Management of Gout in Patients With Comorbidities
The management of gout includes effective therapy of acute attacks and long-term preventive therapy through adequate urate lowering. There are a number of therapies available, and in all cases, the patients' comorbidities, particularly renal function, need to be considered when choosing the most appropriate therapy. In a study of 575 patients with gout, the majority had more than one contraindication to at least one of the commonly used gout therapies, and a number of patients had contraindications to multiple therapies. Furthermore, patients were frequently prescribed medications for which they had a contraindication.
Treatment of Acute Attacks
The aim of treatment of acute gout is rapid resolution of the pain and inflammation induced by monosodium urate (MSU) crystals. There are three therapeutic options: NSAIDs, corticosteroids and colchicine.
NSAIDs and COX-2 Inhibitors There is good evidence for the efficacy of NSAIDs in acute gout,[60–66] and in individuals with normal renal function and no other comorbidities, they are usually the treatment of choice. NSAIDs exert their anti-inflammatory effect by inhibiting cyclo-oxygenase (COX), thereby decreasing production of pro-inflammatory eicosanoids (prostaglandin E2, prostacyclin and thromboxane A2), which have important effects on renal haemodynamics. In patients who are dehydrated, have pre-existing renal or cardiac impairment, inhibition of prostacyclin and prostaglandin E2 by NSAIDs may lead to renal vasoconstriction, reduced renal blood flow, salt and water retention, hyperkalaemia and hypertension, resulting in acute or worsening renal impairment. Within the kidney, both COX-1 and COX-2 have important and overlapping physiological functions, thus COX-2 inhibitors do not offer any significant advantage over traditional NSAIDs with regard to renal adverse effects. COX-2 inhibitors appear to be associated with an increased risk of myocardial infarction when used at high doses in the long term. Some have argued that this effect extends to all NSAIDs. The relationship between NSAIDs, COX-2 inhibitors and CVD remains controversial. Nonetheless, NSAIDs/COX-2 inhibitors should be used at the lowest effective dose for the shortest period.
NSAIDs have multiple drug interactions, which may be of particular relevance in patients with renal impairment and cardiac disease. The combination of an NSAID, diuretic and an ACE inhibitor is of particular concern because of the combined effects on blood pressure and renal function. Therefore NSAIDs need to be used with caution and, in most cases, avoided in the setting of significant cardiac and/or renal disease.
Colchicine Colchicine is commonly used in acute gout, despite the fact that there are only two placebo-controlled trials. In the largest and most recent study, the Acute Gout Flare Receiving Colchicine Evaluation study, placebo, low-dose colchicine (1.8 mg total) and high-dose colchicine (4.8 mg total) were compared. Although both colchicine regimens were effective in reducing pain, low-dose colchicine was associated with significantly fewer adverse effects.
Colchicine is relatively contraindicated in those with CrCL < 60 ml/min. Gastrointestinal adverse effects, which can occur even at a low dose, can be severe and may be poorly tolerated in those with borderline cardiac or renal function. Colchicine myotoxicity typically affects males aged 50–70 years, receiving maintenance low-dose colchicine. Renal impairment (CrCL ≤ 50 ml/min) is an important risk factor. Thus the dose of colchicine should be adjusted for renal impairment, and significant renal impairment should be considered a relative contraindication to colchicine use.
Drug interactions between colchicine and CYP3A4 and P-glycoprotein inhibitors (e.g. diltiazem, verapamil, clarithromycin) have been recently highlighted. CYP3A4 is involved in the conversion of colchicine to its inactive metabolites, whereas P-glycoprotein is thought to limit gastrointestinal absorption of colchicine. Thus CYP3A4 or P-glycoprotein inhibitors may lead to accumulation of colchicine. A recent study examined the effects of CYP3A4 and P-glycoprotein inhibitors on colchicine pharmacokinetics and recommended a reduction in colchicine dose of 33–66% for the treatment of acute gout and 50–75% for prophylaxis. Our recommendation for colchicine is commencing therapy within 12–24 hours of the onset of the acute attack and to use in low dose (i.e. 1.2 mg stat followed by 0.6 mg 1 hour later).
Corticosteroids Oral, intravenous, intra-articular and intra-muscular corticosteroids can all be effective in the management of acute gout. If only one or two joints are involved, intra-articular corticosteroids are useful. Where more joints are affected or the joints are not amenable to injection, oral prednisone is as effective as NSAIDs. In patients with concomitant diabetes, there is reluctance to use corticosteroids. However, these patients frequently have renal impairment, which precludes the use of NSAIDs or colchicine. The increase in blood sugars resulting from corticosteroids can be managed in the short-term while the acute episode is treated. In most patients with significant renal and/or CVD, short-term therapy for acute gout with corticosteroids may be the lesser of the three evils.
IL-1 Inhibitors IL-1 is a key cytokine in the inflammatory response to MSU crystals. IL-1 inhibitors are emerging as a therapy for acute gout and have been shown to be effective in small studies.[74–76] Canakinumab is effective in the treatment of gout flares and prevents gout flares during the initiation of allopurinol. Adverse effects of IL-1 inhibition include infection and injection site reactions. Further data will be required on the use of these agents in patients with multiple comorbidities, and the cost of these agents may also preclude their widespread use.
Sustained reduction of SU is critical to the long-term management of gout. The recommended target SU is <0.36 mmol/l, and achievement of this over time results in dissolution of MSU crystals, suppression of acute gout attacks and resolution of gouty tophi.[78,79] Reduction of SU can be achieved by decreasing production (XO inhibitors: allopurinol, febuxostat), increasing excretion of uric acid (uricosurics: benzbromarone, probenecid) or metabolism of uric acid to allantoin, which is more water soluble (recombinant uricases: pegloticase, rasburicase).
Xanthine Oxidase Inhibitors: Allopurinol Allopurinol is the most commonly used ULT, as it is effective, easy to administer (once daily dosing), inexpensive and generally well tolerated. However, many patients are prescribed sub-therapeutic doses of allopurinol. One of the reasons for such under-prescribing is concern about the rare, but potentially fatal allopurinol hypersensitivity syndrome (AHS), which is characterized by rash (e.g. toxic epidermal necrolysis, exfoliative dermatitis), eosinophilia, leucocytosis, fever, hepatitis and progressive renal failure. The true incidence of AHS is unknown, although it is estimated to be ~0.1%.
A number of studies have reported that recent commencement of allopurinol therapy,[80–83] renal impairment[80,81,83–86] and diuretic use[80,81,84–86] are risk factors for the development of AHS. The presence of HLA-B*5801, particularly in those of Asian descent, has been associated with AHS.[83,87–89] Whether HLA-B*5801 typing can prevent AHS remains to be determined. The Taiwan Department of Health recommends consideration of HLA-B*5801 testing before commencing allopurinol, given the high prevalence of HLA-B*5801 in the Taiwanese population. Such recommendations have not been made elsewhere. The starting dose of allopurinol has also been reported to be a risk factor for AHS.
Allopurinol has also been reported to be the most common cause of drug reaction with eosinophilia and systemic symptoms, which is characterized by fever, rash, eosinophilia, multi-organ involvement and lymphocyte activation. There is some debate as to whether drug reaction with eosinophilia and systemic symptoms is a separate clinical entity from other drug-induced reactions such as AHS.
The observation by Hande et al. that most patients with AHS had pre-existing renal impairment and were treated with full doses of allopurinol (≥300 mg daily) along with studies of oxypurinol clearance in patients with renal impairment led to the development of allopurinol dosing guidelines based on CrCL. However, the relationship between elevated oxypurinol concentrations and AHS has not been confirmed, and no study has demonstrated that administration of lower doses of allopurinol in patients with renal impairment reduces the risk of AHS. Furthermore, these CrCL-based dosing guidelines have resulted in the failure of adequate urate lowering in many patients.
The optimal allopurinol dosing regimen remains controversial, particularly in patients with renal impairment. Recent data would suggest that allopurinol should be commenced at 1.5 mg/ml eGFR and increased at monthly intervals until the CrCL-based dose has been reached. If the target SU is not achieved, compliance should be assessed; measurement of plasma oxypurinol may aid in this regard. If compliance is ensured, increasing the dose above the CrCL-based dose, even in patients with renal impairment, has been shown to be effective in lowering SU (Fig. 1). Although there were no cases of AHS within this small study, larger long-term safety data will ultimately be required for this approach to be accepted by many clinicians. An alternative approach is to add or change to another urate-lowering agent. Combination therapy with allopurinol and probenecid[95,96] or allopurinol and benzbromarone[97,98] results in additional urate lowering.
There are a number of important drug interactions with allopurinol, including diuretics (thiazides and furosemide), warfarin, AZA, aspirin and ACE inhibitors ( Table 2 ). Furosemide decreases urinary uric acid excretion and results in an increase in SU. The increase in SU occurs within a few days of commencing diuretics and persists for the duration of therapy. Patients with gout on furosemide require higher doses of allopurinol relative to their renal function to attain an SU < 0.36 mmol/l compared with those not on furosemide. Patients on allopurinol receiving concomitant furosemide have higher plasma oxypurinol concentrations, despite similar doses of allopurinol, suggesting that allopurinol becomes less effective. The clinical indications for furosemide are unclear in many cases, and in many cases alternative agents that do not have an effect on SU could be used. Clinicians should review the need for furosemide in patients with gout on a regular basis.
XO Inhibitors: Febuxostat Febuxostat, a non-purine XO inhibitor, was approved by the European Medicines Agency in 2008 and the FDA in 2009. In the clinical studies to date, febuxostat has been shown to have a superior urate-lowering effect compared with allopurinol; however, in these studies the allopurinol dose was fixed, with a maximum of 300 mg/day in patients with normal renal function and 100–200 mg/day in patients with mild to moderate renal impairment. This study design may have overestimated the relative urate-lowering efficacy of febuxostat compared with allopurinol, and there is a need for head-to-head comparator trials where the dose of allopurinol is titrated to achieve the target SU. In the interim, there is the potential for patients to be changed to febuxostat based on apparent allopurinol failure or because of concern regarding AHS. One perceived advantage of febuxostat is that dose adjustment is not required for patients with mild to moderate renal impairment (CrCL > 30 ml/min). Fixed dosing of 80 mg/day, increasing to 120 mg/day after 2 weeks if the target SU is not achieved, is recommended. However, there are few data on the use of febuxostat in patients with more severe renal impairment (CrCL < 30 ml/min). Previous AHS is not a contraindication to therapy with febuxostat, although there is a potential for hypersensitivity reactions with febuxostat, therefore this group of patients needs to be closely monitored. Another unresolved issue is the possible increased risk of cardiovascular events in patients receiving febuxostat. The CONFIRMS study reported similar cardiovascular event rates in patients on febuxostat 80 mg/day and allopurinol 200 or 300 mg/day. However, this was a short-term study (52 weeks) and a 120 mg/day febuxostat dose was not assessed. In the long-term extension EXCEL study, there was no significant difference in cardiovascular event rates between allopurinol and febuxostat. Although a causal relationship has not been identified, further cardiovascular safety data are required, and febuxostat should be used with caution in patients with a known history of CVD.
Uricosurics: Probenecid, Sulphinpyrazone, Benzbromarone Benzbromarone, probenecid and sulphinpyrazone lower SU by increasing renal urate excretion. Benzbromarone remains effective in patients with CrCL > 20 ml/min, despite treatment with diuretics.[103,104] However, the efficacy of probenecid declines as renal function declines, and it is generally ineffective with CrCL < 60 ml/min. Benzbromarone is not available in many countries because of concerns about hepatotoxicity. This appears to be rare, with no cases reported in 200 patients treated with 75–125 mg/day of benzbromarone for a mean of 5 years. A risk–benefit assessment concluded that the risks of hepatotoxicity could be reduced by a gradual dose increase and regular monitoring of liver function tests. Whether there is an association between viral hepatitis and benzbromarone is unclear, but it is prudent to screen for viral hepatitis before commencing benzbromarone. Sulphinpyrazone is rarely used, as it is poorly tolerated and ineffective, even when mild renal impairment is present.
A complication of uricosuric therapy is the deposition of MSU crystals within the kidney, which can result in urate nephropathy and/or the formation of uric acid stones. A gradual increase in dose, maintaining adequate urine volume of ≥1500 ml/day, and attaining alkaline urine can help prevent these complications.. In many patients with significant cardiac impairment, strict fluid restrictions mean that maintaining adequate urine volume may be challenging. Furthermore, in patients with renal impairment, acute obstruction due to renal calculi may be poorly tolerated. Thus, in many cases, uricosurics may have the potential for more adverse effects than XO inhibitors.
Recombinant Uricases: Pegloticase, Rasburicase Urate oxidase catalyses the conversion of uric acid to allantoin, which is more water soluble and hence readily excreted via the kidney. The absence of uricase in humans allows the development of hyperuricaemia. Pegylated-uricase (pegloticase), a recombinant uricase, reduces SU and reduces the size of tophi in patients who have failed other ULTs.[109,110] Adverse effects of pegloticase include gout flares and infusion reactions. Exacerbation of cardiac failure has been observed in a small number of patients, thus pegloticase should be used with caution in patients with cardiac failure. A number of issues remain with the use of recombinant uricases, including the optimal duration of therapy and long-term safety and efficacy.
Rheumatology. 2013;52(1):34-44. © 2013 Oxford University Press