2016 updated EULAR evidence-based recommendations for the management of gout.

BACKGROUND: New drugs and new evidence concerning the use of established treatments have become available since the publication of the first European League Against Rheumatism (EULAR) recommendations for the management of gout, in 2006. This situation has prompted a systematic review and update of the 2006 recommendations. METHODS: The EULAR task force consisted of 15 rheumatologists, 1 radiologist, 2 general practitioners, 1 research fellow, 2 patients and 3 experts in epidemiology/methodology from 12 European countries. A systematic review of the literature concerning all aspects of gout treatments was performed. Subsequently, recommendations were formulated by use of a Delphi consensus approach. RESULTS: Three overarching principles and 11 key recommendations were generated. For the treatment of flare, colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), oral or intra-articular steroids or a combination are recommended. In patients with frequent flare and contraindications to colchicine, NSAIDs and corticosteroids, an interleukin-1 blocker should be considered. In addition to education and a non-pharmacological management approach, urate-lowering therapy (ULT) should be considered from the first presentation of the disease, and serum uric acid (SUA) levels should be maintained at<6 mg/dL (360 µmol/L) and <5 mg/dL (300 µmol/L) in those with severe gout. Allopurinol is recommended as first-line ULT and its dosage should be adjusted according to renal function. If the SUA target cannot be achieved with allopurinol, then febuxostat, a uricosuric or combining a xanthine oxidase inhibitor with a uricosuric should be considered. For patients with refractory gout, pegloticase is recommended. CONCLUSIONS: These recommendations aim to inform physicians and patients about the non-pharmacological and pharmacological treatments for gout and to provide the best strategies to achieve the predefined urate target to cure the disease.

[Time course of changes in the clinical manifestations of gout in men: data of a 7-year retrospective follow-up].

AIM: To estimate the time course of changes in the clinical manifestations of gout and their risk factors during a long-term follow-up. SUBJECTS AND METHODS: A total of 160 male patients with gout were examined and followed up for a mean of 6.9 ± 2.0 years. Their clinical assessment included determination of the type of arthritis over time, the frequency of arthritis attacks during one year prior to the examination, the presence and number of subcutaneous tophi, inflamed joints, comorbid or co-occurring diseases (CD), allopurinol adherence, dietary compliance, frequency of taking non-steroidal anti-inflammatory drugs (NSAIDs), diuretics, and alcohol. The serum levels of uric acid (UA), glucose, total cholesterol, and glomerular filtration rate were estimated. RESULTS: The number of patients taking allopurinol increased from 19% to 64% (p < 0.0001), its average daily dose was 167.6 ± 94.6 mg. The serum level of UA decreased; 16% of the patients achieved its target level. The number of patients with chronic arthritis was not significantly changed. Their serum level of UA was unchanged; the detection rate of subcutaneous tophi and CD rose. During one year, arthritis attacks were absent in 13% of the patients; 90% of them took allopurinol. In these patients, serum UA levels and body mass index significantly declined and the rate of CD was unchanged. None of 18 patients who had their diet and no allopurinol achieved the target level of UA. CONCLUSION: Among the gouty patients, 36% refrain from the use of allopurinol, only 23% out of them require that its dose be adjusted to achieve the target level of UA. Dietary compliance is insufficient to reach the target level of UA. Chronic arthritis is associated with the increased incidence of CD.

[Main factors of gender dimorphism of gout (estrogens and diuretics vs alcohol and genetics)].

The article analyses factors underling gender dimorphism of gout, gender epidemiological differences. Discussion covers the role of estrogens and menopause, alcohol, diuretics, gender-associated genetic characteristics in gout genesis.

European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis.

OBJECTIVES: To agree terminology and to develop recommendations for the diagnosis of calcium pyrophosphate deposition (CPPD). METHODS: The European League Against Rheumatism (EULAR) CPPD Task Force, comprising 15 experts from 10 countries, agreed the terms and recommendations for diagnosis of CPPD using a Delphi consensus approach. Evidence was systematically reviewed and presented in terms of sensitivity, specificity and positive likelihood ratio (LR) to support diagnosis; ORs were used for association. Strength of recommendation (SOR) was assessed by the EULAR visual analogue scale. RESULTS: It was agreed that 'CPPD' should be the umbrella term that includes acute calcium pyrophosphate (CPP) crystal arthritis, osteoarthritis (OA) with CPPD and chronic CPP crystal inflammatory arthritis. Chondrocalcinosis (CC) defines cartilage calcification, most commonly due to CPPD and detected by imaging or histological examination. A total of 11 key recommendations were generated on the topics of clinical features, synovial fluid (SF) examination, imaging, comorbidities and risk factors. Definitive diagnosis of CPPD relies on identification of SF CPP crystals. Rapid onset inflammatory symptoms and signs are suggestive but not definitive for acute CPP crystal arthritis. Radiographic CC is not highly sensitive or specific, whereas ultrasonography appears more useful (LR=24.2, 95% CI 3.51 to 168.01) for peripheral joints. Recognised risk factors for CPPD include ageing, OA and metabolic conditions such as primary hyperparathyroidism, haemochromatosis and hypomagnesaemia; familial forms are rare. SORs varied from 53 to 99 (maximum 100). CONCLUSION: New terms for CPPD were agreed and 11 key recommendations for diagnosis of CPPD were developed using research evidence and expert consensus.

EULAR recommendations for calcium pyrophosphate deposition. Part II: management.

OBJECTIVES: To develop evidence-based recommendations for management of calcium pyrophosphate deposition (CPPD). METHODS: A multidisciplinary guideline development group of 15 experts, representing 10 European countries, generated key propositions for management of CPPD using a Delphi consensus approach. For each recommendation research evidence was searched systematically. Whenever possible, the effect size and number needed to treat for efficacy and RR or OR for side effects were calculated for individual treatment modalities. Strength of recommendation was assessed by the European League Against Rheumatism visual analogue scale. RESULTS: Nine key recommendations were generated, including topics for general management, treatment of acute attacks, prophylaxis against recurrent acute attacks and management of chronic symptoms. It was recommended that optimal treatment requires both non-pharmacological and pharmacological treatments. For acute CPP crystal arthritis, cool packs, temporary rest and joint aspiration combined with steroid injection are often sufficient. For prophylaxis or chronic inflammatory arthritis with CPPD, oral non-steroidal anti-inflammatory drugs with gastroprotective treatment and/or low-dose colchicine 0.5-1.0 mg daily may be used. Other recommendations included parenteral or oral corticosteroid for acute CPP arthritis in those unresponsive or unsuited to other measures, and low-dose corticosteroid, methotrexate or hydroxychloroquine for chronic inflammatory arthritis with CPPD. Asymptomatic CPPD requires no treatment. Strength of recommendations varies from 79% to 95%. CONCLUSION: Nine key recommendations for management of CPP crystal associated arthritis were developed using both research evidence and expert consensus. Strength of recommendations was provided to assist the application of these recommendations.

[Carbohydrate metabolic disorders in gout: incidence and clinical features].

AIM: To study the clinical features of gout concurrent with carbohydrate metabolic disturbances. SUBJECTS AND METHODS: One hundred and ninety-five patients with gout were examined. Their mean age was 54.8 +/- 10.4 years; disease duration was 10 (6-15) years. Anthropometry was estimated; the levels of uric acid (UA), creatinine, and lipid metabolic parameters were measured fasting; the concentrations of glucose were estimated fasting and 2 hours after use of 75 g of glucose; UA excretion and glomerular filtration rate were calculated. RESULTS: Carbohydrate metabolic disorders were found in 112 (57.4%) patients with gout: type 2 diabetes (T2D) in 67 (34.3%); impaired fasting glycemia in 23 (11.8%); impaired glucose tolerance in 22 (11.3%); the diagnosis of T2D was first detected in 35 patients with gout, i 12 of the 35 (34%) cases after oral glucose tolerance test (OGTT). The detection rate of carbohydrate metabolic disturbances was in direct proportion to serum UA levels. This value was 513.7 +/- 122.2 pmicromol/l in gouty patients with carbohydrate metabolic disturbances and 472.4 +/- 121.9 micromol/l in normoglycemic patients (p = 0.026). High body mass index and elevated serum were significantly determined in hyperglycemic patients; coronary heart disease (CHD) and arterial hypertension were more frequently diagnosed. CONCLUSION: OGTT causes a 34% increase in the detection rate of T2D in patients with gout. Carbohydrate metabolic disturbances are revealed in the majority of patients with gout and associated with obesity, hypertriglyceridemia, high serum UA levels, chronic disease forms, the high incidence of CHD and arterial hypertension.

[Chronic gout: causes, clinical manifestations, treatment].

Why chronic gout, that is mostly a well diagnosed and controlled disease if it is timely and systematically treated with allopurinol, becomes a topical public health problem following 50 years after the introduction of pathogenetic therapy with xantine oxidase inhibitors is under consideration. The principles of rational therapy for chronic gouty arthritis are outlined.

[Relationship between the intima-media complex thickness, the risk factors of cardiovascular diseases, and the level of C-reactive protein in gouty patients].

AIM: To estimate a relationship between the intima-media thickness (TIM), cardiovascular risk (CVR) factors, and the level of C-reactive protein (CRP) in gouty patients. SUBJECTS AND METHODS: Eighty-nine patients at an interattack interval were examined. The patients' mean age was 46.0 +/- 11.4 years; the duration of the disease was 5.2 (3.0; 8.9) years. The traditional CVR factors were analyzed. Carotid ultrasound scanning was performed to detect vascular atherosclerotic lesion. The serum CRP concentration was measured by a highly sensitive immunonefelometric assay. RESULTS: According to the TIM, the patients were divided into 2 groups: 1) 37 patients with signs of carotid atherosclerotic lesion (TIM > or = 0.9 mm); 2) 52 patients with a TIM of less than 0.9 mm. The ages at the moment of examination and at the onset of the disease, the duration of the disease, as well as systolic blood pressure, and the risk of myocardial ischemia were greater in Group 1 than those in Group 2. In patients with atherosclerosis, the concentration of CRP was statistically significantly higher than that in patients without this condition. CONCLUSION: By complementing the classical CVR factors, CRP may be a predictor of cardiovascular diseases and their complications in patients with gout at an interattack interval.

[Effect of metformin on the clinical course of gout and insulin resistance].

UNLABELLED: The aim of this prospective study was to evaluate results of metformin (MF) therapy during 1 year of uric acid (UA) metabolism and the clinical course of gout with insulin resistance (IR). The study included 30 patients (28 men and 2 women) of mean age 51 yr and duration of he disease 4-11 yr. IR was diagnosed based on the HOMA index. INCLUSION CRITERIA: the absence of anti-gout therapy, normal renal and hepatic function, abstinence. The patients were given 1500 mg MF/day. The measured parameters included anthropometric and clinical characteristics, 24 hour AP, plasma UA, glucose, insulin, urea, creatinine, ALT, AST, lipid spectrum at the first and subsequent visits. UA clearance and excreted UA fraction were calculated. UA level decreased from 569 +/- 109.5 to 442.8 +/-107.4 mcmol/l (p < 0.01) after 12 months of MF therapy. Normouricemia ( < 360 mcmol/l) was achieved in 11 patients. Fasting insulin level dropped by 35% (from 23.9 to 15.9 mcU/ml, p < 0.01), HOMA index from 6.5 to 3. 7(p < 0.01). Serum glucose, cholesterol, triglycerides, and LDL cholesterol decreased while HDL cholesterol increased. Parameters of renal UA regulation and anthropometry remained unaltered. MF therapy resulted in a decrease of serum UA, insulin, and the degree of IR. The hypouricemic effect of MF was unrelated to renal UA excretion, reduced AP and body weight. It is hypothesized that MF reduces production of UA in patients with gout due to inhibition of synthesis of free fatty acids.

[Metabolic syndrome in gout].

The presence of metabolic syndrome (MS) is characteristic for many patients with gout. MS is closely associated with a generalized disorder called insulin resistance (IR) or impaired tissue responsiveness to the normal action in insulin. MS and IR define cardiovascular disease risks and are the main factors leading to severe disease associated with chronic arthritis and struck joints in gout patients. Given serious complications associated with MS, this frequent comorbidity should be recognized and be taken into account in the long-term treatment and overall health of individuals with gout. The review is devoted to studying MS and IR in gout patients.

A modified Delphi exercise to determine the extent of consensus with OMERACT outcome domains for studies of acute and chronic gout.

OBJECTIVES: To reach consensus with recommendations made by an OMERACT Special Interest Group (SIG). METHODS: Rheumatologists and industry representatives interested in gout rated and clarified, in three iterations, the importance of domains proposed by the OMERACT SIG for use in acute and chronic gout intervention studies. Consensus was defined as a value of less than 1 of the UCLA/RAND disagreement index. RESULTS: There were 33 respondents (61% response rate); all agreed the initial items were necessary, except "total body urate pool". Additional domains were suggested and clarification sought for defining "joint inflammation" and "musculoskeletal function". Items that demonstrated no clear decision were re-rated in the final iteration. There were six highly rated items (rating 1-2) with four slightly lower rating items (rating 3) for acute gout; and 11 highly rated items with eight slightly lower ratings for chronic gout. CONCLUSIONS: Consensus is that the following domains be considered mandatory for acute gout studies: pain, joint swelling, joint tenderness, patient global, physician global, functional disability; and for chronic gout studies: serum urate, gout flares, tophus regression, health-related quality of life, functional disability, pain, patient global, physician global, work disability and joint inflammation. Several additional domains were considered discretionary.

[Comparison of the time to analgetic and anti-inflammatory effect in the treatment of gouty arthritis with nimesulide and sodium diclofenac].

AIM: To compare the time to presentation of the analgetic and anti-inflammatory effects of granulated and tablet nimesulide and sodium diclofenac since the start of therapy for gouty arthritis (GA). MATERIAL AND METHODS: Ninety males with gout were randomized into 3 equal groups. The patients were included in the study by the following criteria: a documented diagnosis of gout (Wallace S. criteria), age over 18 years, acute arthritis for less than 3 weeks, affection of 4 and more joints. For 7 days patients of group 1 received nimesil (200 mg/day), those of group 2--aponil (200 mg/day), group 3 --sodium diclofenac (150 mg/day). Swelling, articular, pain indices were estimated daily for 7 days. RESULTS: Patients of group 1 (nimesil) experienced pain relief on min 20; patients taking nimesulide (aponil) experienced pain attenuation within the first hour. Pain (at rest and movement) and the indices declined faster in group 1 than in group 2 as well as in groups 1 and 2 compared to group 3. Arthritis was arrested in 24 (80%) patients of group 1, 11 (36%) of group 2 and 4 (13%) of group 3. CONCLUSION: Efficacy of nimesulide for arrest of an acute gout attack exceeds that of sodium diclofenac. Granulated nimesulide has advantages over tablets.

EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT).

OBJECTIVE: To develop evidence based recommendations for the management of gout. METHODS: The multidisciplinary guideline development group comprised 19 rheumatologists and one evidence based medicine expert representing 13 European countries. Key propositions on management were generated using a Delphi consensus approach. Research evidence was searched systematically for each proposition. Where possible, effect size (ES), number needed to treat, relative risk, odds ratio, and incremental cost-effectiveness ratio were calculated. The quality of evidence was categorised according to the level of evidence. The strength of recommendation (SOR) was assessed using the EULAR visual analogue and ordinal scales. RESULTS: 12 key propositions were generated after three Delphi rounds. Propositions included both non-pharmacological and pharmacological treatments and addressed symptomatic control of acute gout, urate lowering therapy (ULT), and prophylaxis of acute attacks. The importance of patient education, modification of adverse lifestyle (weight loss if obese; reduced alcohol consumption; low animal purine diet) and treatment of associated comorbidity and risk factors were emphasised. Recommended drugs for acute attacks were oral non-steroidal anti-inflammatory drugs (NSAIDs), oral colchicine (ES = 0.87 (95% confidence interval, 0.25 to 1.50)), or joint aspiration and injection of corticosteroid. ULT is indicated in patients with recurrent acute attacks, arthropathy, tophi, or radiographic changes of gout. Allopurinol was confirmed as effective long term ULT (ES = 1.39 (0.78 to 2.01)). If allopurinol toxicity occurs, options include other xanthine oxidase inhibitors, allopurinol desensitisation, or a uricosuric. The uricosuric benzbromarone is more effective than allopurinol (ES = 1.50 (0.76 to 2.24)) and can be used in patients with mild to moderate renal insufficiency but may be hepatotoxic. When gout is associated with the use of diuretics, the diuretic should be stopped if possible. For prophylaxis against acute attacks, either colchicine 0.5-1 mg daily or an NSAID (with gastroprotection if indicated) are recommended. CONCLUSIONS: 12 key recommendations for management of gout were developed, using a combination of research based evidence and expert consensus. The evidence was evaluated and the SOR provided for each proposition.

EULAR evidence based recommendations for gout. Part I: Diagnosis. Report of a task force of the Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT).

OBJECTIVE: To develop evidence based recommendations for the diagnosis of gout. METHODS: The multidisciplinary guideline development group comprised 19 rheumatologists and one evidence based medicine expert, representing 13 European countries. Ten key propositions regarding diagnosis were generated using a Delphi consensus approach. Research evidence was searched systematically for each proposition. Wherever possible the sensitivity, specificity, likelihood ratio (LR), and incremental cost-effectiveness ratio were calculated for diagnostic tests. Relative risk and odds ratios were estimated for risk factors and co-morbidities associated with gout. The quality of evidence was categorised according to the evidence hierarchy. The strength of recommendation (SOR) was assessed using the EULAR visual analogue and ordinal scales. RESULTS: 10 key propositions were generated though three Delphi rounds including diagnostic topics in clinical manifestations, urate crystal identification, biochemical tests, radiographs, and risk factors/co-morbidities. Urate crystal identification varies according to symptoms and observer skill but is very likely to be positive in symptomatic gout (LR = 567 (95% confidence interval (CI), 35.5 to 9053)). Classic podagra and presence of tophi have the highest clinical diagnostic value for gout (LR = 30.64 (95% CI, 20.51 to 45.77), and LR = 39.95 (21.06 to 75.79), respectively). Hyperuricaemia is a major risk factor for gout and may be a useful diagnostic marker when defined by the normal range of the local population (LR = 9.74 (7.45 to 12.72)), although some gouty patients may have normal serum uric acid concentrations at the time of investigation. Radiographs have little role in diagnosis, though in late or severe gout radiographic changes of asymmetrical swelling (LR = 4.13 (2.97 to 5.74)) and subcortical cysts without erosion (LR = 6.39 (3.00 to 13.57)) may be useful to differentiate chronic gout from other joint conditions. In addition, risk factors (sex, diuretics, purine-rich foods, alcohol, lead) and co-morbidities (cardiovascular diseases, hypertension, diabetes, obesity, and chronic renal failure) are associated with gout. SOR for each proposition varied according to both the research evidence and expert opinion. CONCLUSIONS: 10 key recommendations for diagnosis of gout were developed using a combination of research based evidence and expert consensus. The evidence for diagnostic tests, risk factors, and co-morbidities was evaluated and the strength of recommendation was provided.

[Severity of a female gout course].

AIM: Comparison of a gout course in males and females. MATERIAL AND METHODS: The trial enrolled 34 patients (17 females and 17 males). The patients were matched by age and the disease duration. Severity of a gout course was assessed by the disease history, articular syndrome, concomitant diseases, blood biochemistry. Statistical processing was made with a computer program "Statistica 6.0". RESULTS: Events predisposing to purin metabolism disturbances and, therefore, to development of gout occur more frequently in females than in males. For the most part this concerns arterial hypertension and intake of diuretics. Women often have endocrine pathology (artificial menopause, dysmenorrhea, euthyroid goiter). In women gout runs a more severe course manifesting in early chronization, polyarticularity, lingering arthritis, rapid formation of tophuses. Both groups demonstrated marked polymorbidity with accumulation of the diseases related to atherosclerosis. Distinct group differences by content of uric acid seem to arise from early onset of chronic renal failure in women. CONCLUSION: In the absence of sex- and age-related differences, a more severe course of gout is observed in women. This may be due to hyperuricemia and a trend to the disease chronization, high prevalence of arterial hypertension and renal failure.

[Markers of vascular endothelium activation in gout].

AIM: To determine clinical significance of laboratory markers of vascular endothelium activation in gout. MATERIAL AND METHODS: A total of 16 males aged 31-68 years with gout entered the study. The diagnosis satisfied Vallas' criteria, duration of the disease varied from 1.5 to 14 years. Six (37%) patients had chronic gouty arthritis, ten (63%) patients were in the attack-free period. All the patients had metabolic syndrome, 7 (43.7%) of them suffered from diabetes mellitus type 2. Arterial hypertension was diagnosed in 12 (75%) patients. Thickness of the intima-media complex (IMC) of the carotid arteries was measured in 12 patients with duplex ultrasonic scanning. Solid phase enzyme immunoassay studied serum concentrations of a soluble form VCAM-1 (sVCAM-1) and von Willebrand factor antigen (WF:Ag) as laboratory markers of endothelial activation. The above immunoassay was also used to study acute phase inflammatory changes by the levels of C-reactive protein (CRP). RESULTS: Concentration of sVCAM-1 in gout was 1385.2 +/- 341.0 ng/ml and was significantly higher than in the control group (p < 0.001). Mean values of WF:Ag and CRP in the serum were also significantly higher in the study group. The levels of both sVCAM-1 and WF:Ag were elevated in 25% patients. CRP was elevated (8 mg/l) in 6 (37.5%) patients. They had no infectious complications and age-, duration- and stage-related specific features of the disease. There was no significant differences between mean levels of sVCAM-1, WF:Ag, CRP in patients with diabetes mellitus and metabolic syndrome. There was no correlation between uric acid level and IMC thickness (r = 0.12; p > 0.05). A weak positive insignificant correlation was found between concentration of CRP, sVCAM-1 and IMC thickness of the carotid arteries (r = 0.28 and r = 0.36, respectively; p > 0.05). However, this index significantly correlated with WF:Ag(r = 0.62; p < 0.05). A moderate positive but insignificant correlation was detected between the levels of sVCAM-1 and WF:Ag (r = 0.47; p > 0.05). Concentration of sVCAM-1 weakly correlated with that of CRP (r = 0.35; p > 0.05). WF:Ag and CRP levels correlated significantly (r = 0.51; p < 0.05). CONCLUSION: Increased concentrations of sVCAM-1 and WF:Ag in gout reflect not only activation of vascular endothelium but also development of atherosclerotic process in these patients.