Abstract

Allopurinol is the most widely used urate-lowering medication worldwide. However, allopurinol failure is frequently observed in clinical practice. In this review, we provide a framework for assessing allopurinol failure, which includes failure of allopurinol to control serum urate concentrations, failure of allopurinol to control clinical symptoms, and failure of allopurinol due to an adverse drug reaction. Understanding the causes of allopurinol failure underpins the approach required to turn failure into success in gout management.

Key Indexing Terms:

Gout remains one of the most common forms of arthritis worldwide. Typically, gout presents with intermittent, intensely inflammatory gout flares, which represent the immune response to the deposition of monosodium urate (MSU) crystals within and around joints and periarticular structures. In the setting of persistent serum urate (SU) elevations and increasing MSU crystal deposition, some patients also develop tophaceous gout, radiographic gouty erosions, and/or chronic gouty arthritis.1 Nephrolithiasis, with stones composed of uric acid, is also more common in people with gout.2

The mainstay of long-term gout management is urate-lowering therapy (ULT). Maintaining the SU below the saturation concentrations with ULT leads to dissolution of MSU crystals,3 and in the long term, suppression of gout flares and regression of tophi.4,5 The recommended SU for most people with gout on ULT is below 0.36 mmol/L (6 mg/dL).6 Despite the development of several new therapies over the last 2 decades, allopurinol remains the first-line ULT worldwide. Allopurinol can be very effective in reducing SU and managing gout when dosed appropriately and taken regularly. However, in clinical practice, many people are said to experience allopurinol failure. In this review, we will discuss the reasons for allopurinol failure and the options for turning failure into success in gout management.

Currently available ULTs and rank order for use

In contemporary clinical practice, there are a variety of ULTs available; they fall broadly into 3 categories based on mechanism of action: (1) xanthine oxidase inhibitors, which reduce urate production; (2) uricosurics, which increase renal urate excretion; and (3) recombinant uricases, which metabolize urate to the more water soluble allantoin (Figure 1). The American College of Rheumatology (ACR),6 European Alliance of Associations for Rheumatology (EULAR),7 and British Society for Rheumatology (BSR)8 gout management guidelines all recommend allopurinol as the first-line ULT, including in people with impaired kidney function. Its low cost and ease of administration, with once-daily dosing, contribute to allopurinol accounting for more than 90% of all ULT use worldwide.9 The different recommendations and rank order for use of the available ULTs in different rheumatology guidelines are shown in Table 1. Given that allopurinol is the first-line agent, it is important we understand the reasons why allopurinol may not achieve the desired outcomes in people with gout.

Figure 1.

Site of action of different urate-lowering therapies. XO: xanthine oxidase.

Table 1.

Recommendations for use of ULT in the management of gout.

What do allopurinol success and failure look like?

According to Collins Dictionary, “Something that is successful achieves what it was intended to achieve.”10 When defining “success” of ULT, it is important to consider clinical outcomes and not just SU. Although achieving target SU has been the main focus for defining “success” in most gout clinical trials, it is meaningful only if there are associated clinical improvements. Ideally in gout, the clinical improvement would be disease remission, which has been preliminarily defined as absence of gout flares, SU < 0.36 mmol/L, absence of tophi, pain due to gout < 2 and patient global assessment of gout disease activity < 2 on a 10 cm visual analog scale,11 and the absence of adverse effects.

Drug failure can be considered if the expected effects do not occur with a prescribed pharmacological treatment. This could include failing to achieve the desired treatment target or clinical outcome, or occurrence of an adverse drug reaction requiring treatment cessation. In the case of allopurinol, “failure” can therefore be defined as (1) failure to achieve target SU, (2) failure to achieve the desired clinical outcomes, or (3) an adverse reaction requiring cessation, such as allopurinol hypersensitivity syndrome (AHS). The reasons for drug failure are complex and can occur at any point in the therapeutic chain, which is “the process describing the life of medicines in a community”12 (Figure 2). Further, there is a complex interplay between biopsychosocial factors and every step of the therapeutic chain.

Figure 2.

The therapeutic chain. Darker boxes represent the main sources that affect allopurinol success or failure.

Failure of allopurinol to achieve target SU

Failure of allopurinol to achieve target SU may be related to (1) allopurinol manufacture, (2) allopurinol dosing, (3) adherence and persistence with allopurinol, or (4) true nonresponse.

Allopurinol manufacture. Counterfeit medicines are on the rise globally and although there are no specific reports of counterfeit allopurinol, it would be naive to presume it did not exist. Even though we might perceive that the high/middle-income countries are immune to these substandard and/or falsified medicines, the World Health Organization has estimated that 50% of the medicines for sale on the internet are fake, even if the online providers look legitimate.13 In addition, the Alliance for Safe Online Prescribing 2021 survey of Americans’ perceptions and use of online pharmacies identified that nearly half of Americans were purchasing medications online because of perceived benefits of cost and convenience.14 Although these substandard or fake medicines may cause adverse reactions, it is far more likely that they contain little or no active ingredient. In the case of allopurinol, substandard or fake versions should be easy to identify as one would anticipate little reduction in SU.

•    Key message. If target SU is not achieved, practitioners should ask where medicines are being sourced.

Allopurinol dosing. Two of the most common reasons for allopurinol failure are underdosing and lack of regular prescribing by healthcare professionals. Allopurinol is approved by the US Food and Drug Administration to a maximum of 800 mg daily, although doses above 300 mg daily remain infrequent. For example, in the Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients (LASSO) trial, investigators were encouraged (but not required) to titrate allopurinol doses to achieve target SU to < 0.36 mmol/L. Disappointingly, the maximal allopurinol dose during the study was < 300 mg daily in 14.4%, 300 mg daily in 65.4%, and > 300 mg daily in only 20.2% of the 1735 participants, despite only 22.4%, 35%, and 48.3% achieving target SU in the respective dose categories.15 Thus, even in a clinical trial setting, there appears to be prescriber unwillingness and/or inertia in terms of allopurinol dose escalation. Allopurinol dose escalation is even more challenging in real-world primary care settings, where most gout is managed.16

Restricting the dose of allopurinol is undeniably associated with not achieving target SU.17 Further, 300 mg daily, which is often considered the standard dose, is ineffective in achieving target SU in the majority of patients. In the Febuxostat versus Allopurinol Controlled Trial (FACT), in which allopurinol was restricted to a fixed dose of 300 mg even in people with an estimated glomerular filtration rate > 50 mL/min/1.73 m2, only 53/251 (21%) had a SU < 0.36 mmol/L at the last 3 monthly visits.18

Allopurinol dose escalation to achieve target SU is safe and effective even in those with renal impairment.19-22 It is recommended that allopurinol is commenced at a low dose (eg, 50-100 mg daily depending on renal function)6 to minimize the risk of the rare but potentially life-threatening AHS.23 The dose of allopurinol should then be gradually increased in 50 mg to 100 mg increments to achieve target SU. Multiple studies have shown that target SU can be achieved in the vast majority of people with gout with this approach. For example, a community-based randomized controlled trial in the United Kingdom comparing usual general practitioner care and intensive nurse-led care showed that 95% of people achieved target SU with nurse-led care; in this study, allopurinol doses were significantly higher in the nurse-led arm than in the usual general practitioner care arm (mean 460 mg daily vs 230 mg daily, respectively).21 Thus, although the dose escalation strategy with allopurinol may be time consuming and labor intensive, it is effective in achieving target SU.

It is important to recognize that there is a wide dose range for allopurinol (50-900 mg daily), with no one fixed dose allowing target SU to be achieved in the majority. This was highlighted in our allopurinol dose escalation study, in which the mean (range) allopurinol dose in those who achieved target SU was 400 (100-900) mg/day.19,20 A key dose-limiting factor for many prescribers has been impaired kidney function. This stems from a case series and literature review published in 1984, which suggested that the dose of allopurinol should be limited based on kidney function.24 However, we have shown that it is the starting dose of allopurinol that is related to occurrence of AHS rather than the maintenance dose—that is, the dose required to achieve target SU.23 Once established on allopurinol, the dose can be safely increased to achieve target SU, even in those with renal impairment.19,20,22

•    Key message. If SU is not achieved with low-dose allopurinol, the dose should be systematically up-titrated until SU is achieved or to the maximum approved or tolerated dose.

Allopurinol adherence and persistence. Irregular allopurinol prescribing is a barrier to treatment success. In an analysis of global patterns of gout care in which allopurinol was the most widely used ULT, only 26% of people with gout received regular uninterrupted ULT, and for those prescribed any ULT, 50% received regular uninterrupted treatment.9 Health system factors, healthcare provider (HCP) factors, and patient factors all contribute to low rates of allopurinol persistence.25 Health systems may be poorly resourced to support chronic gout management programs. Accessing healthcare for long-term gout management can be expensive and inconvenient for patients.26 HCPs may have concerns about polypharmacy and competing demands for management of other long-term health conditions. Both HCPs and patients may view gout as an acute illness that does not require long-term medication and can be managed with lifestyle changes. The patient experience of gout as an intermittently flaring disease with asymptomatic intercritical periods may contribute to periods of intentional nonadherence to resist illness (“because I want to lead a normal life,” “I want to think of myself as a healthy person again”) and to test treatment (“to see if I can do without it,” “to see if I really need it”).27 People with gout experience high health literacy demands, which can contribute to low allopurinol adherence and persistence.25 Strategies that reduce these demands and build patient understanding about gout as a chronic disease of MSU crystal deposition are essential for effective gout care. For example, in the UK nurse-led gout trial, nurse-led care that included “discussion of illness perceptions, full information on gout (nature, causes, associations, consequences, and treatment options),” shared decision making, and regular follow-up with nurses resulted in significantly greater persistence with ULT (96% vs 56%, respectively, at year 2).21

•    Key message. Practitioners need systems to ensure regular prescribing of allopurinol for people with gout, and build understanding about gout as a chronic disease of MSU crystal deposition that can be treated with long-term ULT.

Nonresponse to allopurinol. There is only a very small subgroup of people with gout who do not achieve target SU despite taking regular allopurinol at a dose that would be expected to result in a reduction in SU. Allopurinol is rapidly metabolized to the active metabolite oxypurinol, and a serum oxypurinol concentration > 100 µmol/L is associated with achieving target SU.28 If allopurinol is systematically dose escalated, only ~10% of people will be on a dose of allopurinol sufficient to achieve serum oxypurinol > 100 µmol/L but not achieve target SU (Figure 3). In these people, switching to a different ULT is required. Although oxypurinol assays are not widely available in clinical practice, these observations indicate that true nonresponse to allopurinol is rare. If allopurinol is dose escalated and the SU does not reduce as expected, the most likely reason is low adherence. In this setting, an open and nonjudgmental discussion about allopurinol adherence is required prior to assuming nonresponse and changing to another urate-lowering medication.

Figure 3.

Percentage of participants achieving target SU stratified by oxypurinol concentration following allopurinol dose escalation using a treat to SU target approach over 24 months (data taken from previous studies18,19). Patients with SU ≥ 0.36 mmol/L and < 100 µmol/L are the true nonresponders. Oxy: oxypurinol; SU: serum urate.

Some patients with gout may require higher doses of allopurinol to achieve the SU target. Genetic variation in ABCG2 has been reported to have a role in allopurinol response. Rs2231142 encodes the Q141K nonsynonymous variation in ABCG2, with the 141K variant causing an approximately 50% reduction in efflux of urate.29 In people enrolled in the LASSO trial,15 rs2231142 has been associated with a poor response to allopurinol (defined as SU > 0.36 mmol/L despite allopurinol > 300 mg daily; odds ratio 2.35, P = 7.3 × 10−4).30 Concomitant medications may also influence the response to allopurinol. For example, frusemide decreases urinary uric acid excretion, which, along with the reduction in extracellular fluid, results in hyperuricemia. When frusemide is used in combination with allopurinol, SU is higher than in those on a similar dose of allopurinol but without frusemide (mean [standard error] SU 0.41 [0.014] mmol/L vs 0.35 [0.014] mmol/L, P = 0.006)31 despite higher plasma oxypurinol concentrations in those on frusemide.31 Thus, allopurinol is a less effective ULT in individuals receiving concomitant frusemide, and higher allopurinol doses may be needed to achieve the SU target.

Failure to achieve the desired clinical outcomes despite reducing the SU to target

Some patients may continue to experience clinical symptoms despite allopurinol reducing the SU to target. This may be due to (1) incorrect diagnosis, (2) gout flares occurring early in the course of treatment, or (3) high MSU crystal burden.

Incorrect diagnosis. Correct diagnosis is the first step in the therapeutic pathway. Gout flares can be mimicked by other types of crystal arthritis such as acute calcium pyrophosphate crystal arthritis or septic arthritis, neither of which will respond to allopurinol. Chronic gouty arthritis may be polyarticular and mimic other forms of inflammatory arthritis such as rheumatoid arthritis (RA) or psoriatic arthritis (PsA). Importantly, both RA and gout can be associated with subcutaneous nodules (rheumatoid nodules and tophi, respectively) and PsA can be associated with hyperuricemia due to increased cell turnover with active psoriatic skin disease. Gout can also coexist with other forms of arthritis. If clinical outcomes do not improve in the expected way following prolonged ULT and other gout treatments, the diagnosis should be reviewed. Further investigations such as synovial fluid aspiration, dual-energy computed tomography, or ultrasound may assist in confirming the diagnosis of gout in this setting, and a careful reassessment for other forms of arthritis may also be needed.

•    Key message. Review the diagnosis if clinical outcomes do not improve as expected with urate lowering.

Gout flares occurring early in the course of treatment. The gout flare is central to the patients’ experience of gout,32,33 affecting nearly every aspect of life.34 Thus, suppression of gout flares is a key goal of management for people with gout and the HCPs caring for them. However, there is an inherent paradox that when initiating any ULT, SU is reduced but flares can occur more frequently. This occurrence of gout flares when commencing allopurinol is an important reason for apparent allopurinol failure. However, this phenomenon is not allopurinol specific, as it can occur with all ULTs. For example, in the 52-week FACT phase III trial of febuxostat vs allopurinol daily, 21% of those receiving allopurinol 300 mg daily, 36% of those receiving febuxostat 120 mg daily, and 22% of those receiving febuxostat 80 mg daily experienced at least 1 gout flare during the first 8 weeks.18 The predictability of gout flares when starting ULT has led to the recommendation that people receive antiinflammatory prophylaxis for the first 6 months of ULT.6,7 Even with the “start low, go slow” dose escalation strategy recommended with allopurinol, those receiving prophylaxis with low-dose colchicine have fewer gout flares than those receiving placebo.35

•    Key message. Gout flares when starting ULT are common and are not specific to allopurinol. Antiinflammatory prophylaxis is appropriate to prevent flares; switching ULT is not required. People starting ULT need to be informed about the potential for gout flares, have a flare action plan, and have a ready supply of their flare medication.

As noted previously, achieving target SU is relevant only if it is associated with an improvement in clinical outcomes. There is evidence that achieving target SU < 0.36 mmol/L is associated with a reduction and cessation of gout flares.4 Continued gout flares despite achieving target SU is another reason cited for allopurinol failure. Importantly, there can be a significant time lag between achieving target SU and an improvement in gout flares. Once again, this delay is not specific to allopurinol; rather, it represents the time for clearance of the MSU crystals.

•    Key message. People starting allopurinol need to be informed that once target SU is achieved, it can still take 12 months for flares to cease and even longer for tophi to resolve. A delay in cessation of flares after achieving target SU with allopurinol is not necessarily an indication to change to an alternate ULT.

High MSU crystal burden. Tophi represent large collections of MSU crystals and a chronic granulomatous tissue response to the deposited crystals.36 Tophi cause joint damage, joint deformity, and restriction of joint movement. MSU crystal volume and tophus size reduce with allopurinol when the SU is < 0.36 mmol/L.37 However, these changes occur slowly at this SU concentration and the persistence of tophi despite SU < 0.36 mmol/L may appear to be allopurinol failure in clinical practice. Faster reductions in MSU crystal volume and tophus size occur with lower SU levels.5 Therefore, once tophi are present, a lower SU level (< 0.30 mmol/L) may be beneficial.7 This lower SU target can be achieved by increasing allopurinol further, switching to another ULT, or combination therapy. Importantly, once established, joint damage and deformity may not improve with allopurinol for years, even with low SU levels.3,38 Treatment with allopurinol aiming for SU < 0.36 mmol/L early in the course of the disease should prevent development of tophaceous gout and joint damage.

•    Key message. Consider the lower SU target of < 0.30 mmol/L in those with high MSU burden.

Adverse reaction requiring cessation of allopurinol

The most feared adverse reactions with allopurinol are AHS and severe cutaneous adverse reactions (SCAR) including Stevens-Johnson syndrome and toxic epidermal necrolysis. AHS, which is characterized by rash, eosinophilia, leukocytosis, fever, hepatitis, and progressive kidney failure,39 is rare, occurring in ~0.1% of those taking allopurinol, but has a high morbidity and mortality. Early recognition and cessation of allopurinol is critical in the management of AHS and supportive care is the mainstay of management. Impaired kidney function has been identified as a risk factor for poor outcomes in AHS, probably secondary to high and sustained oxypurinol concentrations; the efficacy of dialysis to rapidly reduce oxypurinol concentrations needs to be investigated. HLA-B*5801 screening in high-risk populations is recommended; if positive, allopurinol should be avoided and another ULT selected.6 Maculopapular eruptions and other less severe side effects can also occur with allopurinol. Although these do not have the high mortality associated with AHS and SCAR, they may limit the ability to continue or dose escalate allopurinol.

•    Key message. For individuals who have AHS or SCAR due to allopurinol, an alternative ULT is required.

What is the approach to allopurinol failure?

Understanding the causes of allopurinol failure underpins the approach required to turn failure into success. The causes of allopurinol failure and suggested treatment approaches are shown in Table 2. For example, switching to an alternate ULT is unlikely to control SU if nonadherence is the cause of allopurinol failure to achieve target SU. On the other hand, if target SU has not been achieved, adherence is assured, and allopurinol has been dose escalated to the maximum registered or tolerated dose, then adding or switching to another ULT may be successful. If the SU is at target and allopurinol is failing to control clinical symptoms, the diagnosis of gout should be reviewed. If the gout diagnosis is confirmed, gout flare prophylaxis and treatment may need to be intensified (without altering the allopurinol dose), or the SU may need to be lowered further to achieve more rapid dissolution of MSU crystals (by increasing allopurinol further, switching to another ULT, or combination therapy). Finally, if allopurinol failure is due to a severe adverse drug reaction, allopurinol should be stopped, and an alternative urate-lowering medication should be prescribed.

Table 2.

Causes of allopurinol failure and actions required for success.

Conclusion

Allopurinol failure has multiple potential facets and causes. It is important to recognize that many of the common reasons that allopurinol fails will also apply to alternative ULTs. Before labeling allopurinol as having failed, HCPs must explore and address potential reasons and base subsequent treatment decisions on the reasons identified. Most importantly, we agree with Drs. Perry and Madhok that “we must ensure that we have not failed to treat, before we label patients as having treatment failure gout.”40

Footnotes

LKS reports research funding from the New Zealand Health Research Council and consulting fees from Pharmac outside the submitted work. ND reports research funding from the New Zealand Health Research Council, and has received consulting fees, speaker fees, or grants from AstraZeneca, Novartis, Horizon, Selecta, Arthrosi, JW Pharmaceutical, PK Med, LG Chem, JPI, PTC Therapeutics, Protalix, Unlocked Labs, Hikma, Dexcel, and Shanton outside the submitted work.

Accepted for publication March 3, 2024.Copyright © 2024 by the Journal of Rheumatology

This is an Open Access article, which permits use, distribution, and reproduction, without modification, provided the original article is correctly cited and is not used for commercial purposes.