Reumatismo. 2012; 63(4): 276-83
Lioté F

Gout is a very common joint disease which is due to chronic hyperuricemia and its related articular involvements. Yet it can be cured when appropriately managed. Comprehensive management of gout involves correct identification and addressing all causes of hyperuricemia, treating and preventing attacks of gouty inflammation (using colchicine NSAIDs, and/or steroids), and lowering serum urate (SUA) to an appropriate target level indefinitely. The ideal SUA target is, at a minimum, less than 6 mg/dL (60 mg/L or 360 μmol/L), or even less than 5 mg/dL in patients with tophi. The SUA target should remain at less than 6 mg/dL for long in all gout patients, especially until tophi have resolved. Patient education and adherence to therapy are key point to the optimal management of gout, aspects which are often neglected. Adherence can be monitored in part by continuing, regular assessment of the SUA level. More difficult cases of gout often need a combination of urate lowering therapy (ULT) for both refractory hyperuricemia and chronic tophaceous arthritis. Chronic tophaceous gouty arthropathy which do not respond adequately to optimized oral ULT might benefit from the use of pegloticase, when this is available in, for example, Italy and other European countries. By contrast, in calcium pyrophosphate (CPP) crystal deposition disease (CPPD), as evidenced by pseudo gout attacks or chronic polyarthritis, similar anti-inflammatory strategies have been recommended, but there have as yet been no controlled trials. Of note, there is no treatment for the underlying metabolic disorders able to control the CPPD. Management of crystal-induced arthropathies (CIA) depends not only on clinical expression, namely acute attacks or chronic arthropathy, but also on the underlying metabolic disorder. We will mainly focus on gout as an archetype of CIA.

Reumatismo. 2012; 63(4): 263-75
Paparo F, Fabbro E, Ferrero G, Piccazzo R, Revelli M, Camellino D, Garlaschi G, Cimmino MA

Gout, calcium pyrophosphate dihydrate (CPPD) deposition disease, and calcium hydroxyapatite deposition disease (HADD) are the three most common crystal-induced arthropathies. Multimodality imaging may help in their diagnosis, and is useful for a precise and comprehensive assessment and grading of the related osteoarticular damage. Plain film radiography, due to its low cost and wide availability, is the first imaging technique to be used in crystal deposition diseases, providing well-known and specific findings for CPPD deposition disease and HADD, while it may undergrade the early osteoarticular lesions in gouty patients. Ultrasonography (US) is a radiation-free approach that accurately depicts crystal deposits in cartilage, peri- and intra-articular soft tissues, but it does not give a panoramic view of the affected joints. Cross-sectional imaging techniques can examine crystal deposits in the spine and axial joints. CT has the potential to distinguish monosodium urate (MSU) crystals from calcium containing crystals, due to their different attenuation values. MRI may demonstrate synovitis, erosions and bone marrow edema in gouty patients and it may differentiate tophi from other soft tissue nodules due to its high contrast resolution and power of tissue characterization.

Reumatismo. 2012; 63(4): 253-62
Viazzi F, Leoncini G, Pontremoli R

A number of epidemiological studies have reported an association between serum uric acid levels and a wide variety of high-risk conditions including hypertension, insulin resistance, and kidney and cerebro-cardiovascular disease. All things considered, serum uric acid may induce cardiovascular and kidney events both directly and indirectly by promoting other well-known mechanisms of damage. While asymptomatic hyperuricemia is currently not considered to be an indication for urate lowering therapy, there is growing evidence indicating a linear relationship between pharmacological reduction in serum uric acid and incidence of cardiovascular and renal events.

Reumatismo. 2012; 63(4): 238-45
Grassi W, De Angelis R

Gout is a metabolic disease characterized by hyperuricemia and the deposition of monosodium urate (MSU) crystals in the joints and soft tissues, consisting of a self-limited acute phase characterized by recurrent attacks of synovitis and a chronic phase in which inflammatory and structural changes of the joints and periarticular tissues may lead to persistent symptoms. Acute gout is characterized by a sudden monoarthritis of rapid onset, with intense pain, mostly affecting the big toe (50% of initial attacks), the foot, ankle, midtarsal, knee, wrist, finger, and elbow. Acute flares also occur in periarticular structures, including bursae and tendons. The presence of characteristic MSU crystals in the joint fluid, appearing needle-like and showing strong negative birefringence by polarized microscopy, is pivotal to confirm the diagnosis of gout. The time interval separating the first attack from subsequent episodes of acute synovitis may be widely variable, ranging from a few days to several years. During the period between acute attacks the patient is asymptomatic even if MSU deposition may continue to increase silently. The factors that control the rate, location, and degree of ongoing deposition in gouty patients are not well defined. Chronic gout is the natural evolution of untreated hyperuricemia in patients with gouty attacks followed by pain-free intercritical periods. It is characterized by the deposition of solid MSU crystal aggregates in a variety of tissues including joints, bursae and tendons. Tophi can occur in a variety of locations including the helix of the ear, olecranon bursa, and over the interphalangeal joints. Their development is usually related with both the degree and the duration of hyperuricemia. About 20% of patients with gout have urinary tract stones and can develop an interstitial urate nephropathy. There is a strong association between hyperuricaemia and the metabolic syndrome (the constellation of insulin resistance, hypertension, obesity and dyslipidaemia), and gouty patients often have a medical history of kidney disease, diabetes mellitus and signs of vascular illness such as coronary artery disease, heart failure and stroke, resulting with a poor overall quality of life.

Reumatismo. 2012; 63(4): 230-7
Busso N, Ea HK

Recent advances have stimulated new interest in the area of crystal arthritis, as microcrystals can be considered to be endogenous "danger signals" and are potent stimulators of immune as well as non-immune cells. The best known microcrystals include urate (MSU), and calcium pyrophosphate (CPP) crystals, associated with gout and pseudogout, respectively. Acute inflammation is the hallmark of the acute tissue reaction to crystals in both gout and pseudogout. The mechanisms leading to joint inflammation in these diseases involve first crystal formation and subsequent coating with serum proteins. Crystals can then interact with plasma cell membrane, either directly or via membrane receptors, leading to NLRP3 activation, proteolytic cleavage and maturation of pro-interleukin-1β (pro-IL1β) and secretion of mature IL1β. Once released, this cytokine orchestrates a series of events leading to endothelial cell activation and neutrophil recruitment. Ultimately, gout resolution involves several mechanisms including monocyte differentiation into macrophage, clearance of apoptotic neutrophils by macrophages, production of Transforming Growth Factor (TGF-β) and modification of protein coating on the crystal surface. This review will examine these different steps.

Reumatismo. 2012; 63(4): 207-20
Ciancio G, Bortoluzzi A, Govoni M

Gout is the most common cause of inflammatory arthritis affecting at least 1% of the population in industrialized countries. It is closely associated with hyperuricemia and is characterized by formation and reversible deposition of monosodium urate crystals in joints and extra-articular tissues. Several studies suggest that the prevalence and incidence of gout are rising. Numerous risk factors may in part explain this increasing trend including dietary and lifestyle changes, genetic factors, diuretic use and comorbid conditions such as hypertension, diabetes, cardiovascular disease, chronic renal disease and the metabolic syndrome. Chondrocalcinosis is characterized by the deposition of calcium pyrophosphate crystals in articular tissues, most commonly fibrocartilage and hyaline cartilage. Sporadic chondrocalcinosis is a common condition in the elderly and frequently associates with osteoarthritis. Hereditary haemochromatosis, hyperparathyroidism and hypomagnesaemia are metabolic disorders that predispose to secondary chondrocalcinosis.The prevalence of chondrocalcinosis is still rather uncertain and varies depending on the diagnostic criterion used in different studies.

Reumatismo. 2012; 63(4): 199-206
Marson P, Pasero G

The history of microcrystalline arthritis only began in 1961 when Daniel McCarty and Joseph Lee Hollander demonstrated the presence of sodium monourate crystals in the synovial fluid of gouty patients. However, gout is a historical disease, thanks to the descriptions of Hippocrates, Caelius Aurelianus, Soranus of Ephesus and Araeteus of Cappadocia. The relationship between hyperuricemia and gout was first documented in the nineteenth century by Alfred Baring Garrod, who demonstrated deposits of uric acid crystals on a linen thread held dipped in acidified blood (the so-called "thread method"). Gout has always been considered a prerogative of the moneyed classes (arthritis divitum), and history is full of famous gouty personalities, including kings, emperors, popes, commanders, politicians, artists, writers, philosophers and scientists. Another form of microcrystalline arthritis, chondrocalcinosis, was identified as being a rheumatic disorder different from gout in the 1960s. As a specific clinical entity, it was first identified in 1958 by Dušan Žitnˇan and Štefan Sit'aj in a few Slovak families.

Curr Opin Rheumatol. 2012 Mar; 24(2): 145-51
Jordan KM

Gout is a true crystal deposition disease, extremely painful and bone and tissue damaging if untreated. It is the only curable form of arthritis. Although we have many treatments to cure gout, it is a disease that is consistently undertreated/mismanaged and perceived by clinicians and the lay public as a 'laughable condition' with the patients' lifestyle often held erroneously to account. This article would give you a good understanding of modern and established pharmacological and nonpharmacological treatments used in the management of acute and chronic gout and how to 'treat to target' to cure the disease.Many of the drugs we use to manage patients with gouty arthritis have been in existence since the 1970s and 1980s. In the past few years, because of the improved physiological understanding of gout, new innovative treatments such as anti-IL inhibitors, a nonxanthine oxidase inhibitor and the uricase enzymes have been developed adding to our armamentarium of drugs.With the introduction of new research, we have been able to explore how to also use established treatments more effectively, raising the profile of gout and its best management and introducing the principle of treating the patient to urate target.

Curr Opin Rheumatol. 2012 Mar; 24(2): 132-8
Dalbeth N, Doyle A, McQueen FM

Imaging has the potential to assess various pathological manifestations of gout, including monosodium urate (MSU) crystal deposition, tophus formation and cartilage, soft tissue, and bone pathology. This review discusses recent research examining the role of imaging to assess the manifestations of disease.Various imaging techniques are used in the assessment of gout, including plain radiography, ultrasonography, conventional computed tomography (CT), dual energy computed tomography (DECT), and MRI. Potential roles for ultrasonography are MSU crystal detection, measurement of tophi, and assessment of disease complications. Ultrasonography may allow detection of MSU crystals in patients with hyperuricaemia, prior to development of clinically apparent gout. Conventional CT allows excellent visualization of tophi and bone erosion. DECT is a promising method of noninvasive MSU crystal detection. MRI allows assessment of tophi, synovial and soft tissue disease, and bone pathology. The relative absence of MRI bone marrow oedema in gout suggests that the mechanisms of bone erosion in gout are quite different from those in other erosive arthropathies.Imaging modalities have provided important insights into the pathology of gout. The role of various imaging techniques in gout diagnosis, monitoring, and prediction of outcome is rapidly developing.

Br J Clin Pharmacol. 2012 Feb 2;
Stocker SL, McLachlan AJ, Savic RM, Kirkpatrick CM, Graham GG, Williams KM, Day RO

Aims:  Our aim was to identify and quantify the sources of variability in oxypurinol pharmacokinetics and explore relationships with plasma urate concentrations. Methods:  Non-linear mixed effects modeling was applied to concentration-time data from 155 gouty patients with demographic, medical history and renal transporter genotype information. Results:  A one-compartment pharmacokinetic model with first-order absorption best described the oxypurinol concentration-time data. Renal function and concomitant medicines (diuretics and probenecid), but not transporter genotype, significantly influenced oxypurinol pharmacokinetics and reduced the between-subject variability in the apparent clearance of oxypurinol (CL/F(m) ) from 65% to 29%. CL/F(m) for patients with normal, mild, moderate and severe renal impairment were 1.8, 0.6, 0.3 and 0.18 L/h, respectively. Model predictions show a relationship between plasma oxypurinol and urate concentrations and failure to reach target oxypurinol concentrations using suggested allopurinol dosing guidelines. Conclusions:  In conclusion, this first established pharmacokinetic model provides a tool to achieve target oxypurinol plasma concentrations, thereby optimizing the effectiveness and safety of allopurinol therapy in gouty patients with various degree of renal impairment. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

J Thorac Dis. 2012 Feb; 4(1): 17-8
Gout PW, Wang Y

Ann Rheum Dis. 2012 Jan 30;
Scanu A, Oliviero F, Ramonda R, Frallonardo P, Dayer JM, Punzi L

OBJECTIVES: To determine the most relevant parameters in synovial fluid (SF) during the various stages of acute gout.METHODS: SFs from 38 gouty patients were analysed for white blood cell (WBC) count, percentage of polymorphonuclear cells (PMNs) and levels of interleukin 1β (IL-1β), IL-6, IL-8, tumour necrosis factorα (TNFα) and transforming growth factor β1 (TGFβ1). Patients were divided into three groups according to the length of time since onset of the attack: phase I (0-48 h), phase II (days 3-4) and phase III (days 5-7).RESULTS: Levels of WBCs were similar in SFs from phases I and II, while phase III showed the lowest WBC count. Percentages of PMNs were raised in all SFs. None of the cytokines analysed differed between phases I and II except for TGFβ1, which was higher in phase II. IL-1β, IL-6 and TNFα were higher in group 1 than in group 3. Levels of all the cytokines assessed, with the exception of TGFβ1, were significantly lower in phase III than in phase II IL-1β, p<0.05; IL-6, p<0.01; IL-8, p<0.001; TNFα, p<0.05).TGFβ1 levels were highest in SFs from phase III.CONCLUSION: Cytokine levels in SFs may change depending on the different stages of acute gout, highlighting the role of TGFβ1 in the resolution of gout.