Rapid Crystal Dissolution in Gout

Abstract and Introduction

Abstract

Monosodium urate crystals dissolve and are eliminated from joints and soft tissues as serum uric acid levels drop below its saturating point (400 μmol/l). Time to crystal clearance relates to disease duration and to the serum uric acid level achieved with therapy. The current recommended target level by most guidelines is 360 µmol/l (6 mg/dl), but evidence supporting this target is scant. Lower targets warrant a faster crystal clearance – and therefore a faster disease cure – and might be appropriate in the general gouty population but most especially in selected patients such as those with significant cardiovascular risk, poor renal function or tophaceous gout.

Introduction

Deposition of monosodium urate (MSU) crystals is the hallmark of gout. Persistently high serum uric acid (SUA) levels result in MSU crystal deposition not only in joints but also in periarticular structures such as tendons and ligaments.^[1] While hyperuricemia persists, these deposits grow and expand. MSU crystals are known to cause inflammation,^[2] and clinically gout commonly presents as recurrent episodes of acute inflammation, frequently at the joints, but which can also involve the tendons^[3] or the bursa.^[4] In time, joints can become chronically inflamed and deposits can accumulate in the form of tophi. Gout is one of the most common inflammatory arthritis, affecting up to 1–2% of adult men in western countries.^[5] Although in most patients gout is an episodic disease that can be taken as benign, gout is far from innocuous. MSU deposits produce persistent low-grade inflammation as evidenced by an increased synovial fluid leukocyte count in asymptomatic knees with MSU crystals compared with knees without crystals,^[6] increased edema surrounding tophi and other MSU deposits and higher vascularization at asymptomatic joints; the inflammatory cellular components surrounding tophi have been well characterized.^[7] Consequences of this continuous low-grade inflammation are in the way of being characterized but cumulative evidence suggest that this sustained inflammation is harmful for gout patients, as discussed below. Despite this, both European League Against Rheumatism recommendations^[8] and American guidelines^[9] recommend starting urate-lowering therapy only after gout has reached a certain severity. This approach implies that the deposited MSU crystals are considered harmless for the patients, other than for the obvious clinical inflammation during acute inflammatory episodes or the later appearance of tophi and joint damage.

If gout is left untreated, MSU crystal deposits will persist and even increase in size or number. However, the deposition of MSU crystals is reversible when SUA is lowered below its saturation point (about 400 µmol/l or 6.8 mg/dl) and with certainty below 360 µmol/l (6 mg/dl).^[10] In a small study including 18 patients successfully treated with urate-lowering therapy, repeated joint aspiration showed a disappearance of MSU crystals from synovial fluid samples in all patients.^[11] In another study, the evolution of the largest tophi was assessed in 63 tophaceous gouty patients starting urate-lowering therapy.^[12] All patients had a complete resolution of their index tophi by 64 months. These data suggest that gout can be cured as long as low SUA levels can be achieved in a given patient.

Furthermore, the time taken to crystal dissolution is associated with disease duration, likely because of larger crystal burden (though a practical method to measure the total crystal burden has yet to be developed); and the levels of SUA achieved. For example, most patients (90%) with <10 years duration of gout but few patients (25%) with >10 years gout duration, were free of crystals by 12 months (median serum urate levels while on urate-lowering therapy 291 µmol/l [4.9 mg/dl]).^[11] This is likely explained by an increased crystal burden. In addition, the speed of tophi reduction approximately doubles when SUA values are reduced to 238 µmol/l (4 mg/dl), compared with 360 µmol/l (6mg/dl).^[12] Accordingly, by deciding the SUA level cutoff to be achieved by treatment we are determining the rate of MSU crystal dissolution and, more importantly, the time to crystal disappearance and the cure of gout.^[13] Different SUA cutoff points have been recommended, but the level of 360 µmol/l (6 mg/dl), stated by the 2006 European League Against Rheumatism recommendations,^[8] the 2012 ACR guidelines^[9] and the 3e Initiative multinational recommendations,^[14] is widely used both in trials and in clinical practice. Both the 3e Initiative recommendations and the ACR guidelines acknowledge that a lower treatment target (<300 µmol/l [5 mg/dl]) might be appropriate in some patients, especially tophaceous patients. The British Society for Rheumatology guidelines^[15] recommends this stricter treatment target for the general gouty population, as this is the average SUA level in the British men.

Available urate-lowering drugs can decrease SUA in most patients to within the normality range, or even below. Allopurinol is most commonly used at a fixed dose of 300 mg/day,^[16] but its maximal dose in the package insert is up to 800 mg/day in patients with normal renal function; high doses might be achieved safely, as allopurinol hypersensitivity seems to be related to its initial dose, rather than to the highest dose used.^[17] Febuxostat can be dosed up to the licensed 120 mg/dl and other drugs as uricosurics and pegloticase offer valuable alternatives. Combination therapy can also be of use in selected patients not achieving target SUA levels by conventional monotherapy. In general, the SUA level achieved is determined by treatment. But more importantly, the SUA achieved determines the time to the dissolution of deposited MSU crystals. Therefore, a clinically pertinent question is whether clearing the crystals faster (or slower) has any relevance for the patients, and if so, under which circumstances we should aim for a quicker crystal clearance. In our opinion, a rapid dissolution of MSU crystal deposits may be advantageous for gouty patients, especially in certain situations. However, it is worth noting that most of the potential advantages of rapid crystal dissolution lack strong evidence support and come from indirect data; therefore, a formal demonstration of the effect through controlled intervention studies is highly desirable and should also include a detailed safety evaluation.

Patients with gout are well known to have an increased risk of developing cardiovascular (CV) diseases for decades.^[18] Hyperuricemia and gout are common features of the so-called metabolic syndrome, alongside hypertension, diabetes mellitus, dyslipidemia and obesity – the traditional CV risk factors. In gout, the presence of these comorbidities is significantly increased when compared with the general population,^[19] at a rate even higher than other rheumatic diseases.^[20] The coexistence of traditional CV risk factors in patients with gout has commonly been considered the main reason for the increased CV risk. However, in the last years several population-based studies have noted that gout is an independent CV risk factor in itself,^[21–25] leading to an increased mortality.^[26] This circumstance seems especially relevant in younger patients without CV risk factors – a subgroup with a low baseline incidence of coronary heart disease – in which the presence of gout may enhance the CV risk by more than 80%.^[27] The CV risk is particularly high in tophaceous patients,^[23,28] suggesting an association with the crystal deposit burden (and probably the total amount of inflammation associated to the crystals that likely rises as the deposits do). The risk of stroke seems to be increased as well in gouty patients.^[29] Subclinical indicators of CV involvement, such as the carotid intima–media complex thickness and the presence of atherosclerotic plaques, also seem to be more prevalent in gouty patients than in control nongouty patients.^[30] All these data quite strongly suggest that in gouty patients CV complications of atherosclerosis are heightened, explaining the resulting higher mortality.

The same mechanism proposed for other chronic inflammatory conditions, such as rheumatoid arthritis,^[31] systemic lupus erythematosus,^[32] ankylosing spondylitis,^[33] inflammatory bowel disease^[34] or psoriasis,^[35] could apply to gout. Sustained inflammation seems to promote an accelerated form of atherosclerosis.^[36,37] Persistently high levels of proinflammatory cytokines appear to induce pleiomorphic effects that include a proatherogenic lipid profile, with a characteristic reduction in high-density lipoprotein cholesterol and total cholesterol levels, and an increase in triglycerides; insulin resistance and hyperinsulinemia; endothelial dysfunction, with an increased production of cellular adhesion molecules and hemostatic cytokines (such as von Willebrand factor and tissue plasminogen activator antigen); and enhanced oxidative stress, promoting the oxidation of low-density lipoprotein particles. All of these variations highly correlate with the development of the atheromatous plaque and its subsequent disorders.

The mechanism by which MSU crystals produce inflammation is now becoming clearer.^[38] MSU crystals (as well as calcium pyrophosphate and cholesterol crystals) are recognized as danger signals^[39] by the innate immune system cells, such as macrophages and dendritic cells. In vitro studies have shown that MSU crystals interact with the TLR2/TLR4 receptors, which activate the NLRP-3 inflammasome,^[40] promoting the synthesis and activation of the IL-1β, the main proinflammatory cytokine responsible for crystal-related inflammation.^[41] NLRP3 is not the only way crystals induce IL-1β production; crystal phagocytosis, K⁺ effluxes, reaction to reactive oxygen species and lysosomal destabilization has been proposed as alternative, adjuvant mechanisms. Also, a direct interaction with the cell membrane, not driven by Toll-like receptors, and further stimulation of Syk has been recently reported,^[42] although, how this ends with the activation of the inflammosome remains to be elucidated. No matter the exact mechanism, MSU crystals presence does lead to persistent inflammation, both in joints^[6] and tophi.^[7] The extension of crystal deposits will therefore determine the inflammatory load, and inflammation will be particularly elevated in tophaceous forms. As aforementioned, patients with tophaceous gout are also at the highest CV risk in the cohort studies.^[23,28]

In line with other chronic inflammatory conditions,^[43,44] the anti-inflammatory therapy could decrease the CV risk in gouty patients. Colchicine reduces crystal-induced inflammation^[45] and is a standard agent used for both flares and prevention of further episodes.^[8,9,14] Interestingly, a recent population-based study pointed out a lower prevalence of myocardial infarction in those gouty patients that were on colchicine;^[46,47] this could be explained through its anti-inflammatory properties. Whether urate-lowering therapy could revert the inflammation-related proatherogenic state remains to be demonstrated; however, as persistent low-grade inflammation in gout intensely relates to MSU crystal presence in synovial fluid and the joint surface, it appears logical to surmise that crystal clearance will resolve it. In view of current evidence, at least in those gouty patients at a high risk for atherosclerotic vascular disease or having already suffered from its complications, to aim for a rapid elimination of MSU crystal deposits appears more than sensible.

Patients with gout frequently show an abnormal renal function,^[48] ranging from mild increases in serum creatinine to an end-stage renal disease. In some cases gout develops as a consequence of the hyperuricemia resulting from the impaired urate excretion due to poor kidney function. The list of possible causes for this renal dysfunction is large and several often coexist, but nephroangiosclerosis and diabetic nephropathy seem to be the leading causes,^[49] as they are commonly associated with gout and other features of the metabolic syndrome. Besides these, a specific form of urate nephropathy has been identified^[50] which features a slowly decreasing glomerular filtration and hyposthenuria. The deposit of MSU crystals in the renal interstitium and medulla with a secondary local inflammatory reaction (conforming microtophy) found in pathological specimens^[51] has been pointed out as the reason for this condition. The identification of the urate nephropathy in clinical practice remains challenging, especially in presence of other comorbidities such as hypertension or diabetes.

Some studies (which are in keeping with our experience) have noted a mild improvement in the renal function of patients with severe gout after successful SUA lowering therapy.^[52,53] Interestingly, Gibson et al.^[54] found a protective renal effect after a 2-year treatment of allopurinol in comparison to colchicine in gouty patients with a normal baseline renal function. These findings support the involvement of MSU crystals deposition in at least a subset of gouty patients with renal impairment. Their elimination would explain improvements in the renal function, and it might even prevent further evolution to end stage disease. In addition, a lesser use of NSAIDs by the patients might contribute to this point. But as aforementioned, it is currently unclear which group of patients may improve their renal function by proper SUA lowering treatment. However its occurrence cannot be ignored and renal failure associated to gout – especially if gout is severe and precedes renal disease – can justify targeting a lower SUA level and a rapid dissolution of crystals.

Finally, in severe forms of tophaceous gout – especially those with persistent and clinically evident inflammation, joint erosions, loss of function and a poorer quality of life^[55,56] – it appears undeniable to aim for a faster crystal elimination. Recent ACR guidelines^[9] and 3e Initiative recommendations^[14] considered a different SUA level target for tophaceous patients (300 µmol/l [5 mg/dl]), but even lower levels might be more suitable, as all manifestations related to the MSU deposits will resolve or improve far quicker.^[12] Repairing phenomenon and regression of gouty joint erosions has been reported after reducing SUA levels.^[57] MSU crystals are often included in bone matrix by osteoblasts when erosion develops. Interestingly, it has been recently shown that osteoblasts activate and phagocyte crystals through the NLRP3.^[58] Whether crystals included in bone matrix will dissolve similarly to other locations when normouricemia is achieved is currently unknown, and also which might the repercussion of the crystal persistence be in that peculiar environment. Unusual scenarios with clinical nerve compression syndromes by tophi (such as intraspinal tophi or severe carpal tunnel syndrome) also merit consideration for the fastest possible crystal elimination.

However, the proposed strategy needs for a safety evaluation as well. The uric acid is a physiological component of the serum, being considered one of the most active antioxidant agents^[59] – in blood, uric acid tends to be ionized considering its pKa (5.4). It has been reported that sustained very low levels of uricemia might be associated with neurodegenerative disorders, such as multiple sclerosis^[60] or Parkinson's disease,^[61] and it has been related with an increased presence of reactive oxygen species. However, SUA values within the normal range appear safe.^[62]

The previous paragraphs described certain gout scenarios where a faster crystal clearance may be beneficial. As shown, time to achieve crystal dissolution will heavily depend on the SUA level reached. To date no studies have properly evaluated other alternative target levels in terms of advantages, but also in terms of risks. If crystal removal from joints and tissues leads to the disappearance of acute attacks and tophi – which may be considered as the cure of the disease – we should aim to achieve it earlier, as it is feasible and highly advisable.