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Urate-lowering therapies in gout

Introduction

Gout is a disorder of purine metabolism, the cause of which is thought to be a combination of environmental and genetic factors. It is unclear why some patients with elevated levels of serum uric acid, hyperuricemia, go on to develop gout, while others remain asymptomatic, although there is some evidence that genetic factors may go at least some way towards explaining this phenomenon. Available urate-lowering therapies for the treatment of gout can be broadly grouped into the xanthine oxidase inhibitors (allopurinol and febuxostat), uricosuric agents (benzbromarone and probenecid) and a new class of agent, recombinant uricases (pegloticase). While it is recommended that patients with gout receive treatment with urate-lowering therapy to achieve a target serum uric acid level of <6.0 mg/dL, treatment is considered suboptimal in a large proportion of patients.

Editorial

Evolution or revolution in urate-lowering therapies for gout?

Editorial Board member Fernando Pérez-Ruiz reflects on changing concepts in the understanding of gout, and reviews the latest developments in new urate-lowering medications for the management of gout.

Author:
Fernando Pérez-Ruiz

Urate handling in the body, hyperuricemia, and gout

Urate handling in the human body

This paper provides an overview of the ways in which urate is handled by the human body, in terms of production, renal elimination and intestinal elimination.

Summary
  • Elevated serum urate (>6.8 mg/dL) is the primary cause of gout in patients.
  • Metabolism of endogenous (DNA/RNA) and exogenous (dietary) purines leads to the production of urate. Both environmental and physiological changes can lead to significant day-to-day variations in serum urate levels.
  • Urate elimination occurs primarily via the kidneys, accounting for 60–65% of daily urate elimination. Importantly, any given molecule of urate may pass through the kidney multiple times a day before being excreted, with renal transporters driving both secretion and reabsorption of urate.
  • The two most important transporters involved in urate reabsorption from the proximal tubules are the kidney urate transporter, URAT1, and glucose transporter 9 (GLUT9). Other transporters include organic anion transporter 4 (OAT4), shown to be associated with hyperuricemia and gout in genetic studies.
  • Tubular secretion, a significant component of which appears to occur concomitantly with reabsorption, may be mediated by several transporters. The potential transporter candidates can be divided into basolateral transporters and apical transporters.
  • Evidence suggests that fractional urate excretion can change due to changes in serum urate – likely due to an inherent property of the kidney transporters.
  • Renal handling of urate can be altered by various agents, such as the tuberculosis drug pyrazinamide, low-dose aspirin, diuretics and sodium-dependent glucose transporter inhibitors (SGLT2 inhibitors), as well as uricosuric drugs (such as probenecid and lesinurad).
  • Intestinal elimination is responsible for excretion of remaining urate, with urate transporters, such as ABCG2 and NPT5, considered likely to be involved.
  • Handling of urate is considered a “complex, dynamic balance between three major processes: production, renal elimination, and intestinal elimination”.

Hyndman D, Liu S, Miner JN. Curr Rheumatol Rep. 2016;18:34. doi: 10.1007/s11926-016-0587-7.

Genetics of hyperuricemia and gout: implications for the present and future

This paper reviews the role of genetics in the development and management of gout.

Summary
  • Some patients with hyperuricemia are asymptomatic/have mild symptoms and are easily managed, yet others progress to severe disease or experience adverse reactions to urate-lowering therapy. This may, at least in part, be explained by genetics.
  • Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) that are missense mutations in transport proteins. These have been found in a few select genes to date: SCL22A12, SCL2A9 and ABCG2. However, non-genetic risks are still the foundation for developing hyperuricemia and gout.
  • SCL22A12 is the gene encoding URAT1 – the first urate transporter described; it is of clinical importance in urate homeostasis.
  • Two alternative RNAs from SCL2A9 encode the fructose transporters GLUT9a and GLUT9b. Variants in the gene encoding this transporter have been found to be associated with low fractional excretion of urate. Moreover, several groups have published GWAS linking polymorphisms in this gene with hyperuricemia and gout.
  • ABCG2 encodes a transporter of the ATP-binding cassette family, and is expressed in the apical membrane of human kidney proximal tubule cells. A role of variants of this gene in gout has been validated in several studies.
  • Patients with gout usually have several comorbid conditions, often similar to those in metabolic syndrome. There is some debate regarding a causal relationship: is hyperuricemia/gout a consequence or cause of comorbidities such as cardiovascular disease and obesity?
  • Most currently available treatments for gout decrease production of serum urate, decreasing the need for excretion. URAT1 and GLUT9 are both inhibited by probenecid and benzbromarone.
  • GWAS may lead to SNP-targeted therapy, with future potential therapy including pharmacological chaperones, small molecule scaffolds that allow mutant proteins to fold or route correctly during translation.

George RL, Keenan RT. Curr Rheumatol Rep. 2013;15:309. doi: 10.1007/s11926-012-0309-8.

Factors influencing the crystallization of monosodium urate: a systematic literature review

This systematic literature review was conducted to identify factors contributing to monosodium urate (MSU) crystallization in gout.

Summary
  • In this systematic literature review, a total of 35 original studies related to gout and MSU crystallization were identified. Of these, 19 investigated urate solubility, 21 investigated MSU crystal nucleation and nine examined MSU crystal growth.
  • Most of the identified studies used in vitro assays involving crystallization of MSU from supersaturated solutions of urate.
  • Results from papers examining MSU solubility demonstrated that urate solubility is affected by temperature (colder temperatures were ideal for MSU crystallization), pH (slightly basic conditions were better for MSU crystallization), concentration of various ions such as sodium ions, proteins and various connective tissue factors.
  • Elevated urate concentrations were identified as the main factor required for all three states of MSU crystallization: reduced urate solubility, MSU nucleation and MSU crystal growth; this was the only factor shown to be associated with MSU crystal growth.
  • Other factors associated with MSU nucleation included the presence of uric acid binding antibodies, globulins, collagen, lead and human serum or synovial fluid.
  • Further research examining the role of connective tissues in MSU crystallization will improve understanding of gout, and of why only a subset of people with hyperuricemia eventually develop gout.

Chhana A, Lee G, Dalbeth N. BMC Musculoskel Disord. 2015;16:296. doi: 10.1186/s12891-015-0762-4.

Physiopathology of gout

This chapter provides an overview of gout, in terms of genetics, mechanisms of disease, and the inflammation and joint damage that occurs, as well as a discussion of the association between the chronic inflammation in gout and cardiovascular outcomes.

Summary
  • Gout is defined as the presence of monosodium urate (MSU) crystals in tissues, but not all patients with such hyperuricemia develop gout. The prolonged presence of hyperuricemia appears to be the fundamental contributing factor to the formation of MSU crystals.
  • Several genetic factors associated with hyperuricemia have been identified, such as polymorphisms encoding hyperactive variants of renal tubular uric acid transporters that have been associated with increased risk of hyperuricemia and gout.
  • There are several purported mechanisms of hyperuricemia that may, alone or in combination, explain why serum urate rises above that expected for normal function. These can be broadly categorized as an increase in the production of uric acid, inefficient renal excretion and inefficient intestinal excretion of uric acid.
  • Up to 90% of patients with gout exhibit inefficient renal excretion of uric acid, with only 5-10% of hyperuricemia being associated with increased uric acid production.
  • Gout is associated with inflammation and joint damage, which occurs as a result of deposition of MSU crystals in the joints, usually first appearing in the surface of the hyaline cartilage. One important major route of crystal-induced inflammation is the NALP3 inflammasome.
  • An emerging area of research interest is that of the impact of hyperuricemia on cardiovascular outcomes, with a mild-to-moderate impact of hyperuricemia on cardiovascular events shown in recent systematic reviews and meta-analyses.

Perez-Ruiz F, Castillo E. In: Perez-Ruiz F, Herrero-Beites AM (Eds). Managing gout in primary care. Springer Healthcare, London. 2014:13–24. doi: 10.1007/978-1-907673-67-2.

Overview of urate-lowering therapies

Comparative efficacy and safety of urate-lowering therapy for the treatment of hyperuricemia: A systematic review and network meta-analysis

This paper provides the findings of a systematic review and network meta-analysis investigating the comparative efficacy and safety of urate-lowering therapies in the treatment of hyperuricemia.

Summary
  • Researchers conducted a network meta-analysis comparing the efficacy and safety of five urate-lowering drugs in terms of their ability to achieve target serum urate levels as well as their safety.
  • A total of 15 studies involving 7246 adult subjects were included, with the earliest study conducted in 1999 and the most recent one in 2016. The trial durations ranged from 4 through to 52 weeks, and baseline serum urate levels were >8.0 mg/dL.
  • The pairwise meta-analysis showed that allopurinol, febuxostat and pegloticase were highly effective at achieving target serum urate levels compared with placebo. Febuxostat was more likely to achieve the target than allopurinol. Allopurinol was more likely than febuxostat to cause adverse events.
  • On network treatment comparisons, febuxostat, benzbromarone, probenecid, pegloticase and allopurinol were all highly effective in comparison to placebo at achieving the treatment target. Febuxostat was mostly more effective than allopurinol at achieving the treatment target of hyperuricemia. The urate-lowering efficacy of febuxostat improved with increasing dosages. In terms of safety, probenecid was associated with a higher rate of adverse events than allopurinol, febuxostat and placebo.
  • Overall, this network meta-analysis approach demonstrated that febuxostat tended to have higher efficacy and safety than other urate-lowering drugs, especially at a dose of 120 mg once daily. Ranking found benzbromarone to be second to febuxostat at achieving urate-lowering targets.
  • There was no evidence that adverse events outweighed the benefits of any of the urate-lowering therapies, with the exception of probenecid.
  • Overall, these results support the use of drugs such as febuxostat and allopurinol, whereas for benzbromarone and probenecid, therapeutic effects were moderate, and these agents were associated with unpleasant side effects.

Li S, Yang H, Guo Y, Wei F, Yang X, Li D, et al. Sci Rep. 2016;6:33082. doi: 10.1038/srep33082.

Factors associated with initiation and persistence of urate-lowering therapy

This population-based cohort study was conducted to investigate the proportion of patients who initiated and subsequently continued urate-lowering therapy following a gout diagnosis, with a focus on predictors of receiving such therapy.

Summary
  • The aim of this study was to determine the proportion of patients who receive urate-lowering therapy following a gout diagnosis, and predictors of such therapy as well as the proportion of patients persisting with treatment, using regional healthcare registers linked with several national mandatory population-based registers in Sweden.
  • A total of 7709 incident cases of gout were identified between 2011 and 2013. Of these incident cases, 19% had received urate-lowering therapy within 30 days post diagnosis, with 32% receiving urate-lowering therapy within 365 days post diagnosis. The majority of patients received allopurinol, <2% received probenecid and no patients received febuxostat.
  • Factors predictive of start of urate-lowering therapy within 365 days were male sex, and the presence of at least one comorbidity; renal disease was also predictive of start of urate-lowering therapy.
  • Of the 7709 incident cases, 2087 (27%) were followed up following their first dispensation of urate-lowering therapy, of whom 75% did not persist with such treatment.
  • The risk for not persisting with therapy was higher for those aged <50 years, a lack of any comorbidities, no renal disease, and normal kidney function.
  • There was no significant effect of year of gout diagnosis for any of the analyses, suggesting that there were no major changes in treatment patterns during the study period.
  • The results of this study demonstrate that initiation and persistence with urate-lowering therapy continues to be poor, although rates are higher in those with a stronger indication for therapy.
  • The long-term consequences of poor urate-lowering therapy for gout need to be more clearly determined.

Dehlin M, Ekstrӧm EH, Petzold M, Strӧmberg U, Telg G, Jacobsson LTH. Arthritis Res Ther. 2017;19:6. doi: 10.1186/s13075-016-1211-y.

A joint effort over a period of time: factors affecting use of urate-lowering therapy for long-term treatment of gout

This paper examines reasons for lack of urate-lowering therapy (ULT) in many patients with gout, using patient interviews to explore patient experience with, and understanding of, such therapy.

Summary
  • Current literature demonstrates that there is a need for improved quality of care for patients with gout, but the reasons behind the current suboptimal management of such patients remain to be fully elucidated.
  • To explore reasons for under prescription of ULT and poor adherence to such therapy, researchers conducted a qualitative study, using face-to-face semi-structured interviews with 43 participants in their homes or workplaces within the UK.
  • Three anticipated themes (knowledge and understanding of gout, experience using ULT, information needs) and two emergent themes (resistance to medication and uncertainty about starting ULT) were discussed.
  • Knowledge and understanding of gout and its treatment:
    • Perceptions and understanding of gout influenced attitude to treatment – failing to see it as serious or long-term reduced likelihood of taking ULT.
    • Understanding could change over time, moving patients towards increased likelihood of taking ULT.
  • Resistance to medication:
    • Reasons for such resistance included the long-term nature of treatment, sense of identity, dislike of multiple medications and desire for self-management.
  • Uncertainty about whether and/or when to start ULT:
    • Many patients discussed an ‘acceptable’ number of attacks, which may lead to patients continuing to experience regular attacks, following a wait and see approach to medication.
  • Patients' experiences of taking ULT:
    • A key theme was the patient feeling that the process of achieving the right dosage was one of trial and error, which could be frustrating for patients, particularly when combined with a lack of explanation.
  • Desire for information and monitoring:
    • Most knew little about gout prior to diagnosis, and the impact of long-term treatment on patients was often underestimated by healthcare practitioners. Patients expressed a desire for ongoing dialogue with their healthcare professional.
  • This study suggests that rather than prescription as a GP issue and adherence as a patient issue, patient factors play an important role in the decision to prescribe, and GPs can influence whether patients continue to take prescribed medication.

Richardson JC, Liddle J, Mallen CD, Roddy E, Hider S, Prinjha S, Ziebland S. BMC Musculoskelet Disord. 2016;17:249. doi: 10.1186/s12891-016-1117-5.

Urate-lowering therapy: current options and future prospects for elderly patients with gout

This paper discusses the use of urate-lowering therapies in elderly patients, with a focus on the available therapeutic options and their risks and benefits in this patient population, as well as a mention of pipeline therapeutics.

Summary
  • Treatment with urate-lowering therapy is recommended for an established diagnosis of gout with two or more attacks of acute gout per year, presence of tophi, and chronic kidney disease that is at least stage 2, or renal stones.
  • Gout is seen more frequently with advancing age, due to factors such as the presence of renal impairment and chronic diuretic use.
  • Available treatment options include the xanthine oxidase inhibitors:
    •  Allopurinol – the more established agent, commonly used as first-line therapy. Use in renal impairment remains controversial. There are several notable drug interactions, including with azathioprine and with furosemide. Importantly, allopurinol may have beneficial effects on cardiovascular disease.
    • Febuxostat – a newer agent, unlike allopurinol it is primarily metabolized in the liver. It provides an alternative option for patients who have experienced severe reactions to allopurinol. The cardiovascular safety of febuxostat has been questioned.
  • The other main group of urate-lowering therapies are the uricosuric agents – which lower serum urate by increasing renal urate excretion. This group includes benzbromarone, not widely available due to concerns over hepatotoxicity, and probenecid, which is generally reserved for those who do not tolerate or fail to achieve target serum urate on a xanthine oxidase inhibitor.
  • The recombinant uricases (pegloticase) are a new class that may rapidly decrease both serum urate and number and size of tophi. Due to lack of knowledge around these agents, they are usually reserved for patients refractory to other treatments.
  • Pipeline agents include:
    • Lesinurad – an inhibitor of urate transporters in the proximal tubule of the kidney.
    • Levotofisopam – a 2,3-benzodiazepine derivative thought to act as a uricosuric agent.
    • Ulodesine – a purine nucleoside phosphorylase inhibitor, inhibiting uric acid production.
    • Arhalofenate – a peroxisome proliferator-activated receptor-ligand (PPAR)-γ modulator.
    • Topiroxostat – binds and inhibits xanthine oxidase.
    • Tranilast – inhibits renal urate transporters, increasing renal urate excretion.
  • For most patients, first-line therapy for gout will be allopurinol, with febuxostat a welcome alternative. Uricosuric acids have utility in selected patients, and pegloticase, although effective, is currently restricted to severe cases and usually administered in specialist centres.

Stamp LK, Chapman PT. Drugs Aging. 2014;31:777–786. doi: 10.1007/s40266-014-0214-0.

Allopurinol

Safety of allopurinol compared with other urate-lowering drugs in patients with gout: a systematic review and meta-analysis

This systematic review was conducted to compare the safety of allopurinol with that of placebo or other urate-lowering drugs in the treatment of gout.

Summary
  • This systematic literature review and meta-analysis was conducted to assess the safety of allopurinol compared with placebo or other urate-lowering drugs for the treatment of gout.
  • From a search conducted to identify all studies published up until January 2014 providing information about allopurinol safety, a total of 11 met inclusion criteria. There were seven randomized, double-blind, placebo-controlled trials and four systematic reviews, with a total of 4506 adults with gout/hyperuricemia. A total of 696 participants were randomized to allopurinol (up to 300 mg), 134 to placebo, 3585 to febuxostat (40–240 mg), 56 to benzbromarone and 35 to probenecid.
  • Four randomized controlled trials compared the safety of allopurinol to placebo and febuxostat. The most common adverse events were abnormal liver function, diarrhea, and rash. Allopurinol was generally well tolerated and there were no differences in risk of any type of adverse events between allopurinol (300 mg) and febuxostat (40–240 mg).
  • Two studies compared safety of allopurinol versus probenecid and benzbromarone. In one study, there was a higher rate of treatment discontinuation with probenecid, followed by allopurinol then benzbromarone, and gastrointestinal symptoms were more frequent with probenecid that with either of the other two agents. In the second, a greater number of patients discontinued treatment in the benzbromarone group than in the allopurinol group.
  • In summary, the study authors state “we can conclude that the safety of allopurinol is that of febuxostat at doses below 120 mg and that of probenecid and benzbromarone (level of evidence 1B, evidence from at least one high quality RCT)”.
  • Overall, allopurinol can be considered a safe treatment option compared with other urate-lowering drugs, but the use of higher doses and longer follow-ups need to be evaluated.

Castrejon I, Toledano E, Rosario MP, Loza E, Pérez-Ruiz F, Carmona L. Rheumatol Int. 2015;35:1127–1137. doi: 10.1007/s00296-014-3189-6.

An open-label, 6-month study of allopurinol safety in gout: the LASSO study

This paper outlines the results of a 6-month safety study of allopurinol in the treatment of gout, the LASSO study.

Summary
  • The Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients (LASSO), was a 6-month, open-label study conducted to assess the safety of allopurinol, with investigators encouraged to titrate treatment to target serum urate levels.
  • Included patients were aged 18–85 years with a diagnosis of gout and at least two flares in the past year, enrolled at 169 study sites in seven countries; a total of 1735 patients were enrolled, with the 6-month study period completed by 1238 patients.
  • The mean daily allopurinol dose during the study was 269.5 mg over a mean duration of 148.3 days. The maximum daily allopurinol dose during the study was <300 mg in 250 patients (14.4%), 300 mg in 1132 patients (65.4%), and >300 mg in 350 patients (20.2%).
  • A total of 955 (55.1%) patients experienced a treatment-emergent adverse event (TEAE), of whom 185 patients had a TEAE possibly related to allopurinol, occurring in 15.2%, 9.5% and 11.4% of patients in the <300, 300 and >300 mg categories, respectively.
  • The most common TEAEs overall were upper respiratory tract infection, diarrhea, and arthralgia.
  • Serious adverse events occurred in 51 (2.9%) of patients, none of which were considered possibly related to allopurinol or to flare prophylaxis, with an incidence of TEAEs leading to allopurinol withdrawal or study discontinuation of 4.3% (10.8% for <300 mg, 3.6% for 300 mg and 1.7% for the > 300 mg group).
  • At 6 months, target serum urate levels (<6.0 mg/dL) were achieved by 35.9% of patients.
  • While this study showed allopurinol, administered using a dose-titration strategy, to have a good safety profile, a large proportion of patients did not achieve target serum urate levels, despite encouragement to treat to target.

Becker MA, Fitz-Patrick D, Choi HK, Dalbeth N, Storgard C, Cravets M, Baumgartner S. Semin Arthritis Rheum. 2015;45:174–183. doi: 10.1016/j.semarthrit.2015.05.005.

Allopurinol hypersensitivity: Investigating the cause and minimizing the risk

This review examines allopurinol hypersensitivity, with a focus on risk factors and mechanisms, in the context of reducing the risk of this rare, but serious, adverse reaction.

Summary
  • While allopurinol is an effective urate-lowering therapy, it can cause adverse effects ranging from a mild form of hypersensitivity with maculopapular eruption (MPE; occurs in 2% of patients), to severe cutaneous adverse reactions, and the rare, but life-threatening systemic manifestation, allopurinol hypersensitivity syndrome (AHS; 0.1%).
  • Risk factors for the development of AHS can be grouped into three categories as follows:
    • Time from start of treatment – typically develops shortly after commencing allopurinol.
    • Genetic factors – the human leukocyte antigen (HLA-B)*58:01 allele has been reported to be associated with increased risk.
    • Factors influencing drug concentration – including allopurinol dose, the presence of kidney impairment and use of diuretics.
  • There is evidence to suggest that oxypurinol may play a role in the development of AHS, with the associations between allopurinol dose, kidney impairment, concomitant diuretic use and drug concentration leading to the suggestion that excessive concentrations of oxypurinol may be a key causative factor.
  • Allopurinol hypersensitivity may arise due to certain T-cell responses. Drug-specific cytotoxic CD4+ T cells appear to carry out a key role in MPE, whereas drug-specific cytotoxic CD8+ T cells are implicated in more severe cutaneous adverse reactions. The ability of oxypurinol to induce T-cell responses has been shown to be increased in those with the HLA-B*58:01 allele, with oxypurinol shown to bind with higher affinity to HLA-B*58:01 than other HLA molecules.
  • Potential methods of reducing the risk of AHS include use of alternative agents (although given that allopurinol is cheap, readily available and effective, it is likely to remain first-line therapy for most patients), genetic screening (recommended in those populations considered to be at elevated risk of AHS), and modifying the dosing strategy (specifically, reducing the starting dose).
  • Early identification of AHS and discontinuation of allopurinol treatment appear to be crucial for outcome of patients.
  • With the identification of factors that increase the risk of AHS, there is now a need for sufficiently powered studies to explore strategies to reduce this risk.

Stamp LK, Day RO, Yun J. Nat Rev Rheumatol. 2016;12:235–242. doi: 10.1038/nrrheum.2015.132.

Febuoxstat

Febuxostat: a review of its use in the treatment of hyperuricaemia in patients with gout

This paper provides a review of febuxostat in the treatment of hyperuricemia in patients with gout, including pharmacokinetic and pharmacodynamic properties, efficacy and safety, and its place in therapy.

Summary
  • Febuxostat, like allopurinol, is a xanthine oxidase inhibitor, acting to reduce serum uric acid levels by impeding transformation of hypoxanthine to xanthine and of xanthine to uric acid.
  • Febuxostat dose dependently decreases serum uric acid levels, an effect that is not altered by renal impairment.
  • Data from randomized, double-blind studies demonstrate:
    • Febuxostat 80 and 120 mg/day were significantly more effective that allopurinol 100-300 mg/day in lowering serum uric acid levels.
    • The antihyperuricemic activity of febuxostat is largely dose dependent.
    • Target serum uric acid level of <6.0 g/dL at final study visit was achieved in over two thirds of patients receiving febuxostat 80 mg/day, compared with less than half for allopurinol.
    • During the prophylaxis period, significantly more febuxostat 120 mg/day recipients than febuxostat 80 mg/day or allopurinol recipients required treatment for gout flares.
    • No significant differences between febuxostat 80 mg/day, 120 mg/day and allopurinol 100–300 mg/day in percentage reduction in tophus area or reduction in the number of tophi.
  • In open-label extension studies, long-term treatment with febuxostat was associated with maintenance of target serum uric acid levels.
  • In terms of tolerability, both short-term and longer-term tolerability was generally good, with most adverse events of mild to moderate severity; in general, the adverse event profiles of febuxostat and allopurinol were similar in clinical trials.
  • Febuxostat is an established alternative to allopurinol, which remains the gold standard, most widely prescribed urate-lowering therapy for gout. Febuxostat offers the advantage of no requirement for dose adjustment in patients with mild to moderate renal impairment, as well as offering a potential alternative in patients with allopurinol hypersensitivity syndrome.

Frampton JE. Drugs. 2015;75:427–438. doi: 10.1007/s40265-015-0360-7.

Comparative effectiveness of urate lowering with febuxostat versus allopurinol in gout: analyses from large U.S. managed care cohort

This study compared febuxostat and allopurinol in terms of their ability to lower serum urate levels, using data from a large US managed care database.

Summary
  • Patterns of allopurinol and febuxostat usage were assessed using data from a large managed care organization. The main study objective was the comparison of the serum urate lowering capabilities of febuxostat and allopurinol.
  • The study sample included 2015 patients assigned to the febuxostat cohort and 14025 to the allopurinol cohort. The main analysis of this study used 873 matched pairs with no evidence of treatment with allopurinol of febuxostat in the pre-index period (treatment naïve patients). In these patients, the most common doses were allopurinol 300 mg/day and febuxostat 40 mg/day.
  • Of the treatment-naïve febuxostat patients, 56.9% attained the serum uric acid goal of <6.0 mg/dL compared to 44.8% of the allopurinol patients (P<0.001). A total of 35.5% of the treatment-naïve febuxostat patients attained the serum uric acid goal of <5.0 mg/dL versus 19.2% of the allopurinol patients (P<0.001).
  • Post-index achievement of target serum uric acid levels differed significantly between cohorts. Again, a higher proportion of febuxostat users compared with allopurinol users attained the serum uric acid goal of <6.0 mg/dL (58.5% vs47.1%, P<0.001) and <5.0 mg/dL (36.2% vs 21.8%, P<0.001).
  • Febuxostat users also had a shorter average length of time to target goal attainment than allopurinol users (<6.0 mg/dL: 348 days vs 410 days, P<0.001; <5.0 mg/dL: 443 days vs 501 days, P<0.001).
  • Given their availability, a comparative study of these two drugs is needed to help patients, providers and policy makers in making treatment decisions.

Singh JA, Akhras KS, Shiozawa A. Arthritis Res Ther. 2015; 17:120. doi: 10.1186/s13075-015-0624-3.

Pegloticase

Tophus resolution with pegloticase: a prospective dual-energy CT study

This study investigated the ability of pegloticase to reduce tophus in patients with refractory gout.

Summary
  • In this prospective observational study, a total of 10 patients with gout received pegloticase 8 mg intravenously every 2 weeks, after discontinuation of all other uric acid-lowering therapy. Dual-energy computed tomography (DECT) scans were used to investigate the regression of tophi.
  • Enrolled patients, seven males and three females, had a mean age of 58.2 years, mean disease duration of 55.2 years, and received treatment for a mean of 13.32 weeks.
  • Five of the patients were considered responders, with a serum uric acid level below 6 mg/dL for more than 80% of the treatment period, with the remaining five considered as partial responders, losing treatment efficacy due to immunogenicity to pegloticase and development of infusion reactions.
  • DECT scans were performed for both hands and feet for seven patients and for feet alone in the remaining three. Prior to therapy, mean tophus volume was 9.15 cm3, decreasing to 1.89 cm3 following therapy. Among responders, mean tophus volume was reduced to very small lesions (mean 0.12 cm3), a 95% volume reduction; there was a 48% volume reduction in partial responders.
  • The reduction in tophi varied based on location, with articular tophi rapidly resolving, but tophi persisting longer in bradytrophic tissues such as tendons; large bulky tophi remained virtually unchanged around the Achilles tendon
  • The researchers conclude that “the profound lowering of uric acid levels by pegloticase effectively and rapidly resolves tophi in the musculoskeletal tissues of patients with advanced gout”.

Araujo EG, Bayat S, Petsch C, Englbrecht M, Faustini F, Kleyer A, et al. RMD Open. 2015;1:e000075. doi: 10.1136/rmdopen-2015-000075.

Lesinurad

Lesinurad, a novel, oral compound for gout, acts to decrease serum uric acid through inhibition of urate transporters in the kidney

This paper profiles lesinurad, a novel uric acid-lowering therapy for the treatment of gout.

Summary
  • This study was conducted to define the molecular mechanisms of action of lesinurad, a uric acid reabsorption inhibitor.
  • To determine the effects of lesinurad on urate, uric acid and lesinurad levels were measured in the blood and urine of healthy volunteers:
    • Lesinurad produced a dose-dependent increase in fractional excretion of uric acid.
    • Fractional excretion of uric acid increased with lesinurad plasma concentrations.
    • Single doses of lesinurad led to a dose-dependent reduction in serum uric acid.
  • In vitro, lesinurad was shown to inhibit the activity of reabsorptive urate transporters URAT1 and OAT4 in a dose-dependent manner, at similar potency.
  • Lesinurad was also shown to inhibit OAT1 and OAT3, which are transporters involved in both urate secretion and drug-drug interactions, with no effect on ABCG2.
  • In contrast to benzbromarone (associated with hepatotoxicity), lesinurad did not show any mitochondrial toxicity even at the highest concentration tested.
  • In contrast to benzbromarone, lesinurad did not show any peroxisome proliferator-activated receptor gamma (PPARγ) activation, or PPARγ agonism which are associated with increased cardiovascular risk.
  • Lesinurad-mediated inhibition of these transporters is consistent with increasing urinary uric acid excretion, and its OAT4 activity in particular may counteract diuretic-induced hyperuricemia.

Miner JN, Tan PK, Hyndman D, Liu S, Iverson C, Nanavati P, et al. Arthritis Res Ther. 2016;18:214. doi: 10.1186/s13075-016-1107-x.

Lesinurad, a selective uric acid reabsorption inhibitor, in combination with febuxostat in patients with tophaceous gout: findings of a phase III clinical trial

This phase III study was conducted to investigate the use of lesinurad combined with febuxostat in the treatment of tophaceous gout.

Summary
  • The current phase III study was conducted to examine the benefits and risks of lesinurad (200 mg or 400 mg once daily) in combination with febuxostat 80 mg in patients with tophaceous gout.
  • Included patients had a diagnosis of gout with serum urate at least 8.0 mg/dL, or at least 6.0 mg/dL with urate-lowering therapy, and at least one measurable target tophus.
  • After 3 weeks’ febuxostat 80 mg, patients were randomized 1:1:1 to receive placebo plus febuxostat 80 mg, lesinurad 200 mg plus febuxostat 80 mg or lesinurad 400 mg plus febuxostat 80 mg; baseline demographic and disease characteristics were similar between treatment groups.
  • A total of 330 patients were randomized at 102 study sites, of whom 324 patients received at least one dose of randomized study medication.
  • Significantly more patients treated with lesinurad 400 mg plus febuxostat achieved the primary end point of a serum urate level of <5.0 mg/dL by month 6 compared with febuxostat alone (76.1% vs 46.8%; P<0.0001); the difference was not significant for lesinurad 200 mg plus febuxostat (56.6%; P=0.13).
  • The number of patients with complete resolution of tophus did not differ significantly between groups, although treatment with lesinurad plus febuxostat was associated with a reduction in total target tophi area compared with febuxostat alone.
  • Lesinurad was generally well tolerated. While the incidence of treatment emergent adverse effects (TEAEs) was higher with lesinurad plus febuxostat than febuxostat alone, most events were grade 1 or 2, and the incidence of serious AEs and of TEAEs leading to study withdrawal were comparable across groups. Patients in the lesinurad 400 mg plus febuxostat group had a higher incidence of TEAEs leading to treatment discontinuation compared with lesinurad 200 mg plus febuxostat or febuxostat alone.
  • Therapy with lesinurad and febuxostat targets both uric acid excretion and urate production, and may represent a treatment option for patients with tophaceous gout who are taking febuxostat but require additional therapy.

Dalbeth N, Jones G, Terkeltaub R, Khanna D, Kopicko J, Bhakta N, et al. Arthritis Rheumatol. 2017;69:1903–1913. doi: 10.1002/art.40159.

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