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.

Treat-to-target (T2T) recommendations for gout.

OBJECTIVES: The treat-to-target (T2T) concept has been applied successfully in several inflammatory rheumatic diseases. Gout is a chronic disease with a high burden of pain and inflammation. Because the pathogenesis of gout is strongly related to serum urate levels, gout may be an ideal disease in which to apply a T2T approach. Our aim was to develop international T2T recommendations for patients with gout. METHODS: A committee of experts with experience in gout agreed upon potential targets and outcomes, which was the basis for the systematic literature search. Eleven rheumatologists, one cardiologist, one nephrologist, one general practitioner and one patient met in October 2015 to develop T2T recommendations based on the available scientific evidence. Levels of evidence, strength of recommendations and levels of agreement were derived. RESULTS: Although no randomised trial was identified in which a comparison with standard treatment or an evaluation of a T2T approach had been performed in patients with gout, indirect evidence was provided to focus on targets such as normalisation of serum urate levels. The expert group developed four overarching principles and nine T2T recommendations. They considered dissolution of crystals and prevention of flares to be fundamental; patient education, ensuring adherence to medications and monitoring of serum urate levels were also considered to be of major importance. CONCLUSIONS: This is the first application of the T2T approach developed for gout. Since no publication reports a trial comparing treatment strategies for gout, highly credible overarching principles and level D expert recommendations were created and agreed upon.

Fluctuation and change of serum urate levels and flares in gout: results from the NOR-Gout study.

A gout attack may evolve after a purine-rich diet or alcohol and after starting urate-lowering therapy (ULT). The relationships between fluctuation and change in serum urate (SU) with the occurrence of flares were investigated in this study. In the prospective NOR-Gout study, gout patients with increased SU and a recent flare were treated to target with ULT over 1 year, with follow-up at year 2 with SU and flare as outcomes. SU and flares were assessed at both monthly and 3-monthly intervals until target SU was reached. Fluctuation over periods and changes in SU between two time points were assessed and compared in patients with and without flares. At year 1, 186 patients completed follow-up (88.2%) and 173 (82.0%) at year 2. Mean age (SD) at baseline was 56.4 (13.7) years, disease duration was 7.8 (7.6) years, and 95.3% were men. The first-year SU fluctuation and change were related to flare occurrence during year 1 (both p < 0.05). High fluctuation with an absolute sum of all SU changes during the first 9 months was related to flares over 3-month periods (all p < 0.05), and high fluctuation during the first 3 months was related to flares in months 3-6 (p = 0.04). Monthly and high SU changes or again reaching higher SU levels > 360 µmol/l were not related to flares. Fluctuation and change in SU were related to flare occurrence during the first year of ULT, while changes between visits and reaching SU levels > 360 µmol/L were not related to flares. Key Points • Urate-lowering therapy seeks to achieve a treatment target and prevent gout flares, and changes in serum urate are related to gout flares. • Fluctuation and changes in serum urate were associated with gout flares, suggesting that fluctuation in serum urate is unfavourable during gout treatment. • During urate-lowering therapy in gout in clinical practice, fluctuation of serum urate, for example, due to lack of adherence, should be observed and avoided.

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.

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.

Potency on lowering serum uric acid in gout patients: a pooled analysis of registrative studies comparing febuxostat vs. allopurinol.

OBJECTIVE: Hyperuricemia leading to urate crystal formation in tissues represents the pathophysiological mechanism of gout. Guidelines recommend a therapeutic target of serum urate concentration (sUA) <6 mg/dL, or even lower (≤5 mg/dL) in patients with large deposits. We conducted an analysis with the aim to achieve additional insights into the urate-lowering efficacy of two xanthine oxidase inhibitors, allopurinol and febuxostat. PATIENTS AND METHODS: This was a pooled analysis of phase III trials on allopurinol and febuxostat, including 4101 patients with gout and hyperuricemia. The efficacy outcomes were: mean reduction of sUA concentration from baseline; number of patients with target sUA levels (<6.0 mg/dL or ≤5 mgdL); time to reach target sUA levels. RESULTS: Three registrative, phase III, randomized, multicenter, placebo-controlled/allopurinol-controlled trials assessing the efficacy of febuxostat, were included. The mean reduction of sUA concentration with any dose of febuxostat was higher (-2.92±2.87 mg/dL; -27%), with respect to placebo- (-0.62±1.84 mg/dL; -5%) and allopurinol-pooled groups (-2.41±2.20 mg/dL; -24%). Moreover, febuxostat showed a higher probability to achieve the recommended target sUA concentration than allopurinol [odds ratio: 2.43 (95% CI: 2.119-2.789) and 4.05 (95% CI: 3.41-4.82) for sUA levels <6 mg/dL and ≤5 mg/dL, respectively]. Patients on any-dose febuxostat reached target sUA faster than allopurinol-treated patients (86.04±71.47 vs. 98.76±70.88 days and 52.08±49.97 vs. 90.42±68.03 days for reaching sUA levels <6 mg/dL and ≤5 mg/dL, respectively; p <0.001 for both comparisons). CONCLUSIONS: In patients with gout and hyperuricemia, febuxostat was significantly more effective and faster than allopurinol in obtaining the recommended target sUA levels, which were reached by a higher number of patients. Therefore, febuxostat was confirmed as an effective option for the treatment of hyperuricemia in gout.

Urate lowering therapies in the treatment of gout: a systematic review and meta-analysis.

OBJECTIVE: In patients with gout, serum uric acid (sUA) concentrations should be lowered at least below the target of 6 mg/dL (even below 5 mg/dL in patients with severe gout). To achieve this goal, urate lowering medications (ULMs) should be considered. Currently-used ULMs include xanthine-oxidase inhibitors such as allopurinol, febuxostat, as well as available uricosuric agents. However, evidence comparing these agents remains scant. We have conducted a systematic review and meta-analysis to retrieve evidence on the clinical trials on the above-mentioned drugs in the treatment of gout. MATERIALS AND METHODS: The following efficacy outcomes were considered in the meta-analysis: (1) % of patients meeting the therapeutic target for sUA level (<6 mg/dl) and (2) percentage reduction in sUA concentration at the end of the study compared with baseline values. An explorative analysis on safety was also conducted. RESULTS: In total, 16 papers concerned febuxostat, 15 allopurinol, 4 benzbromarone and none involved probenecid. Overall, 70.7% of patients reached the target of sUA with febuxostat therapy; the reduction in sUA was 45.3%. Corresponding figures with allopurinol were 44.4% and 33.8%, respectively. The number of patients on benzbromarone (N=129) was too low to retrieve definitive findings. The advantage for febuxostat over allopurinol was evident also in patients with renal dysfunction. Safety analysis favored febuxostat over allopurinol (OR 0.85; 95% CI: 0.75-0.97). CONCLUSIONS: On the basis of the reported data, febuxostat can play a major role in the treatment of hyperuricaemia and gout. Febuxostat is a suitable pharmacological option for first line treatment of gout, given its established efficacy and safety, documented in a high number of clinical studies and in daily practice.

Cost-effectiveness analysis of febuxostat in patients with gout in Spain.

UNLABELLED: Objectives Cost-effectiveness of febuxostat compared with allopurinol in the treatment of hyperuricemia in patients with gout. Methods Costs, clinical outcomes, and QALYs were estimated using a Markov model. Febuxostat 80 mg and 120 mg sequentially, used as first line and second line therapy, was compared with allopurinol 300 mg. Patients switched to the next treatment in the sequence according to a dichotomous response vs no response (target serum urate level < 6 mg/dl outcome) after 3 months of active treatment. A 3% discount rate and 5-year time horizon were applied. PERSPECTIVE: National Health System. Results The addition of febuxostat to any therapeutic strategy was an efficient option, with incremental cost-effectiveness ratios (ICER) compared with allopurinol 300 mg ranging from €5268-€9737. Conclusions Febuxostat is a cost-effective treatment in Spain for the management of hyperuricemia in gout patients, with ICERs far below accepted Spanish efficiency thresholds (30 000€/QALY).

Inflammation: a possible mechanism for a causative role of hyperuricemia/gout in cardiovascular disease.

Hyperuricemia and gout are independent risk factors associated with the development of hypertension, metabolic syndrome, vascular damage, and renal disease. Whether these risk factors are causally related to these important chronic co-morbidities remains uncertain, but inflammation may provide a mechanistic explanation. Hyperuricemia and gout negatively affect vascular function by exerting pro-oxidant effects and by decreasing nitric oxide bioavailability, thus inducing inflammation and endothelial dysfunction, which may promote hypertension, metabolic syndrome, and cardiovascular (CV) disease. This paper presents and discusses current understanding of the diverse influences promoting hyperuricemia and gout and the basis of acute and chronic hyperuricemia/gout-related inflammation. This review is based on a PubMed/Embase database search for articles on hyperuricemia and its impact on cardiovascular and renal function.

Toxic oil syndrome. A long-term follow-up of a cohort of 332 patients.

Toxic oil syndrome is a multisystemic, epidemic disease that appeared in Spain in 1981, related to the intake of rapeseed cooking oil sold in bulk. It affected 19,748 people, of whom 457 died. The toxic substance was never identified. We report the 8-year follow-up of a cohort of 332 patients. The disease was usually severe and disabling during the first 2 years, but the clinical condition of most of the patients improved thereafter. The acute phase lasted 2 months, and was characterized by pulmonary edema, rash, eosinophilia, and myalgia. During the intermediate phase (second to fourth months), severe myalgia, skin tenderness, subcutaneous edema, altered liver function, and pulmonary hypertension developed. Later on, an early chronic phase developed, from the fourth month to the end of the second year. It was marked by scleroderma, sicca syndrome, polyneuropathy, joint contractures, weight loss, and functional limitations. The clinical manifestations improved during the late chronic phase. Its most prominent clinical features were muscle cramps, chronic musculoskeletal pain, chronic lung disease, Raynaud phenomenon, carpal tunnel syndrome, and psychologic disturbances. Only 9% of the patients achieved remission after the acute phase, the rest developing late clinical manifestations of the disease. The severity of the chronic manifestations was rather variable. At the end of the 8-year follow-up, there were 10 TOS-related deaths (3%), 47% of the patients had some kind of complaint, albeit subtle in most cases, and 16% showed organic involvement related to TOS. The most important pathologic features of TOS were widespread interstitial infiltrates, non-necrotizing angiitis, endothelial proliferation, and tissue fibrosis. Toxic oil syndrome is a dramatic example of an induced scleroderma-like syndrome, similar to the eosinophilia-myalgia syndrome. Patients with EMS may develop some of the late clinical features of TOS in the years to come.

"Pseudoseptic" pseudogout associated with hypomagnesemia in liver transplant patients.

Hypomagnesemia has been associated with deposition of calcium pyrophosphate dihydrate crystals in articular structures, causing pseudogout, also known as calcic gout. Occasionally, pseudogout may mimic septic arthritis; this "pseudoseptic" attack may be of especial concern in the immunocompromised host, such as transplant recipient patients, who may be indeed at risk of developing septic arthritis. We report the cases of two patients in whom pseudogout developed after liver transplantation. Synovial fluid appearance and leukocyte counting in synovial fluid mimicked septic arthritis, but calcium pyrophosphate dihydrate crystals were observed. Magnesium depletion before transplantation and further tacrolimus-induced renal magnesium leakage were probably working in these patients.

Nodular regenerative hyperplasia of the liver in rheumatic diseases: report of seven cases and review of the literature.

Nodular regenerative hyperplasia (NRH) of the liver is an uncommon pathologic finding associated, in most cases, with rheumatic and hematologic diseases. Although its pathogenesis remains unclear, NRH probably results from liver regeneration to maintain its functional capacity after ischemia-induced injury. An intrahepatic microvascular occlusive mechanism has been considered most likely pathogenetically. NRH may lead to portal hypertension. Thus, the diagnosis of Felty's syndrome must be considered with caution in patients with rheumatoid arthritis (RA) and NRH of the liver. We report seven additional cases of NRH in patients with rheumatic disorders and review the literature to determine the patterns of clinical presentation and natural history of this condition. We also report four patients (three systemic lupus erythematosus [SLE] and one primary antiphospholipid syndrome [PAPS]) in whom antiphospholipid antibodies may have played a role in the genesis of NRH.

Optimisation of the treatment of acute gout.

Most of the drugs prescribed to treat acute gouty attacks were used before the introduction of modern clinical trials. Thus, there are few well-designed studies available to evaluate these drugs. Nevertheless, worldwide clinical experience supports the use of most nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine and corticosteroids in the treatment of acute gout. Colchicine has been widely used but toxicity, especially gastrointestinal adverse effects, are a major concern. Therapeutic regimens involving hourly or 2-hourly administration were based on the short initial half-life of colchicine in plasma. Other therapy schedules, such as early 8-hourly administration, may be equally effective and have fewer adverse effects. Unfortunately, comparative studies to investigate this have not been performed. Colchicine should not be prescribed to patients with either severe renal insufficiency or combined hepatic-renal insufficiency. Doses should be halved in patients with moderate renal function impairment. NSAIDs are the most widely prescribed drugs in the treatment of acute gout. Few comparative data are available, but any of the most potent NSAIDs are probably useful in the control of pain and inflammatory signs of acute gouty arthritis. Pharmacokinetic properties should be taken into account when selecting an NSAID for the treatment of gout, as rapid absorption and a short half-life may help to avoid accumulation in patients with subclinical renal function impairment. Comorbidities should always be kept in mind when prescribing NSAIDs. Patients with previous or recent gastrointestinal bleeding, those receiving anticoagulant therapy or with haemorrhage diathesis, and those with renal insufficiency are at risk of developing severe adverse effects from NSAID administration. Corticosteroids are probably a reasonable choice for patients in whom colchicine and NSAIDs may be hazardous or for those with a history of previous intolerance to these drugs. Few trials using prednisone, prednisolone or triamcinolone acetonide are available, and dosages are prescribed following empirical data. Corticotropin has also been used to treat acute gout. Although it has been proven to be as effective as other corticosteroids or indomethacin, the need for multiple doses, parenteral administration and the high cost are major limitations for its use. Currently, the choice of a drug for the treatment of acute gout will depend on the balance between its efficacy and the potential adverse effects in a particular patient.

Comparative study of the efficacy and safety of aceclofenac and tenoxicam in rheumatoid arthritis.

To compare the efficacy and safety of aceclofenac (AC) and tenoxicam (TX) in the treatment of rheumatoid arthritis (RA), a multicentric parallel, randomized, double-blind trial of three months duration was performed in 292 patients: 145 were randomized to the AC treatment group and 147 to the TX treatment group. The trial was completed by 237 (81.1%) patients. Both treatment groups showed amelioration of clinical parameters monitored at 15 days, and this improvement continued until the end of the trial, no statistically significant differences being observed between AC and TX. Twenty-four patients (8.2%, 12 AC and 12 TX) did not complete the trial because of inefficacy, and 15 because of side effects (5.1%, 6 AC and 9 TX), in 7 of them due to gastrointestinal intolerance (2,4%, 1 AC, 6 TX, p = 0.052). These data demonstrate that AC shows similar efficacy to TX in the treatment of rheumatoid arthritis and better safety profile than TX, mainly regarding gastrointestinal tolerability.

Efficacy of radiosynovectomy of the knee in rheumatoid arthritis: evaluation with magnetic resonance imaging.

The intra-articular injection of a radiopharmaceutical agent (radiosynovectomy) produces a reduction of the synovial inflammatory process. The inflammed synovial membrane can be identified with magnetic resonance imaging after the intravenous administration of gadolinium (MRI-Gd). A 6-month prospective study was carried out in 10 patients with rheumatoid arthritis after radiosynovectomy of the knee. The efficacy was evaluated with clinical parameters and MRI-Gd. A progressive amelioration of synovial effusion, pain, articular range of mobility, total leucocytes count in synovial fluid and synovial membrane thickness through MRI-Gd was observed. The global efficacy was considered to be good in six patients, fair in three and bad in one. The study shows for the first time that MRI-Gd allows the evaluation of the response of the synovial membrane to radiosynovectomy.

Serum uric acid and metabolic risk.

OBJECTIVES: This review presents the information available on the role of uric acid (UA) on metabolic risk and on the link between hyperuricemia and metabolic syndrome. METHODS: Key papers for inclusion were identified by a PubMed search and articles were selected according to their relevance for the topic, according to the authors' judgment. RESULTS AND CONCLUSIONS: An elevated UA is both strongly associated and predictive of the metabolic syndrome, and increasing evidence suggests that UA may have a causal role. The classical viewpoint that UA is simply an innocuous marker of metabolic syndrome that should not even be measured will likely have to be modified. Lowering UA may be a novel treatment target for preventing diabetes and justify prospective clinical trials on the possible benefits of the measurement and lowering of serum UA on multiple chronic disease end points.

Epidemiology of gout: an update.

Gout is the most common inflammatory joint disease in men, characterised by formation of monosodium urate (MSU) crystals in the synovial fluid of joints and in other tissues. The epidemiology of gout provides us with the understanding of the disease distribution and its determinants. In an attempt to update the knowledge on the topic, more recent research reports on the descriptive epidemiology of gout are reviewed in this article. The review describes clinical characteristics and case definitions of gout, including the Rome and New York diagnosis criteria of gout, '1977 American Rheumatism Association (ARA) criteria' and the 10 key propositions of the European League Against Rheumatism (EULAR) recommendations. Gout incidence, prevalence, morbidity and mortality, geographical variation of the disease, relevant risk factors for both the occurrence and outcome of gout and trends of the disease over time are then described. Difficulties in obtaining the information and data reported are also discussed.

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.