Treat to target in gout

Abstract

The treat-to-target (T2T) approach has been successfully implemented in a number of diseases. T2T has been proposed for rheumatic diseases such as RA, spondyloarthritis, lupus, and recently for gout. The level of evidence for such approaches differs from one condition to the other (moderate to high for hyperlipidaemia, for example). Practice is based on the best available evidence at any time, and in absence of good evidence for T2T in gout, some suggest a conservative only-treat-symptoms approach. Evidence suggests that not treating gout to target in the long term is overall associated with worsening outcomes, such as flares, tophi and structural damage, which is associated to loss of quality of life and mortality. Different targets have been proposed for hyperuricaemia in gout; lower than 6 mg/dl (0.36 mmol/l) for all patients, at least <5 mg/dl (0.30 mmol/l) for patients with severe—polyarticular or tophaceous—gout.

Introduction

Gout is a crystal deposition disease. It is caused by nucleation, growth and apposition of crystals formed by monosodium urate monohydrate [1] that induce both acute and chronic inflammatory responses leading to different clinical manifestations [2]. The unique feature of gout, compared with other rheumatic diseases, is that we can reverse the most important pathophysiological mechanism leading to crystal formation: hyperuricaemia.

Reducing serum urate levels (sUA) in the long term, below that of the saturation threshold, will lead to dissolution of crystals and disappearance of the pathophysiological mechanism causing disease. This in turn results in gout cure [3].

Treat to sUA target strategies

The use of therapeutic targets in medicine has become commonplace over the last two decades. Common examples include targets for prescriptions and monitoring in hypertension, hyperlipidaemia, and diabetes as effective methods to prevent cardiovascular (CV) outcomes and organ damage [4, 5]. Interestingly, targets may differ according to different clinical settings, as it happens depending on co-morbidities and risk factors.

The amount of evidence gathered has been overwhelming for some diseases to support targeted therapy, viz hypertension, diabetes or hyperlipidaemia. Here, the development of a number of new medications has promoted a lot of highly powered clinical trials. As an example, the recent American College of Endocrinology Gudelines for the management of hyperlipidaemia [6] are supported by meta-analyses of nearly 200,000 patients in close to 30 randomized clinical trials [7, 8].

In contrast, the American Association for the Study of Liver Diseases guidelines for the management of haemochromatosis conclude that ‘a stated target is better than a statement of to normal’ [9], and although the same therapeutic target for ferritin is also inserted in the European Association for the Study of the Liver clinical practice guidelines, is it recognized that ‘there are no data from which to base the optimal treatment regimen and target serum iron indices’ [10]. Despite this, phlebotomy prescription based on monitoring serum ferritin is the milestone of the treatment of hemochromatosis unless alternative evidence becomes available.

Treat to sUA target strategies in other musculoskeletal inflammatory diseases

In the last decade, treat to target (T2T) strategies have been evaluated and recommended for the treatment of RA [11], spondyloarthritis (SA)—including AS and PsA—[12], and SLE [13]. Another important but often unanswered question is whether these T2T-based recommendations are or are not implemented in real-life clinical practice as frequently as would be desirable [14].

A detailed review of the 2010 RA-T2T recommendations [11] finds that 8 out of 10 (80%) of them were level of evidence III–IV and strength of recommendation C to D, while the more recent 2014 SA-T2T recommendations would disclose that all (100%) 11 recommendations were level of evidence grade IV, and strength grade D. Scarce number of T2T-designed trials, lack of post hoc analysis by achievement of targets in registration trials, and heterogeneous definition of targets may jeopardize the quality of the available evidence. Until high quality evidence-based targets become available (and assuming they are shown to be clinically useful) expert led, clinical-experience-based definition of targets may help to get to an overall agreement on targets that may be generalized for clinical practice and investigation and lead to achievement of future best evidence. In reality, large amount of clinical guidance continue to be based on this.

Rational of treating to target sUA in gout

The use of T2T strategy was suggested for gout a decade ago [15]. The million-dollar question is how much we should lower sUA in clinical practice. As much as needed to dissolve crystals is the logical answer [16], but it remains to be ascertained if there is a real target and whether this target would be dichotomous or linear (one or several targets) [17]. Recently, the pro-active T2T recommendations for gout have been published [18], very much opposed to that of the American College of Physicians (ACP) [19, 20]. The ACP’s approach discourages the target-and-monitor sUA strategy basing on absence of or inconclusive evidence in the reviewed literature to support any action, as expert opinion and clinical experience are low quality evidence to base recommendations on.

Although unfortunately, there is no randomized trial in which a T2T approach was undertaken (something that is greatly needed), there is strong, indirect evidence that at least a minimum target for sUA can be established (<6 mg/dl or 0.36 mmol/l). The strength of this evidence has increased substantially over the last decade (see Table 1) from the EULAR 2006 recommendations [21] to the 2016 EULAR and T2T recommendations [18]. As such, the ACP’s approach to discourage a target-and-monitoring of sUA is clinically concerning and appears to contradict the available and growing (although indirect) evidence that we have which is suggestive of the need for a target-and-monitoring approach of sUA.

Outcomes in untreated (undertreated to target?) gout

We argue that if in the absence of good-quality evidence to make a positive recommendation [19, 20], refraining from making any recommendation [27] will lead to clinical inertia, clinical apathy producing undesirable outcomes [28]. In a condition such as gout where there is good evidence that doing nothing is clinically harmful then such an approach of apathy could be considered unethical.

While it is true that there is no clinical trial to test a not-intensive, not-to-target, symptoms-centred approach, there is data coming from the pre-urate-lowering age, when patients had no effective medications to be prescribed. These papers indicate that untreated gout led to an increase in the number and severity of flares and development of bone damage in X-ray, due to the development of tophi in over two-thirds of the patients during a 20-year follow-up [29].

Gout has replaced RA as a common cause of hospitalization throughout the last decades [30], and while the gap for mortality, compared with controls, has closed for RA [31], it remains open for gout [32]. The authors speculate thoughtfully that improvement in control to remission or low activity (targets in the biologic era), may have contributed to the improvement in outcomes in RA, while a conservative approach to gout is common practice.

Gout has been shown to result in loss of perceived quality of life (20-year loss compared with control population in a study [33]) and productivity, higher utilization of healthcare resources [34] and patientś willingness to pay for improvement [35]. In addition to this, development of severe (tophaceous) gout has been associated with increased risk of overall and CV mortality [36]. This increased risk has been shown to occur independently of as well as interacting with other classical CV risk factors [32, 37]. This independent, increased risk of mortality is present also in recent-onset gout [38].

Attainment to a treat-to-avoid-symptoms strategy will repeatedly expose gout patients to anti-inflammatory agents, mostly NSAIDs, and not infrequently prescribed inadequately [39]. Patients with gout, especially those with chronic kidney disease, show benefits from NSAIDs withdrawal due to long-term proper control of sUA [40]. A treat-to-avoid-symptoms vs a T2T-sUA trial would be scientifically sound, but ethically questionable for us. There is sound evidence that use of NSAIDs, as would be expected in a treat-to-avoid-symptoms strategy with high dose NSAIDs prescription approach, and especially in patients with co-morbidities (kidney disease, ischaemic heart disease, hypertension, chronic heart failure and anticoagulation) would presumably induce undesirable outcomes in the long term. This kind of evidence has not been yet considered, and it is not plausible that it would be tested in a clinical trial.

Evidence of benefits of lowering sUA levels

While historical cohorts previous to the availability of urate-lowering medications showed clear worsening of long-term outcomes in gout, it was clinically evident for those highly observant clinicians that lowering sUA was associated with evident clinical benefits such as reduction of tophi [41]. This clinically observed benefit was enhanced by further reduction of sUA when combining medications [42].

An open, prospective 10-year follow-up study showed that despite most patients being compliant on ULT, 50% of them showing subcutaneous tophi at baseline increased the size of their tophi while showing mean sUA 8.2 mg/dl (0.48 mmol/l) [43, 44]. In contrast, those patients who experienced a reduction in the size of their tophi had a mean sUA 6.2 mg/dl (0.37 mmol/l), while the only patient who cleared their tophi completely had a sUA < 4 mg/dl (0.24 mmol/l) [45]. This study highlights the accepted review of the evidence, namely that long-term-to target control of sUA has been shown to be associated with reduction and disappearance of subcutaneous and articular tophi [43, 44], although unfortunately for scientific purity this has only been shown in open, non-comparative clinical studies.

Currently we do not know whether early treatment of hyperuricaemia in patients with gout compared with delayed treatment of patients with a definite diagnosis of gout is beneficial. Similarly, even assuming that early treatment is beneficial we do not know when treatment should be started in order to outweigh the risks of taking medications, or what is the best approach to selection of drugs, dosing and combination of drugs (the latter, if required). Once cessation of clinical symptoms has been achieved we remain unaware of whether and what type of prophylaxis would be the best according to the highest standard of scientific evidence. We believe that it will take a long time to clarify these queries, assuming it is possible. Until that may happen, the fact is that our patients deserve the best treatment available according to the best current knowledge. This aspiration is made more challenging by the fact that gout, while a relatively simple and already effectively curable disease, is poorly understood by clinicians and the public alike. That means that knowledge that lowering treatment to be effective has little uptake and is often poorly applied and/or complied with [3].

Absence of evidence vs evidence of absence for T2T of sUA in gout

Increasingly we hear that the practicing of the art of medicine (experience/expertise/serendipity/clinical sense) has been replaced by evidence-based medicine. Whilst this is undoubtedly good where such clinical evidence exists, unfortunately best-quality evidence is not available for all/many aspects of clinical practice even in the most prevalent diseases, such as gout. The fixation on evidence-based medicine means that we sometimes lose sight of what is important, the health of our patients. This should not stop us practicing what we consider to be best practice, especially where there is accumulating evidence that doing so improves patient outcomes, for example, in the use of long-term T2T ULT for gout.

Industry-driven clinical trials for the registration of new medications have been designed to show differences between arms of medication using randomized assignment. The outcomes for these trials are agreed with the agencies that are in charge of evaluating the benefit to risk ratio of these medications: typically clinical efficacy to placebo in terms of licensing, or cost-effectiveness. While important, such trials are often limited in scope as such they do not necessarily answer the clinical questions of relevance to patients, such as how best to treat the disease in terms of what makes the most difference to patient outcomes, in terms of improvements in their quality-of-life and life expectancy. As an example for the reader, the double blind randomised controlled trial for the clinical development of febuxostat showed no short-term reduction in the rate of flares in either arm of treatment. The reduction in the flare rate of gout only happened in the long-term, open-label extension studies, when there was no placebo arm. Patients were to be reassigned to a different treatment, if necessary, to get sUA below 6 mg/dl (0.36 mmol/l) by protocol, benefit thus appearing when a T2T design was implemented [46]. The rational explanation for these contradictory conclusions is that these trials were not designed to evaluate flares as the primary outcome, but to compare the rates of patients achieving sUA <6 mg/dl (0.36 mmol/l) in each arm of treatment. Patients were started on febuxostat [47], at doses of 80–240 mg/day from the very first day. In those patients who had a sharp decrease of sUA they frequently experienced an acute flare of their gout. The analysis of flares was based on comparison in the rate of flares during the prophylaxis period: these were 20% for placebo, 23% for allopurinol, 28% for febuxostat 80 mg, 36% for febuxostat 120 mg and 46% for febuxostat 240 mg. The rates were significant higher for the two higher doses of febuxostat, but there was no difference between the other arms. To our knowledge there has been no post hoc analysis by sUA strata reported to date, but we would anticipate that those patients with the lowest sUA initially experienced the highest risk of an acute flare. Indirect evidence is supportive of this showing that if you achieve sudden reduction to very low sUA (as in the pegloticase trials), the rate of flares will reach 80%, 2-fold of that of febuxostat 120 mg (indirect comparisons, low evidence). This is why expert opinion recommends to apply a start low go slow dosing approach for urate-lowering medications [21] whenever possible.

More recently, a pooled, post hoc analysis by continuous sUA strata of the pivotal phase 3 trials of the lesinurad clinical development programme showed a clear benefit in reduction of both tophi and rate of flares in patients reaching target sUA < 6 mg/dl (0.36 mmol/l) independently of the treatment they were assigned to, compared with those not reaching sUA target [48]. In addition, the benefit in reduction of tophi and flares was achieved more frequently in the short term when the lower strata of sUA were achieved. These results replicate results from clinical follow-up cohorts (17).

The available evidence also depends on how outcome variables are defined. Comparing differences in the rates of patients suffering a flare in the different arms has been common in registration trials, while in cohort or small-sized clinical trials paired variables methods have been used, comparing whether patients do worse or better after an intervention compared with previous status. Comparing these two techniques for the same trial might give very different results: for example, in one trial [49] assessing the rates of occurrence of the flares gives the change in the percentage of patients suffering a flare in a period of time: while 47.2% of patients experienced a flare in the first 6-month period of treatment, everyone had at least one in the year prior to treatment and 4% during the second year of treatment) [49]. While an initial rate of flares close to 50% could be considered unacceptable, a reduction of 50% compared with previous year could be considered as improvement.

Statistical differences are important when comparing trial data. As is well known in evidence-based medicine ranking the level of evidence offered by small, low-powered, randomized trials (using secondary hypotheses) is not considered best evidence. Unfortunately, as already stated, there are no large, randomized controlled trials looking specifically at the benefit of long term T2T of sUA in gout. As such we only have indirect evidence using existing small and often underpowered trial data to guide us. Therefore a peer reviewed, published meta-analysis which compares all these small trials using the same statistical technique and has sufficient power for statistical validity is overdue and would be a welcome addition to providing direction in the best way to treat gout from a clinical perspective.

sUA targets in gout

It would be great to have only one target for one disease or condition. It would be wonderful that no patient would develop severe (polyarticular involvement, tophaceous deposition, structural damage) because not necessarily early, but at least timely start of urate-lowering treatment had been implemented. Unfortunately there is as yet no high quality evidence to take that decision. Maybe the trigger would be asking the patient if they would be prone to suffer that kind of gout-associated-pain once again in their life [50]. In the end clinical inertia is a large driver in the development of severe gout in a number of patients. While different targets have been recommended for such different clinical scenarios of gout severity [23].

The ultimate goal of ULT is to reduce sUA levels to that necessary to induce dissolution of MSU crystals present in tissues. This is the clinically relevant end point and achieving this would define a therapeutic target. While if crystal dissolution rate differs with different sUA levels, then different therapeutic targets may be defined. Once, after adequate reduction (preferably to therapeutic target) of sUA levels, the last MSU crystal is dissolved gout is conceptually cured [3]. From then on, we would just need to keep sUA below the saturation threshold and prescribe ULT only if needed to avoid rise in sUA over that saturation threshold, that is to consider a preventive target [51].

Therapeutic targets

Different therapeutic targets have been recommended for different clinical settings [21, 23, 52]. As previously mentioned, there is evidence (not highest quality, but the best we have got) showing that when a sUA well below the saturation threshold for nucleation of urate in tissues—that is, 6.8 mg/dl (0.41 mmol/l). It was empirically chosen for clinical studies and it worked: patients who achieved sustained long term control of sUA below 6 mg/dl (0.36 mmol/l) showed improvement in outcomes (flares, tophi) that most probably were not to be expected in patients with untreated hyperuricaemia, as discussed above regarding the historically-not-treated cohorts. Indeed, sUA has been considered to fulfil criteria to be a disease biomarker [25].

There is an overall agreement to consider sUA 6 mg/dl (0.36 mmol/l) as the minimum cut-off to obtain meaningful benefit from urate-lowering interventions, whereas sUA 5 mg/dl (0.30 mmol/l) has been considered the minimum target to reach in patients suffering gout with severe clinical characteristics (polyarticular, with established structural joint damage or tophi).

These therapeutic targets have been endorsed by EULAR [21, 25], ACR [23] among other many groups and scientific societies supported by different levels of evidence (see Table 1), with less evidence to date for the more stringent 5 mg/dl (0.30 mmol/l) target for severe gout. These therapeutic targets have been endorsed by the European Medicine Agency as to indicate combination of xanthine-oxidase inhibitors with lesinurad [53], and to raise febuxostat dose from 80 to 120 mg daily if the therapeutic sUA target <6 mg/dl (0.36 mmol/l) is not reached [54].

Lifelong control of hyperuricaemia has been recommended in gout [23], very low sUA levels not being necessary (if questionably deleterious) after the therapeutic goal of dissolving MSU crystals is definitively achieved [25]. Therefore, a two-stage approach to hyperuricaemia could be considered in gout [51]: T2T to obtain therapeutic cure then treat less aggressively in order to prevent recurrence.

Preventive sUA target

Conceptually, once body tissues have been depleted from the last MSU crystal after sustained to-target treatment, long-term control of sUA levels should be aimed just to avoid new formation of crystals. Therefore, maintaining sUA below the saturation threshold level would be a preventive target, as absence of crystals means absence of disease.

Withdrawal of urate-lowering therapy is associated with an increase in sUA; the longer the withdrawal time period and the higher sUA during treatment—to-target—and after treatment withdrawal, the shorter the time to relapse of gout [55]. This was an inverse demonstration of the benefit of intense lowering of sUA during active treatment [43]. Subsequent analysis of further follow-up of the same cohort—and not two different cohorts as published recently in a systematic review [27] —included a number of patients who did not raise sUA after withdrawal over 7 mg/dl (0.42 mmol/l): none of these patients suffered relapse of gout [51], and that was associated with withdrawal of diuretics, losing weight and prescription of other medications with urate-lowering effect, as losartan [51]. This should not be interpreted as if some patients may not need treatment [27].

Conclusions

There is no randomized, double-blind, controlled trial specifically designed to support a T2T approach to the treatment of hyperuricaemia of gout. Nevertheless, if we fix to the best evidence available for practice, there is a considerable amount of indirect evidence that treating-to-target in gout is clinically effective in real practice. In addition some indirect evidence from clinical open label extension and post hoc analysis of clinical trials also supports such an approach.

Lower sUA targets may be considered for patients with severe gout, and whether these severely diseased patients should be managed with collaborative efforts between family physicians and rheumatologists is a debate to take into consideration.

A two-stage approach to long-term management of hyperuricaemia and gout is being considered, and still has to be supported by the best scientific evidence we can get.

Acknowledgements

F.P.R. would like to dedicate this paper to Prof Alvarez-Blanco, who encouraged him to become a rheumatologist. F.P.R. has been partially funded by Asociación de Reumatólogos de Cruces.

Supplement: This supplement was funded by Grunenthal.

Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript.

Disclosure statement: F.P.R. has declared fees for consultancies or lectures from AstraZeneca, ArdeaBiosicences, Grunenthal and Menarini. A.D. has received fees for advisory work to Grunenthal UK and Grunenthal GambH regarding the drug lesinurad, a treatment for gout. The other authors have declared no conflicts of interest.

References