• Gout
• Inflammation
• Treatment

Monosodium urate (MSU) crystal deposition in gout precedes the first attack1 ,2 and, while hyperuricaemia persists, it grows and expands to other sites. Fortunately, the crystal deposit is reversible and slowly dissolves when serum uric acid (SUA) is lowered below its saturation point of about 6.8 mg/dl and with certainty below 6 mg/dl.3 Crystals finally disappear from joints, taking longer in those patients with longer disease duration, probably because of a larger accumulated load of crystals.4 Moreover, the velocity of tophi reduction is about double when SUA values are reduced to 4 mg/dl, compared with 6 mg/dl.5 Accordingly, by deciding the SUA level cut-off point to be achieved by treatment we are determining the rate of MSU crystal dissolution and, more importantly, the time of crystal disappearance and cure of gout.6

The 2006 EULAR evidence-based recommendations for gout management state that maintaining SUA below the saturation point for MSU (6 mg/dl–360 µmol/l) is appropriate for promoting crystal dissolution.6 Recently published American College of Rheumatology guidelines7 state a level of at least 6 mg/dl as a target, but affirm that 5 mg/dl might be appropriate in some patients to strongly improve signs and symptoms of gout. British guidelines8 also recommended a level of 5 mg/dl, but the reason given here is because 5 mg/dl is the median SUA concentration of British men. Available urate-lowering drugs can reduce SUA in most patients to the lower values of normal, or even below. Allopurinol is most commonly used at a fixed dose of 300 mg/day, but its maximal dose in label is up to 800 mg/day with normal renal function9; that could be achieved safely, as allopurinol hypersensitivity seems to relate to the starting dose, not to the higher dose achieved.10 Febuxostat is licensed for doses up to 120 mg/day, and other drugs such as uricosuric agents and pegloticase are valuable alternatives. Within a range, the SUA level achieved—and more importantly, the time to dissolution of deposited MSU crystals—can be determined by treatment and we can decide on the time required to free our patients from crystals. So, a pertinent question is whether clearing the crystals faster (or more slowly) has any relevance for patients and if so, why and under what circumstances.

After their initial formation, MSU crystal deposits grow and expand to other sites if SUA values remain high; crystals are in the joint at the time of the first attack and precede it.1 ,2 Despite this, both EULAR and American recommendations are that SUA-lowering treatment should not be started until gout has reached a certain severity and at that moment, one should aim for a SUA level just below the saturation point. This approach implies that the deposited MSU crystals are considered to be harmless for the patients—other than for the obvious joint inflammation during the attacks or the later appearance of tophi or joint damage.

However, MSU crystals are now recognised as an endogenous danger signal by the native immune system11 ,12 and through the activation of NALP3 inflammasome they induce the production of interleukin 1β (IL-1β).13 ,14 At the start of a gout attack,15 and in vitro,16 ,17 proinflammatory cytokine production—including IL-1β—predominates to decrease later. At the same time the production of transforming growth factor β—with a role in resolution of inflammation, but also in tissue remodelling, angiogenesis and fibrosis in granulomatous diseases18—rises, probably contributing to the spontaneous resolution of the attacks that occurs naturally. In the inflammatory infiltrate that surrounds tophi, both IL1β and transforming growth factor β are being expressed,19 suggesting a chronic inflammatory tissue response against crystals.20 Interestingly, both ultrasound21 and contrast-enhanced MRI studies22 show raised vascularity in, and surrounding, tophi. Also in relation to tophi and associated inflammation, bone erosions and joint damage do occur.23 Asymptomatic joints containing MSU crystals are inflamed as shown by regular crystal phagocytosis24 indicative of active cell–crystal interaction, probably the cause of raised synovial fluid cell counts15 that decrease after prophylactic colchicine administration.25

In summary, all these data show that there is continuing crystal-related chronic inflammation in patients with gout in relation to the crystal deposits, both at tophi and in joints. The total amount of inflammation probably relates to the total burden of crystal deposits, and if patients remain untreated, the inflammation load may increase as deposits expand and enlarge. On the other hand, inflammation is likely to reduce and may finally disappear after crystals are dissolved by appropriate SUA-lowering treatment, although we still lack proof for this.

A rapid clearance of MSU crystal deposits may be advantageous for patients in certain situations. A higher independent risk for coronary heart disease, with increased mortality, probably related to clinical and subclinical gout-associated inflammation, has been reported in patients with gout,26–28 being higher in a subgroup of younger tophaceous patients.27 This fact is significant in elderly women with gout, whose risk seems to be higher than that of age-matched gouty men.29 Carotid intimae–media thickness in patients with gout has been found to be higher than in asymptomatic hyperuricaemia subjects or in patients with rheumatoid arthritis; patients with gout also showed more atheromatous plaques.30 All these data strongly suggest that in patients with gout cardiovascular complications of arteriosclerosis are increased, resulting in higher mortality.31 Inflammation is a well-known cause of accelerated arteriosclerosis associated with other chronic inflammatory diseases, such as rheumatoid arthritis32 or systemic lupus erythematosus.33 So, at least in those patients with gout and a raised risk for arteriosclerotic vascular disease—or who have already had complications of this disease—aiming for a rapid elimination of MSU crystal deposits appears more than reasonable.

In some patients with severe gout, renal function has been found to improve after successful SUA-lowering treatment34 ,35; also, MSU crystal deposits have been detected in the renal medulla of patients with gout.36 This suggests that in a subset of patients renal insufficiency may at least be partly due to the presence of MSU crystals in the kidneys and their related inflammation. So, their elimination would explain improvements in the renal function and might prevent further evolution to end-stage disease. Unfortunately, we are unable to easily define this group of patients in whom renal function might improve by proper SUA-lowering treatment. But its occurrence cannot be ignored and renal failure associated with gout—especially if gout is severe and precedes renal disease—justifies a rapid dissolution of crystals and close attention to the renal function.

Finally, in severe tophaceous gout, especially if associated with joint erosions and loss of function, it appears most appropriate to aim for a faster elimination of crystals. Unusual situations with clinical compressions by tophi (such as intraspinal tophi or severe carpal tunnel syndrome) merit considering the fastest possible crystal elimination. Even in average patients, although decreasing SUA levels below 6 mg/dl finally results in crystal dissolution,3 we lack any proof that this is preferable to earlier clearance of the crystals by aiming at a lower SUA level (unless this proves to be more risky).

Some reports suggest that sustained hypouricaemia (<2 mg/dl) might be associated with the development and progression of multiple sclerosis37 or Parkinson's disease.38 This makes persistent, extremely low SUA levels unadvisable, whereas values within the normal range appear safe. The recommended cut-off level is 6 mg/dl6 ,7 because we lack evidence for any other alternative, not because it has been proved to be advantageous for patients.