicin**, isoniazid + pyrazinamide + rifampicin + ethambutol**, isoniazid + pyrazinamide + rifampicin + ethambutol + pyridoxine**)) leads to a significant increase in serum uric acid levels, although it remains unclear to what extent they affect the risk of developing gout [58, 59]. Low-dose acetylsalicylic acid** (60–300 mg/day) reduces uric acid excretion and can cause hyperuricemia, whereas higher doses have a uricosuric effect [60].

LeveL of Evidence C, Grade of Recommendation 5

Comments. A sudden attack of arthritis with rapid development of severe pain and inflammation peaking within 24 hours, especially accompanied by marked swelling and erythema, is highly suspicious of microcrystalline inflammation, primarily gout, although not specific for it; moreover, if a typical attack of acute arthritis affects the joints of the feet, especially the 1st metatarsophalangeal and ankle joints, the number of acute arthritis attacks exceeds one (presence of similar episodes of acute arthritis), the patient is male, and the duration of the acute arthritis attack does not exceed two weeks, this increases the likelihood of gout in the patient [36, 61, 63]. In studies conducted to develop classification criteria [62], these features are the main clinical "markers" of acute arthritis in gout. However, despite high sensitivity, the level of evidence for this recommendation is not maximal. For example, 1st metatarsophalangeal joint arthritis classified as gouty solely based on the clinical picture is confirmed in only 77% of cases [64]. The presence of only one of the listed clinical features (involvement of the 1st metatarsophalangeal joint, foot joints, acute onset with maximum pain and inflammation, history of acute arthritis attacks) is insufficient to diagnose gout.

2.2 Physical Examination

Level of Consensus Reliability C, Level of Evidence Data 2

Comments. Palpable subcutaneous tophi are more frequently localized in areas subject to pressure or friction; when forming around the small joints of the hands, they can mimic nodular osteoarthritis or rheumatoid arthritis nodules, while on the auricles they are found in 12% of cases, more often in men, and in patients receiving glucocorticoids, subcutaneous tophi develop more rapidly [63, 65, 66]. In some cases, subcutaneous tophi may be the first clinical manifestation of the disease, but most often they are late symptoms of gout (forming on average 7–10 years after the onset of gout) [67].

• All patients with gout are recommended to have their body mass index (BMI) determined to detect overweight/obesity and blood pressure measurement [34, 35, 44, 68].

Reliability of Evidence Grade C, Consensus Level of Evidence 5

Comments. Physical examination of a patient with gout aims to identify risk factors for the disease, among which obesity, detected using anthropometric indicators (calculating body mass index by the Quetelet formula: body weight in kilograms divided by height in meters squared (kg/m2)), as well as arterial hypertension, occupy a leading place [40, 69]. Table P3 in Appendix A3.2 summarizes the main provisions and requirements for the clinical examination of the patient.

• All patients with gout are recommended to undergo a general therapeutic examination to identify comorbidities, assess general condition, and detect cardiovascular risk factors, including renal failure, coronary artery disease, heart failure, stroke, peripheral arterial disease, obesity, hypertension, and diabetes [70].

LoE C, GoR 5

Comments. A general therapeutic examination is necessary to identify signs of chronic and acute diseases, risk factors for their development, as well as to determine medical indications for additional examinations and appointments (examinations, consultations) by medical specialists to clarify the diagnosis of the disease (condition).

2.3 Laboratory Diagnostics

Level of Consensus Reliability A, Level of Evidence Data 2

Comments. The specificity of polarized light microscopy for demonstrating crystals is extremely high (close to 100%), making it the gold standard for diagnosing gout, whereas the maximum specificity of various combinations of clinical features of gout does not exceed 88.5%, and sensitivity is 70% [72]. Nevertheless, the absence of monosodium urate crystals in synovial fluid does not completely rule out the diagnosis of gout (the sensitivity of the method is only 70%) [73–75]. Diagnosing gout without searching for monosodium urate crystals remains imprecise, emphasizing the importance of examining synovial fluid for diagnostic purposes in routine clinical practice. Since atypical manifestations of gout are not uncommon, and crystal identification allows for a precise diagnosis of gout, synovial fluid examination is necessary in all cases of undiagnosed inflammatory processes [44]. Available data show that gout is the most frequent cause of undifferentiated acute arthritis [63, 76–78].

GoR C, LoE 4

Comments. Synovial fluid can be obtained not only from an inflamed joint, but also from an currently intact yet previously affected joint (the probability of detecting monosodium urate crystals exceeds 70%), as well as from a previously unaffected joint. In the latter case, the probability of detecting monosodium urate crystals in patients meeting the clinical criteria for gout reaches 40% [72].

Level of Evidence C, GR 4

Comments. According to population data, the probability of developing septic arthritis in gout is almost three times higher than in the absence of this diagnosis [80, 81]. The similarity between the clinical picture of gout and septic arthritis frequently precludes making a diagnosis based solely on clinical data.

GoR C, LoE 4

Comments. Epidemiological studies demonstrate a correlation between elevated serum uric acid levels and gout [11, 13, 83, 84], and currently hyperuricemia is the only proven obligatory risk factor for the development of the disease. The maximum available serum uric acid level is used as a diagnostic marker [62].

Reliability of Evidence Grade C, Consensus Level of Evidence 5

Comments. Far from all patients with hyperuricemia suffer from gout or will develop gout [11, 13, 83, 84], and during an acute attack of gouty arthritis, serum uric acid levels may be normal [62]. The lower the serum uric acid level, the lower the chance of detecting gout in a patient, but a single normal value does not allow ruling out the diagnosis. Hyperuricemia should be considered exclusively as a major risk factor for the development of gout, rather than as a surrogate marker for the diagnosis.

• If polarizing microscopy is unavailable for establishing a diagnosis of gout, it is recommended to use a combination of clinical symptoms, laboratory findings, and diagnostic imaging methods [44].

Reliability of Evidence Grade C, Consensus Level of Evidence 5

Comments. Given the insufficient prevalence of the method, the lack of appropriate equipment (polarizing microscope) and trained specialists to perform synovial fluid analysis, it is acceptable to rely on gout classification criteria, taking into account their high sensitivity and specificity [61, 65].

• All patients with gout are recommended to undergo a complete blood count (CBC) with differential to detect characteristic signs of inflammation [86, 87].

Level of Evidence C, GR 4

Comments. An acute gout attack may be accompanied by changes in the complete blood count, characterized by leukocytosis, neutrophilia, and an elevated erythrocyte sedimentation rate (ESR) [86, 87].

• To detect prediabetes and diabetes mellitus (DM) in all patients with gout, it is recommended to test blood glucose levels and glycated hemoglobin (HbA1c) levels [88-92].

Level of Evidence B, Grade of Recommendation 3

Comments. Carbohydrate metabolism disorders, specifically type 2 diabetes mellitus, are significantly more frequently detected in patients with gout and hyperuricemia than in the general population, with hyperuricemia being considered one of the potential risk factors for type 2 diabetes mellitus [93-95]. If blood glucose levels are ≥ 6.1 mmol/L, testing should be repeated in all cases, except for unequivocal hyperglycemia with acute metabolic decompensation or obvious symptoms. Determination of HbA1c may be used as a diagnostic test [90, 91]. Values of the aforementioned glycemic assessment parameters that are above normal but below the diabetic threshold indicate the presence of prediabetes. HbA1c can be used for the diagnosis of diabetes mellitus and prediabetes if the assay method is certified in accordance with the National Glycohemoglobin Standardization Program (NGSP) or the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and standardized according to the reference values adopted in the Diabetes Control and Complications Trial (DCCT) [96, 97]. An elevated HbA1c level in patients with gout is associated with a high cardiovascular disease risk [91].

• In doubtful cases to clarify the diagnosis of diabetes mellitus, as well as to detect prediabetes, it is recommended to perform an oral glucose tolerance test (OGTT) [89].

Level of Evidence B, Grade of Recommendation 3

Comments. OGTT is the sole method for detecting impaired glucose tolerance as a variant of prediabetes [90]. The use of this test increases the detection rate of type 2 diabetes mellitus in patients with gout by an average of 34% [94].

• Quantitative serum C-reactive protein (CRP) testing is recommended for all patients with gout to perform differential diagnosis with other joint diseases and assess inflammation activity [70, 86, 87, 98, 99]

Level of Evidence C, GR 4

Comments. CRP is a classic acute-phase serum protein, which is the most sensitive laboratory biomarker of inflammation, infection, and tissue damage. In patients with early undifferentiated arthritis, CRP determination contributes to correct diagnosis [70]. In gout patients, CRP levels are higher than in the general population and decrease with anti-inflammatory and urate-lowering therapy [86, 100].

• All patients with gout are recommended to have a blood creatinine test and estimated glomerular filtration rate (eGFR) calculation to detect renal dysfunction [44, 70, 83, 101-105].

Reliability of Evidence Grade C, Consensus Level of Evidence 5

Comments. Gout and hyperuricemia are independent risk factors for CKD, and conversely, renal failure increases the risk of developing gout and hyperuricemia [101-103]. GFR is calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, in mL/min/1.73 m² [102] using specialized calculators (Table P3, Appendix A3.3).

• All patients with gout are recommended to undergo blood total cholesterol (TC) testing, high-density lipoprotein cholesterol (HDL-C) testing, low-density lipoprotein cholesterol (LDL-C) testing, and blood triglyceride testing to assess cardiovascular risk [106, 107].

Level of Evidence B, Grade of Recommendation 3

Comments. Hyperuricemia and gout are associated with increased cardiovascular risk. Elevated uric acid levels increase the development of dyslipidemia, including high LDL-C levels, as well as hypertriglyceridemia. Determining the TG-to-HDL ratio has demonstrated high prognostic value, similar to determining the atherogenic index [106].

• All patients with gout are recommended to undergo a general (clinical) urinalysis to detect kidney disease [44, 108].

Level of Evidence C, GR 4

Comments. Performed in all patients with gout because renal impairment is a significant negative prognostic factor in gout, given the proven association between the detection of albuminuria and increased cardiovascular mortality [101, 102, 109].

• To identify contraindications and potential risk factors for adverse drug reactions (ADRs) prior to prescribing therapy (all drug classes), all patients with gout are recommended to undergo the following laboratory tests [44, 108]:

- complete blood count (CBC) with differential;

- urinalysis;

- general clinical blood chemistry panel (including determination of uric acid, ALT, AST, creatinine, glucose);

- determination of GFR (study of nephron function by creatinine clearance (Rehberg's test) or calculation using the CKD-EPI formula).

LoE C, GoR 5

• An intradermal test with a tuberculosis allergen, a focal tuberculin test, and determination of blood interferon-gamma levels in response to Mycobacterium tuberculosis complex antigens are recommended for all patients with gout to identify contraindications and potential risk factors for adverse drug reactions before prescribing biologic DMARDs (IL-1 inhibitors), and every 6 months during treatment with biologic DMARDs (IL-1 inhibitors) [110-113].

Level of Certainty of Evidence B, Level of Reliability of Data 1

• Determination of serum human chorionic gonadotropin (free beta-subunit) is recommended for women of childbearing potential with gout before prescribing urate-lowering therapy contraindicated during pregnancy and breastfeeding [114-117].

LoE C, GoR 5

Comments. Determination of serum human chorionic gonadotropin (free beta-subunit) can be a simple diagnostic method for pregnancy when ultrasound is not feasible. The use of uric acid synthesis inhibitors (xanthine oxidase inhibitors (XOIs)) (allopurinol** and febuxostat) belongs to FDA pregnancy category C, and prescribing these drugs during pregnancy is undesirable [114-117].

2.4 Instrumental Diagnostics

• Joint ultrasound is recommended for all patients with suspected gout when synovial fluid analysis by polarizing microscopy is not available [44, 71, 85, 118].

Level of Evidence C, Grade of Recommendation 1

Comments. Given that the method can be used for early diagnosis of gout, including the preclinical stage of the disease—since some patients with hyperuricemia exhibit typical ultrasound signs of gout ("double contour", "snowstorm" appearance in synovial fluid, hyperechoic heterogeneous lesions surrounded by anechoic margins (tophi)) before the disease manifests as an acute arthritis attack—ultrasound is of great interest for the diagnosis of gout due to its low cost, wide availability, and safety. [119, 120]. The inclusion of this method in modern classification criteria for gout has increased their sensitivity from 0.85 to 0.92 and specificity from 0.78 to 0.89 [62].

• Radiography of the tarsus, phalanges of the feet, and/or hands is recommended for all patients with suspected gout to determine radiological signs of gout [35, 62].

LoE C, GoR 5

Comments. Typical radiographic signs of gout include: bone erosions with overhanging edges and a sclerotic rim; joint space narrowing, which occurs in the later stages of the disease; soft tissue masses, sometimes calcified, corresponding to soft tissue tophi. However, these changes usually become apparent several years after the onset of the disease, have low diagnostic value in the early diagnosis of gout, are not always detected even in patients with chronic arthritis, and are classified as late manifestations of the disease, although very rarely they may form within the first years of the disease onset [67]. The formation of intraosseous tophi often occurs simultaneously with subcutaneous tophi, so X-ray examination is also used to determine the severity of tophaceous involvement [75, 121]. Performing radiography is justified for differential diagnosis with trauma, other musculoskeletal disorders, etc.

• All patients with gout are recommended to undergo a renal ultrasound to assess kidney size, structure, and the presence of nephrolithiasis [44, 62, 122, 123].

LoE C, GoR 5

Comments. Renal involvement in gout occurs in the majority of gout patients, is not limited to nephrolithiasis, and is characterized by the development of tubular atrophy, renal vascular degeneration, and nephrosclerosis [104, 124, 125].

• If joint ultrasound is not available or if there are doubtful signs of gout on ultrasound, it is recommended that all patients with suspected gout undergo dual-energy computed tomography (DECT) to verify urate deposits [44, 62, 85, 126].

Level of Certainty of Evidence B, Level of Reliability of Data 1

Comments. In accordance with the classification criteria for gout, DECT is included in the list of possible diagnostic procedures, but due to its high cost, the method has not become widespread. DECT has high diagnostic accuracy in established gout, but low diagnostic value in patients with recent-onset gout [65, 126-127]. According to meta-analysis results, the specificity of DECT for detecting MSU crystal deposition signs does not exceed that of joint ultrasound, while the sensitivity of ultrasound is higher than that of DECT [128].

• Chest X-ray is recommended for all patients with gout prior to prescribing bDMARDs (IL-1 inhibitors) to detect respiratory tract involvement and comorbid pulmonary diseases [110].

LoE C, GoR 5

• Esophagogastroduodenoscopy (EGD) is recommended for all patients with gout (at least once a year) who regularly receive NSAIDs and/or GCs, in the presence of anemia, to rule out erosive and ulcerative lesions of the stomach and duodenum [129 - 131].

LoE C, GoR 5

• Electrocardiography (ECG) (recording of the electrocardiogram; decoding, description, and interpretation of electrocardiographic data) is recommended for all patients with gout at least once a year [132, 133].

LoR B, LoE 2

Comments. In patients with gout, the incidence of intracardiac conduction disorders, myocardial injury, and heart failure is higher than in the general population [134-136]. ECG is used as a standard screening method for cardiovascular pathology.

• Echocardiography (EchoCG) is recommended for patients with gout when chronic heart failure or cardiac lesions associated with atherosclerosis are suspected [133, 137 - 141].

LoR B, LoE 2

• X-ray densitometry of the lumbar spine and X-ray densitometry of the proximal femur are recommended for all patients with gout every 12 months in the presence of the following indications [142, 143]:

- age over 50 years for women and 60 years for men;

- early menopause in women;

- body weight less than 60 kg;

- glucocorticoid use (for more than 3 months at a dose > 5 mg/day).

LoE C, GoR 5

2.5 Other Procedures

• Consultations (examinations, visits) with specialist physicians are recommended to diagnose or determine treatment tactics for diseases that may influence the choice of therapy and prognosis in patients with gout [133, 144 - 148]:

- cardiologist — if cardiovascular diseases develop against the background of progression and/or treatment of gout;

- endocrinologist — to diagnose endocrine system disorders, primarily diabetes mellitus, which may influence the choice of therapy in gout;

- gastroenterologist — if gastroenterological complications develop during the treatment of gout;

- phthisiatrician — when prescribing biologic DMARDs if latent tuberculosis infection is suspected;

- oncologist — upon the development of malignant neoplasms, for the diagnosis of malignant neoplasms, and for the development of patient management tactics;

- neurologist — for the diagnosis of tunnel syndromes, myelopathy, neuropathy, and other neurological disorders associated with gout;

- nephrologist — for the diagnosis and treatment of CKD, urolithiasis, and other kidney diseases associated with gout;

- trauma surgeon and orthopedist — for gout patients with indications for surgical treatment (significant impairment of hand, foot, and knee joint function, etc., including tophi, contractures, ankylosis, osteonecrosis) or orthotist fitting;

- physical and rehabilitation medicine physician — to develop an individualized rehabilitation plan;

- clinical pharmacologist — in cases of identifying serious, unexpected adverse drug reactions associated with the use of medications; the need to prescribe medications with an expectedly high risk of serious adverse drug reactions; the prescription of drug combinations that increase the frequency of adverse drug reactions; as well as the need for simultaneous prescription of five or more medications to a patient, or more than ten medications during course treatment (polypharmacy);

- dietitian — for patients with gout in combination with chronic diseases of the endocrine, cardiovascular, and digestive systems (e.g., diabetes mellitus, peptic ulcer disease, etc.);

- obstetrician-gynecologist — for female patients planning pregnancy or pregnant women, in order to determine treatment and delivery tactics.

LoE C, GoR 5

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1. Conservative management

• Conservative treatment for gout is recommended for all patients without exception and includes the following components [149 - 153]:

1. Symptomatic treatment aimed at halting an arthritis attack.

2. Urate-lowering therapy (ULT), the goal of which is to maintain the target serum uric acid level.

3. Prophylaxis of arthritis attacks upon initiation of ULT.

4. Non-pharmacological treatment, including lifestyle recommendations and a low-purine diet.

Level of Evidence B, Grade of Recommendation 3

3.1.1. Symptomatic treatment (halting an acute arthritis attack)

LoE C, GoR 5

Comments. Gout manifests as rapidly developing, extremely painful, recurrent inflammatory exacerbations with a severe onset. Patients usually seek emergency care, but they do not always see a physician as quickly as necessary. At the same time, delays in prescribing appropriate medications should be avoided by training patients in self-treatment skills during arthritis exacerbations, since early anti-inflammatory therapy during arthritis attacks (within the first 24 hours) leads to better clinical outcomes. For example, colchicine has been shown to be most effective when administered within the first 12 hours after an exacerbation [154]. The "pill-in-the-pocket" treatment strategy for gout attacks is recommended for all patients.

LoE C, GoR 5

Comments. Gout is often perceived as an acute disease, since the resolution of arthritis attacks leads to the complete disappearance of clinical symptoms. Nevertheless, attacks occur as a result of chronic monosodium urate crystal deposition, so a high risk of arthritis recurrence persists as long as crystal deposits remain, which can be avoided by long-term administration of urate-lowering drugs. Thus, patients must be informed that monosodium urate crystal deposition continues and that treatment aimed solely at relieving arthritis exacerbations is insufficient [155, 156].

Level of Evidence B, Grade of Recommendation 3

Comments. Due to the high prevalence of comorbidities in gout patients, up to 90% of patients have at least one absolute or relative contraindication to nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids (GCs), and up to 2/3 to colchicine [88, 157].

Reliability of Evidence Grade C, Consensus Level of Evidence 5

Comments. Local therapy, such as intra-articular GC injections, should be preferred for monoarthritis of large joints, whereas systemic methods are more relevant for arthritis exacerbations involving multiple joints or sites difficult to access for intra-articular injections [88, 157].

Leveled Clinical Recommendations (LCR) B, Level of Evidence (LoE) 1

Comments. According to meta-analyses and RCTs, NSAIDs, colchicine, and GCs are effective in treating an acute gout flare [158–172]. There is insufficient evidence to rank them by efficacy.

• Colchicine is recommended to be started as early as possible, ideally within the first 12 hours, at low doses and using the following dosing regimen: 1 mg at the onset of the flare, followed by 0.5 mg one hour later, and 0.5 mg 2–3 times daily in subsequent days depending on arthritis severity [82, 169, 172, 173].

LCR C, LoE 2

Comments. The efficacy of colchicine in treating acute gout flares was demonstrated in two randomized placebo-controlled trials. The AGREE trial compared high and low doses of colchicine administered within the first 12 hours of arthritis onset; the efficacy of low and high doses was comparable and superior to placebo, while the incidence of adverse events with the low dose was lower than with the high dose [169]. The efficacy of colchicine at a dose of 0.5 mg 3 times daily is comparable to naproxen at 750 mg daily [174]. The efficacy of a short course of low-dose colchicine (1.5 mg on the first day and 1 mg on the second) in patients with acute arthritis due to calcium pyrophosphate deposition disease, another microcrystalline arthritis characterized by a similar mechanism and severity of acute joint inflammation, was not inferior to prednisolone at 30 mg daily for 2 days [175].

• In case of colchicine-induced diarrhea, which is the first sign of toxicity, it is recommended to reduce the dose or discontinue treatment, and also to reduce the colchicine dose in patients with impaired renal function (recommended doses based on estimated GFR are presented in Appendix A3-5) when co-prescribed with drugs affecting colchicine metabolism [176–179] (list available at: https://www.drugbank.ca/drugs/DB01394).

Level of Certainty of Evidence B, Level of Reliability of Data 1

Comments. The toxic effect of colchicine most commonly manifests as symptoms mimicking gastroenteritis (diarrhea, nausea, vomiting), which are the first signs of colchicine poisoning that can lead to fatal consequences such as pancytopenia, encephalopathy, myopathy, as well as renal, hepatic, or cardiac failure [180–182]. The pharmacokinetics of colchicine involves two main enzymes: P-glycoprotein, responsible for its clearance via the gastrointestinal tract and kidneys, and CYP3A4, responsible for colchicine metabolism in the liver [182]. Several commonly prescribed P-glycoprotein/CYP3A4 inhibitors, such as cyclosporine**, clarithromycin**, verapamil**, or ketoconazole, increase plasma colchicine levels and cause serious adverse effects in at-risk patients [176, 177]. A full list of drugs interfering with colchicine metabolism can be found online: https://www.drugbank.ca/drugs/DB01394. (Table P3, Appendix A3.4)

• In patients with impaired liver function, taking colchicine is not recommended [180, 183, 184].

LCR C, LoE 3

Comments. Since colchicine is known to be metabolized in the liver [182], the drug is not recommended for patients with hepatocellular insufficiency, although relevant studies have not been conducted.

• GCs (prednisolone**, methylprednisolone**) are recommended to be prescribed at a dose of 30–35 mg daily (in terms of prednisolone**) for 3–5 days, followed by a gradual dose taper to complete discontinuation over 10–14 days, whereas intra-articular GC injections should be preferred for monoarthritis if the affected joint is easily accessible for such a procedure [82, 161, 163, 185].

Level of Certainty of Evidence B, Level of Reliability of Data 1

Comments. Available results from several randomized and open-label controlled trials have demonstrated efficacy of prednisolone** comparable to NSAIDs regarding the dynamics of arthritis symptoms at doses of 30 to 35 mg daily and local GC injections [171, 186].

• Regardless of the chosen treatment method, the use of GCs is not recommended in patients with uncontrolled type 2 diabetes mellitus and high blood pressure [71, 187, 188].

LoE C, GoR 5

Comments. GC therapy, regardless of the chosen treatment method, can lead to circulatory disturbances, blood pressure elevation, and hyperglycemia [187].

• NSAIDs (#nimesulide 100 mg twice daily, etoricoxib 120 mg daily, diclofenac** 75 mg twice daily, #ibuprofen** 800 mg 3 times daily, indometacin 50 mg 3–4 times daily, ketoprofen** 100 mg twice daily) are recommended to be administered orally at the maximum dose for relieving an acute arthritis flare, but must be avoided in stage 4–5 CKD or severe cardiovascular disease [146, 147, 189–196].

LCR B, LoE 1 for all drugs except nimesulide and ibuprofen; LoE 5, LCR C for ibuprofen and nimesulide.

Comments. The use of NSAIDs for treating gout flares is well-studied and their efficacy proven; however, NSAID prescription must be preceded by careful cardiovascular risk factor screening and renal function assessment [146]. Although the duration of NSAID therapy for an acute flare is usually limited to a few days, the risk of serious cardiovascular events (including stroke) increases as early as the first week of treatment and is dose-dependent [197].

• Administration of monoclonal antibodies to IL-1 (canakinumab**, #anakinra** 100 mg daily s.c.) is recommended for patients with absolute contraindications and/or ineffectiveness of NSAIDs, colchicine, and GCs, including their combinations, to relieve an acute arthritis flare for at least 3 days in the absence of contraindications to their use [71, 82, 100, 147, 150, 160, 198, 199].

LoR B, LoE 2

Comment. The efficacy of canakinumab** as a single subcutaneous injection of 150 mg in relieving an acute gout flare exceeds that of triamcinolone and colchicine; however, the risk of serious adverse events, primarily infections, is higher with canakinumab** [100]. The efficacy of anakinra** 100 mg once daily via subcutaneous injections is not inferior to colchicine, naproxen, prednisolone**, or triamcinolone according to RCTs and clinical studies [198, 199]; however, the drug does not have an approved indication for gout and can only be prescribed off-label by decision of a medical commission after obtaining informed consent from the patient. The decision on the duration of #anakinra** treatment is made by the attending physician and depends on the efficacy and tolerability of therapy. A 5-day course of #anakinra** therapy in gout patients does not increase the risk of infectious complications and is sufficient for the majority of patients [198]. Active infection is an absolute contraindication to IL-1 inhibitors; prior to their administration, blood tests must be performed to rule out leukopenia and neutropenia ( blood leukocyte count; differential leukocyte count (leukogram)).

3.1.2. Urate-lowering therapy

LoE C, GoR 5

Comment. It is known that gout is caused solely by monosodium urate (MSU) crystals, which activate inflammasomes leading to acute attacks of arthritis, and also accumulate as tophaceous deposits, including in bone tissue, leading to erosive bone damage [200]. Patients need to be aware that eliminating these crystals—which is possible when serum uric acid (UA) drops below the saturation threshold—will ultimately lead to the complete resolution of gout and arthritis attacks, and the resorption of tophi [201].

• Lifelong ULT is recommended for all patients with gout immediately after diagnosis [149, 202].

LoR B, LoE 2

Comments. Gout may be an independent risk factor for premature all-cause and cardiovascular mortality [203]. Cardiovascular and renal diseases and risk factors accumulate over time [204], which complicates the later management of gout [88]. Furthermore, attacks of gouty arthritis typically cause excruciating pain, and patients are maximally motivated to eliminate the risk of recurrence as early as possible [78].

• For all patients with gout, achieving and maintaining a target serum UA level of < 360 µmol/L (< 6 mg/dL) is strongly recommended [71, 147, 152].

Level of Evidence B, Grade of Recommendation 3

Comments. Maintaining a serum UA level < 360 µmol/L (< 6 mg/dL) (which corresponds to the minimum threshold at which UA crystallization occurs in the human body [205]) over the long term is equated with a gradual decrease in frequency and ultimate complete cessation of gouty arthritis attacks, as well as the dissolution of subcutaneous tophi [206, 207].

Level of Evidence B, Grade of Recommendation 3

Comments. The dissolution of MSU crystals is a slow process. Recent dual-energy computed tomography (DECT) studies have shown that at a serum UA level < 360 µmol/L, MSU crystal dissolution is not always complete even after 2 years of treatment if the crystal burden is substantial [208]. Given the correlation between MSU crystal burden and the likelihood of gout flares [209], and the fact that the relationship between reduced serum UA, decreased frequency of arthritis attacks, and reduction in tophus size is achieved at a serum UA level < 300 µmol/L [74, 210], this level should be adopted as the target in patients with chronic arthritis and tophi. Individuals who achieved and maintained a serum UA concentration < 360 µmol/L had gout flares between 12 and 24 months of follow-up 2.4 times less frequently than non-responders (serum UA > 360 µmol/L) (27% vs. 64% of patients, respectively, p < 0.0001); the mean number of flares per person per month was also significantly lower in individuals with serum UA < 360 µmol/L (p < 0.0001) [211].

Level of Evidence B, Grade of Recommendation 3

Comments. Extremely low serum UA levels (< 180 µmol/L) increase the risk of certain neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis) [212–216].

• Treatment with allopurinol** as a first-line agent is recommended for all gout patients with normal renal function [84, 148, 150, 217, 218].

Level of reliability of evidence A, level of bibliographic data validity 1

Comments. Long-term clinical experience and proven efficacy with proper titration of allopurinol** (final dosage > 300 mg daily, but not exceeding the maximum allowed dose of 900 mg daily) allow it to be considered the first-line therapy for gout [217–220]. The probability of achieving the target serum UA level with dose titration of allopurinol and febuxostat up to the maximum tolerated doses, as well as the frequency of adverse drug reactions, are comparable [221]. Furthermore, pharmacoeconomic studies on these xanthine oxidase inhibitors (allopurinol** and febuxostat) have demonstrated that a dose-escalation strategy with allopurinol** as first-line therapy is cost-effective [222]. However, in chronic kidney disease (CKD), the efficacy of low-dose allopurinol** is inferior to that of febuxostat [220], and low doses frequently fail to achieve the target serum UA level [223]. The presence of CKD increases the risk of severe cutaneous adverse reactions associated with allopurinol** [224], and therefore allopurinol** must be used with caution in patients with CKD.

Level of Evidence B, Grade of Recommendation 3

Comments. Allopurinol** should be started at a low dose (100 mg/day) to mitigate the risk of acute gout flares, which increases with a rapid drop in serum UA levels [227], and to reduce the risk of severe cutaneous adverse reactions, the probability of which multiplies significantly with higher starting doses [228]. The most commonly used dose of allopurinol** (300 mg/day) fails to achieve target serum UA levels in 30–50% of patients with normal renal function; therefore, in such cases, it is advisable to continue dose escalation until the target UA level is reached (the maximum allowable dose of allopurinol** is 900 mg/day), which allows target UA levels to be achieved in 75–92% of cases [221, 226, 228]. Sequential allopurinol titration by 50 mg every 2–4 weeks in patients with reduced eGFR allows target UA levels to be achieved at lower doses compared to patients with normal renal function [152, 229].

• For patients in whom allopurinol** is ineffective (failure to achieve the target UA level at maximum doses), prescribing febuxostat at a dose of 80–120 mg daily or #40 mg daily is recommended as an alternative [82, 147, 149, 230–235].

Level of Evidence A, Grade of Recommendation 1 for dosing regimens of 80–120 mg/day; Level of Evidence A, Grade of Recommendation 2 for the 40 mg/day regimen

Comments. In cases of allopurinol** ineffectiveness or intolerance, prescribing febuxostat allows target serum UA levels to be reached in more than half of cases [236–239]. According to the latest ACR and French Society of Rheumatology management guidelines, the initial dose of febuxostat is 40 mg/day [147, 149]. A febuxostat dose of 40 mg/day is equivalent in UA-lowering efficacy to allopurinol 300 mg/day and is sufficient to achieve the target UA level in 30–50% of patients [231, 233, 240]. Thus, in certain clinical scenarios—particularly in patients with CKD, for whom the mean effective dose of febuxostat may be lower [233]—it is feasible to use 40 mg/day as a starting dose.

• In patients with impaired renal function (estimated GFR < 60 mL/min/1.73 m², and particularly eGFR < 30 mL/min/1.73 m²), febuxostat is the drug of choice alongside allopurinol [149, 150, 241].

Level of Evidence A, Grade of Recommendation 1

Comments. Febuxostat is an effective alternative to allopurinol** in patients with CKD because, unlike allopurinol**, it is only partially eliminated by the kidneys. Febuxostat has demonstrated efficacy while maintaining a favorable safety profile even when estimated GFR falls below 60 mL/min/1.73 m2, as supported by data from several studies utilizing standard doses of the drug (40[80]–120 mg/day) [230, 242–245].

• During dose titration of allopurinol** and febuxostat, it is recommended to monitor serum UA, AST, and ALT activity, as well as serum creatinine (blood uric acid assay; blood aspartate aminotransferase activity assay, blood alanine aminotransferase activity assay, blood creatinine assay) 14–28 days after initiating or modifying ULT [82, 220, 246, 247].

Reliability of Evidence Grade C, Consensus Level of Evidence 5

Comments. Assessment of ULT efficacy is typically performed after 14–28 days. Elevations in transaminases are the most frequent adverse reactions associated with allopurinol** and febuxostat use; the probability of such adverse reactions may be dose-dependent, although this relationship is not strictly linear [220, 230, 237, 247, 248].

• Once the target UA level is reached, continuation of ULT for an indefinite period is recommended [147].

Reliability of Evidence Grade C, Consensus Level of Evidence 5

Comments. In cases of multi-year clinical remission (absence of gouty arthritis attacks alongside persistently low serum UA levels), discontinuation of ULT resulted in arthritis relapse within 5 years of follow-up in only 13% of patients (27 out of 211), even in the presence of mild hyperuricemia (< 420 µmol/L [< 7 mg/dL]) [249]. Furthermore, the higher the serum UA level after drug withdrawal, the more rapidly and frequently new arthritis attacks occur [219].

LoE C, GoR 5

Comments. Even if the target serum UA level is achieved, it may change over time, including during stable dosing of UA synthesis inhibitors (XO inhibitors [allopurinol** and febuxostat]). This necessitates continuous monitoring of serum UA levels [250].

• For patients with indications for antihypertensive therapy, it is recommended to consider prescribing losartan**, which possesses a moderate urate-lowering effect [82, 147, 251].

CGR C, LVE 3

Comments. For patients with gout and hypertension, losartan should be considered as a first-line antihypertensive agent given its proven urate-lowering effect. However, because the reduction in serum UA levels with this drug is modest, its use cannot replace allopurinol** and febuxostat [251 - 253].

• For patients with hypertriglyceridemia, it is recommended to consider prescribing fenofibrate**, which possesses a urate-lowering effect [82].

Level of Evidence C, Grade of Recommendation 1

Comments. The urate-lowering effect of fenofibrate, associated with prominent inhibition of renal urate transporters, significantly reduces serum UA levels, as confirmed by meta-analysis data [254], and in some cases enables achieving the target UA level in patients with gout [255]. These findings support considering fenofibrate** as an option for patients with hypertriglyceridemia.

• For patients with gout and type 2 diabetes mellitus, it is recommended to consider prescribing sodium-glucose cotransporter 2 (SGLT2) inhibitors as glucose-lowering agents, as they possess a moderate urate-lowering effect [256 - 261].

Level of Consensus Reliability A, Level of Evidence Data 2

Comments. Pharmacological inhibition of sodium-glucose cotransporter 2 (SGLT2) by SGLT2 inhibitors leads to excess glucose in primary urine, which promotes increased activity of the GLUT-9 transporter to reduce glucosuria while simultaneously enhancing UA excretion in exchange for glucose [262]. The uricosuric effect is class-specific and supported by meta-analysis results [256 - 260].

• For patients with gout taking loop or thiazide diuretics, it is recommended to consider discontinuing these drugs [40, 56, 81, 147, 149, 263, 264].

Level of Evidence B, Grade of Recommendation 3

Comments. Given that loop and thiazide diuretics lead to hyperuricemia and an increased risk of gout [56], they should be discontinued or replaced with other antihypertensive agents whenever possible. Nevertheless, target serum UA levels can still be achieved with urate-lowering therapy during concurrent diuretic use (in 68% of cases with allopurinol** and 81% with febuxostat) [265].

• Discontinuation of low-dose acetylsalicylic acid** in patients with gout is not recommended [147].

LoE C, GoR 5

Comments. Since the negative impact of low-dose acetylsalicylic acid** on serum UA levels is negligible, and according to a recent RCT, even absent [266], discontinuing the drug when clinically indicated is inappropriate.

3.1.3. Prevention of arthritis flares

• For all patients with gout, it is recommended to use prophylactic low-dose colchicine (0.5–1.0 mg/day), NSAIDs, or GCs during the first 6 months of urate-lowering therapy [71, 81, 149].

LoE C, GoR 5

Comments. Initiation of ULT is typically associated with an increased risk of gout flares compared to placebo during the first 6 months after reaching the target serum UA level [207]. Low doses of colchicine (0.5–1.0 mg daily) [267, 268], NSAIDs (e.g., #naproxen 250 mg twice daily, meloxicam 7.5 mg daily) [269, 270], and GCs (prednisolone** 7.5 mg daily) [267] can effectively reduce the frequency of arthritis flares during the first 6 months of therapy in patients taking allopurinol** and febuxostat [207, 271]. Evidence supports the cost-effectiveness of using low-dose colchicine (0.5 mg twice daily) for 6 months to prevent acute gout flares upon ULT initiation (titrating allopurinol** dose from target serum UA level [360 µmol/L]) [250, 267]. The choice of a specific drug is made individually based on contraindications for each agent. An additional factor favoring colchicine as a priority drug for arthritis flare prevention is the favorable impact of long-term low-dose therapy (0.5–1.0 mg/day) on cardiovascular event risk in both patients with gout [272, 273] and the general population [274 - 278]. Furthermore, contraindications to colchicine in patients with gout are less frequent than contraindications to NSAIDs and GCs [157, 279].

• When prescribing NSAIDs for the prevention of arthritis attacks, it is recommended to use non-selective cyclooxygenase-2 (COX-2) inhibitors (e.g., naproxen, diclofenac**, amtolmetin guacil, aceclofenac, etc.) in patients with a low risk of gastrointestinal (GI) complications, and — selective COX-2 inhibitors (meloxicam) with concomitant proton pump inhibitors (omeprazole**, pantoprazole, lansoprazole, rabeprazole, esomeprazole**, etc.) in patients at risk for GI complications [71, 82, 280].

LoE C, GoR 5

Comment. Comparative studies on the long-term use of various NSAIDs for arthritis flare prophylaxis have not been conducted. Expert opinion is based on an analysis of fundamental principles of long-term NSAID therapy outlined in national and international consensus statements [279]. Practical experience with long-term NSAID use in patients with gout for flare prophylaxis during ULT initiation has demonstrated high efficacy [271].

LoE C, GoR 5

Comment. High and very high cardiovascular risk in gout is very common (identified in 17–29% of patients according to various risk scoring scales) [281]; the use of NSAIDs in this patient category must comply with current guidelines for NSAID therapy.

• When prescribing colchicine for the prevention of arthritis flares in patients with gout, it is recommended to assess the risks of adverse drug reactions: perform a clinical examination, routine biochemical blood test, complete blood count (CBC), and blood creatine kinase isoenzyme levels/activity at least once every 2–3 months [82, 147, 282].

LoE C, GoR 5

Comments. Rare adverse reactions associated with colchicine include severe conditions such as myopathy [283], neuropathy [284], cytopenia (thrombocytopenia, leukopenia, pancytopenia, aplastic anemia) [285], which necessitates dynamic monitoring during long-term therapy.

• When prescribing low-dose GCs (e.g., prednisolone** 7.5 mg daily) for the prevention of arthritis flares, it is recommended to assess the risk of adverse reactions (erosive and ulcerative GI lesions, cardiovascular diseases, carbohydrate metabolism disorders, osteoporosis, etc.) [268, 286 - 288].

GoR C, LoE 4

Comments. This recommendation is based on an analysis of risks associated with long-term GC therapy; however, existing studies on long-term GC use in patients with gout are insufficient to quantify the probability of these risks materializing.

3.1.4. Lifestyle recommendations

• For all patients with gout, it is recommended to limit alcohol consumption [46, 29, 290].

LoR B, LoE 2

Comments. Consumption of any alcohol, especially beer and spirits, leads to increased serum UA levels and dose-dependently increases the risk of developing gout, as well as the risk of arthritis flares in patients with gout, both with regular intake and consumption immediately prior to a flare. Therefore, alcohol consumption should be restricted in patients with gout [291, 292].

• For all patients with gout, it is recommended to limit the consumption of red meat, fish, and seafood [46, 54, 71, 82, 293, 294].

CGR A, LVE 2

Comments. Recent consumption of certain foods, primarily red meat, fish, and seafood, increases serum UA levels and the probability of acute gouty arthritis flares [291 - 294]. According to one of the largest studies, the probability of an acute arthritis flare in gout patients consuming purine-rich animal-derived foods increases the risk of arthritis flares by almost 5-fold [292].

• All patients with gout are recommended to limit the intake of fructose-containing beverages [45, 46, 71, 82, 294].

Level of Consensus Reliability A, Level of Evidence Data 2

Comments. According to a meta-analysis, excessive fructose intake exceeds the risks of hyperuricemia development compared to the consumption of meat and seafood [293]. Fructose consumption at a dose of 1 g/kg of body weight in gout patients increases serum UA levels by 60–120 µmol/L [295].

• Weight loss is recommended for all patients with gout and obesity or overweight [71, 82, 296 – 298].

Level of Evidence B, Grade of Recommendation 3

Comments. Weight loss, regardless of whether it is achieved through diet or physical activity, is associated with the normalization of UA levels [296, 298]. A detailed analysis of 10 key studies showed that weight loss in overweight and gout patients during medium- to long-term follow-up leads to a decrease in serum UA levels and the frequency of arthritis flares [296].

• Patients with gout are recommended to engage in dosed physical activity [82, 299 - 301].

Level of Evidence C, Grade of Recommendation 4

Comments. Physical activity regimens for hyperuricemia have not been developed, and RCT data are lacking. Single studies have shown that physical activity > 150 min/week in patients with hyperuricemia significantly reduces the risk of death compared to those with low physical activity [299]. Regular, dosed physical activity is associated with lower UA levels [296, 301].

3.2 Surgical Treatment

• Surgical treatment of gout, consisting of the removal of superficially located foreign bodies or the removal of a foreign body with dissection of soft tissues containing monosodium urate (MSU) crystals (tophi), is recommended in cases of nerve trunk compression by tophi with the development of neurological symptoms (in spinal lesions, carpal tunnel syndrome, etc.) [152, 153, 302 - 304].

Level of Evidence B, Grade of Recommendation 3

Comments. Comparative studies on the surgical treatment of gout have not been conducted; isolated clinical case reports demonstrate the efficacy of surgical decompression of nerve trunks by removing tophaceous masses [305, 306]. In most cases, surgical treatment of gout is resorted to when patients do not receive urate-lowering therapy (ULT), and it is not considered an effective method of treating the disease (a way to reduce the amount of urates in the body) [302].

• Joint replacement (arthroplasty) or arthrodesis is recommended in the presence of pronounced structural changes accompanied by persistent pain and joint function impairment in cases of ULT failure [100, 307, 308].

GoR C, LoE 4

Comments. In the absence of adequate gout therapy, the risk of bone tissue damage is high, and the need for large joint replacement is higher than in the general population [307].

Medical Services (NMU codes):

• Joint replacement;

• Hip joint orthopedic replacement;

• Hip joint orthopedic replacement (resection of the proximal femur);

• Joint replacement ( revision arthroplasty );

• Total knee replacement;

• Ankle replacement;

• Metatarsophalangeal joint replacement;

• Interphalangeal joint replacement;

• Spinal arthrodesis;

• Foot and ankle arthrodesis;

• Arthrodesis of other joints.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Level of Evidence B, Grade of Recommendation [missing value in Russian]

Comments. Educational programs, whose main objective is to explain to patients the goal of gout therapy (complete disease control, which is possible only by maintaining the target serum UA level), help achieve better adherence to drug therapy and better long-term treatment outcomes [207, 210].

5. Prevention and Dispensary Observation

• Drug prophylaxis of hyperuricemia development, acute urate nephropathy, tumor lysis syndrome, and secondary gout (prescription of #allopurinol** 200–300 mg daily or febuxostat) is recommended for patients receiving chemotherapy for malignant neoplasms, primarily patients with lymphoproliferative disorders, in order to prevent hyperuricemia and the development of tumor lysis syndrome [71, 247, 310 - 312].

Level of Evidence C, Grade of Recommendation 2

Comments. Patients at high risk for tumor lysis syndrome, characterized by rapid cytolysis leading, among other things, to hyperuricemia and acute renal failure [313], include patients with high tumor burden, high tumor growth rate, high sensitivity to chemotherapy or biotherapy, as well as with hematological malignancies, in particular acute leukemias or high-grade lymphomas [314, 315]. The frequency of sometimes irreversible urate nephropathy reaches 30% [316]. According to meta-analyses and RCTs, tumor lysis syndrome prophylaxis with allopurinol** and febuxostat is equally effective with a similar safety profile [311, 312].

6. Organization of Medical Care

• Treatment of patients with gout is recommended to be carried out by rheumatologists (as an exception, by general practitioners and family physicians, but with consultative and organizational support from a rheumatologist) involving other specialists (clinical pharmacologist, nutritionist, etc.) and based on close interaction between the doctor and the patient [317, 318].

GoR C, LoE 4

Comments. Treatment outcomes and the need for emergency medical care in gout patients managed by rheumatologists are better than in those managed by general practitioners and internists [319]. A multidisciplinary approach to the management of patients with gout helps reduce the negative impact of comorbid pathology on the level of uricemia and clinical manifestations of the disease, as well as improve the efficacy of pharmacotherapy and prognosis.

6.1 Indications for referral to a rheumatologist

GoR C, LoE 4

Comments. According to several population and cohort studies, both the diagnosis and treatment of gout are associated with a huge number of errors made by primary care physicians, which predetermines a large and unremitting number of severe tophaceous gout cases [321 - 324].

6.2 Indications for hospitalization in a specialized rheumatology department or therapeutic department

- Inability to establish a diagnosis at the outpatient stage / performing differential diagnosis and selecting therapy.

- Chronic gouty arthritis with concomitant diseases, including cardiovascular diseases, metabolic disorders, kidney diseases.

- Decision-making on the prescription and administration of biologic DMARDs (IL inhibitors) and initiation of these treatment methods.

6.3. Discharge criteria from the hospital

- Absence of swollen joints or a reduction in their number by at least 50% in oligo- or polyarthritis.

- Absence of joint pain or a reduction in its intensity by 50% or more compared to baseline according to the VAS (improvement in at least one of the listed indicators is mandatory) (Appendix G2).

6.4. Diagnosis

1. To diagnose gout in all patients with at least one episode of swelling, pain, or tenderness in a peripheral joint or bursa, the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria (Appendix G1) have been developed, which should be used when enrolling patients in clinical studies and for diagnosis in clinical practice [62, 65].

2. The diagnosis of gout is established either by visual detection of MSU crystals in synovial fluid or tophus contents, or by the presence of a combination of clinical, laboratory, and instrumental features of the disease scored in points. According to the criteria, if the score is 8 or more, the disease can be classified as gout

6.5. Principles of formulating the diagnosis in gout

The formulation of the diagnosis must indicate:

• Course of the disease:

- chronic — if the patient has chronic arthritis;

- intermittent — in case of relapses of acute arthritis flares.

• Arthritis characteristics:

- intercritical period;

- acute arthritis;

- chronic arthritis.

• Presence of tophi:

- tophaceous form — presence of tophi;

- non-tophaceous form — absence of tophi.

Examples of diagnosis:

1. Gout, chronic course, chronic arthritis, tophaceous form.

2. Gout, chronic course, chronic arthritis, non-tophaceous form.

3. Gout, intermittent course, intercritical period, tophaceous form.

4. Gout, intermittent course, intercritical period, non-tophaceous form.

5. Gout, intermittent course, acute arthritis, tophaceous form.

6. Gout, intermittent course, acute arthritis, non-tophaceous form.

7. Additional Information

7.1. Comorbidity

The nature of concomitant (comorbid) diseases is of paramount importance for selecting treatment tactics in terms of both efficacy and safety of therapy [82].

• Before initiating IL-1 inhibitors, all patients with gout are recommended to be evaluated to rule out active or latent tuberculosis infection, including medical history taking, diagnostic tests (intradermal test with tuberculosis allergen, tuberculin skin test, blood interferon-gamma release assay for Mycobacterium tuberculosis complex antigens), and chest radiography [110 - 113].

Level of Certainty of Evidence B, Level of Reliability of Data 1

• If a tuberculosis infection is detected, initiating or continuing treatment with IL-1 inhibitors is not recommended [325].

Level of reliability of evidence A, level of bibliographic data validity 1

Comments. Although cases of tuberculosis detection during IL-1 inhibitor therapy are sporadic, the likelihood of respiratory tract infections in patients receiving IL-1 inhibitors is higher than in those receiving placebo [326].

7.2. Vaccination

LCR C, LoE 3

Comments. Aluminum and non-aluminum adjuvants contained in many other adult vaccines (tetanus toxoid vaccines, diphtheria toxoid vaccines, pertussis vaccines, pneumococcal vaccines, viral hepatitis (hepatitis B) vaccines, varicella vaccines), by promoting IL-1 production, may serve as trigger factors for the development of acute gouty arthritis attacks; however, this cannot be a reason to refuse vaccination, as its benefits for both individual and public health are immense [328].

7.3. Pregnancy

• Pregnant women with gout are not recommended to take urate-lowering therapy (allopurinol**, febuxostat) [114, 115, 117, 329, 330].

Reliability of Evidence Grade C, Consensus Level of Evidence 5

Comments. Although high serum UA levels are hypothesized to be associated with preeclampsia [329, 331], and the probability of arthritis attacks during pregnancy persists in the absence of control over serum UA levels, the potential risk to the fetus associated with the use of allopurinol and febuxostat in pregnant women cannot justify their use, although proper studies of these drugs have not been conducted, and the described cases of teratogenic effects of allopurinol have a low causal relationship [115, 116, 332].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Evgeny L. Nasonov — Scientific Supervisor of the V.A. Nasonova Research Institute of Rheumatology, MD, PhD, Professor, Academician of the Russian Academy of Sciences, Moscow, President of the Association of Rheumatologists of Russia

2. Aleksandr M. Lila — Director of the V.A. Nasonova Research Institute of Rheumatology, Head of the Department of Rheumatology at the Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, MD, PhD, Professor, Corresponding Member of the Russian Academy of Sciences, Moscow, Member of the Board and Presidium of the Association of Rheumatologists of Russia.

3. Alesya A. Klimenko — Associate Professor, Head of the Academician A.I. Nesterov Department of Faculty Therapy at the Pirogov Russian National Research Medical University, Member of the Association of Rheumatologists of Russia, Member of the Russian Cardiological Society, MD, PhD, General Practitioner, Cardiologist, Rheumatologist of the highest qualification category.

4. Dmitry A. Voytko – Senior Research Fellow at the Department of Urolithiasis, Lopatkin Scientific Research Institute of Urology and Interventional Radiology – Branch of the National Medical Research Radiological Centre of the Russian Ministry of Health, PhD, Urologist.

5. Maksim S. Eliseev — Senior Research Fellow, Head of the Laboratory of Microcrystalline Arthropathies at the V.A. Nasonova Research Institute of Rheumatology, PhD, Rheumatologist of the highest qualification category.

6. Maria E. Eliseeva — Head of the Department at the Levoberezhny Gerontological Center of Moscow, PhD, Gerontologist, General Practitioner of the first qualification category.

7. Olga V. Zhelyabina — Junior Research Fellow at the Laboratory of Microcrystalline Arthropathies at the V.A. Nasonova Research Institute of Rheumatology, PhD, Rheumatologist.

8. Yanina I. Kuzmina - Junior Research Fellow at the Laboratory of Microcrystalline Arthropathies at the V.A. Nasonova Research Institute of Rheumatology, Rheumatologist.

9. Vadim I. Mazurov — Head of the E.E. Eichwald Department of Therapy, Rheumatology, Certification of Temporary Disability and Quality of Medical Care at the North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health, Head of the Research Laboratory of Rheumatology at the Almazov National Medical Research Centre of the Russian Ministry of Health, MD, PhD, Professor, Academician of the Russian Academy of Sciences, St. Petersburg, Vice-President of the Association of Rheumatologists of Russia.

10. Evgenia I. Markelova — Senior Research Fellow at the Rheumatology Department, Associate Professor at the Department of Rheumatology, Faculty of Advanced Medical Training at the Moscow Regional Research Clinical Institute named after M.F. Vladimirsky, PhD, Cardiologist, Physician of Functional Diagnostics of the highest qualification category.

11. Andrey A. Nemykin — Head of the patient organization "Gout XXI Century" Medical Foundation for the Treatment and Prevention of Gout, Head of Sector at the Order of the Red Banner of Labour Moscow Technical University of Communications and Informatics.

12. Natalia N. Pavlova — Head of the Department of Internal Diseases of the Pediatric and Dental Faculties at the Chita State Medical Academy of the Russian Ministry of Health, Professor, MD, PhD, Cardiologist.

13. Mikhail Yu. Prosyannikov – Head of the Department of Urolithiasis at the Lopatkin Scientific Research Institute of Urology and Interventional Radiology – Branch of the National Medical Research Radiological Centre of the Russian Ministry of Health, Professor at the Department of Biomedical Safety of the Bauman Moscow State Technical University, MD, PhD, Urologist.

14. Vladimir V. Tsurko — Professor at the Department of Faculty Therapy, Faculty of General Medicine, Pirogov Russian National Research Medical University, MD, PhD, General Practitioner, Rheumatologist.

15. Maria N. Chikina — Junior Research Fellow at the Laboratory of Microcrystalline Arthropathies at the V.A. Nasonova Research Institute of Rheumatology, PhD, Rheumatologist.

Appendix A2. Methodology for Developing Clinical Guidelines

Appendix A2–1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Appendix A2–2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Appendix A2–3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)

Procedure for updating clinical guidelines.

The clinical guidelines updating mechanism provides for their systematic revision—at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of specific conditions, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Appendix A3.1. Baseline information to be obtained during medical history taking

Appendix A3.2. Main requirements for physical examination

Appendix A3.3. Calculation of GFR using the CKD Epidemiology Collaboration 2009 formula*

GFR calculator: https://www.kidney.org/professionals/KDOQI/gfr_calculator

Appendix A3.4. General characteristics of drugs used for the treatment of gout

Appendix A3.5. Optimal doses of colchicine in reduced GFR [149]

Appendix B. Physician Action Algorithms

Name of the "Diagnostics" subschema in the flowchart "Management Algorithm in Clinical Guidelines 'Gout': 1.1 Management Algorithm

Appendix C. Patient Information

• Gout is a disease associated with inflammation occurring in areas where uric acid salts (crystals) are deposited. These crystals can form when there is a high level of uric acid in the blood (the higher the level, the greater the risk). However, not everyone with a high uric acid level develops gout—only about 20%. Uric acid is produced within the body (approximately 75%) and obtained from food (about 25%).

• Uric acid levels can rise for various reasons. Some of these are beyond our control: inherited impaired function of the renal tubules through which uric acid is excreted by the kidneys; age; male gender. Other factors can be controlled: alcohol, overweight, high blood pressure, and dietary errors.

• Gout manifests as attacks of severe pain and inflammation in one or more joints (arthritis), most commonly in the joints of the feet. The affected joint swells, feels hot, and turns red. If gout is suspected, the doctor may examine fluid obtained from the joint using a specialized polarizing microscope.

• Treatment is prescribed by a physician. The doctor should explain what the patient can do independently if gout attacks occur in the future. It is important to remember that starting treatment early (in the first hours after an attack begins) yields better results.

• Treating an arthritis attack is not the same as treating the disease itself. The goal is to prevent similar attacks and rid tissues and organs of uric acid deposits, which is achievable in almost all cases. To do this, it is necessary to persistently lower the uric acid level to a point where existing crystals dissolve and new ones do not form. This "target" uric acid level is no higher than 360 µmol/L (in all cases) and 300 µmol/L (in severe forms of gout).

• The mainstay of gout treatment is urate-lowering therapy. The drug, dosage, and treatment regimen are determined by the physician. Diet is an important component of treatment.

• In the first months of treatment, the likelihood of attacks increases; therefore, along with urate-lowering drugs, the doctor may prescribe low doses of anti-inflammatory drugs or colchicine for the next few months.

• With long-term maintenance of normal uric acid levels, arthritis attacks will gradually cease, and existing uric acid deposits will dissolve.

• Gout treatment is lifelong. If stopped, crystals will form again, and attacks will recur. The absence of adequate treatment can lead to the destruction of joints and tissues, resulting in disability and damage to various organs (for example, severe kidney disease).

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) Gout Classification Criteria.

Russian title: American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) Gout Classification Criteria.

Original title (if applicable): ACR-EULAR Gout Classification Criteria

Source (official developer website, validation publication): 2015 Gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015;74:1789-1798/

https://goutclassificationcalculator.auckland.ac.nz/

Type (underline):

- assessment scale

- score

- questionnaire

- other (specify): classification criteria

Purpose: verification of the diagnosis of gout

Content (template): swelling, pain, or tenderness upon palpation in a peripheral joint or bursa.

† – Ever-experienced symptomatic episodes that include swelling, pain, or tenderness upon palpation in a peripheral joint or bursa.

‡ – If serum UA is <4 mg/dL (240 µmol/L), 4 points should be subtracted; if serum uric acid is ≥4 mg/dL – 6 mg/dL (≥240 – <360 µmol/L), score this item as 0 points.

§ – If compensatory polarized light microscopy of synovial fluid obtained from a previously affected joint performed by a trained specialist does not detect monosodium urate crystals, 2 points should be subtracted. If synovial fluid was not evaluated, score this item as 0 points.

¶ – If methods are unavailable, score this item as 0 points.

# – A hyperechoic irregular band along the surface of the hyaline cartilage independent of the angle of insonation (note: a false-positive double contour sign may appear on the cartilage surface but should disappear with a change in the angle of insonation).

* – Presence of urate color-coded areas within joints or periarticularly. Images must be obtained using dual-energy computed tomography (DECT) with data acquired at 80 and 140 kV and analyzed using gout-specific software with two-tissue material decomposition for urate color-coding. A positive scan is defined as the presence of urate color-coding in articular or periarticular areas. Nail bed, micro-reflections, skin, motion, beam hardening, and vascular artifacts must not be interpreted as evidence of urate deposits by dual-energy computed tomography.

†† – Erosion is defined as a cortical defect with a sclerotic margin and overhanging edges, excluding the distal interphalangeal joints and the "gull wing" sign.

Key (interpretation):

The diagnosis of gout is established either by visual detection of MSU crystals in SF or tophus contents, or by the presence of a combination of clinical, laboratory, and instrumental signs of the disease scored in points. According to the criteria, if the score is 8 or more, the disease can be classified as gout.

Appendix G2. Visual Analogue Scale (VAS)

Russian title: Visual Analogue Scale for pain (VAS)

Original title (if available): A Visual Analogue Scale – VAS

Source (official developer website, publication with

validation): Gélinas C, Puntillo KA, Levin P, et al: The Behavior Pain Assessment Tool for critically ill adults: A validation study in 28 countries. Pain 2017; 158:811–821.

Type (underline):

- rating scale

- index

- questionnaire

- other (specify):

Purpose: assessment of pain intensity

Content (template):

0 points – no impairment;

1–3 points – mild pain (mild impairment);

4–6 points – moderate pain (moderate impairment);

7–8 points – severe pain (severe impairment);

9–10 points – excruciating pain (absolute impairment).