The optimal serum urate levels necessary for elimination of tissue deposits of monosodium urate in patients with chronic gout is controversial. This observational, prospective study evaluates the relationship between serum urate levels during therapy and the velocity of reduction of tophi in patients with chronic tophaceous gout.
Sixty-three patients with crystal-confirmed tophaceous gout were treated with allopurinol, benzbromarone, or combined therapy to achieve serum uric acid levels less than the threshold for saturation of urate in tissues. The tophi targeted for evaluation during followup were the largest in diameter found during physical examination.
Patients taking benzbromarone alone or combined allopurinol and benzbromarone therapy achieved faster velocity of reduction of tophi than patients taking allopurinol alone. The velocity of tophi reduction was linearly related to the mean serum urate level during therapy. The lower the serum urate levels, the faster the velocity of tophi reduction.
Serum urate levels should be lowered enough to promote dissolution of urate deposits in patients with tophaceous gout. Allopurinol and benzbromarone are equally effective when optimal serum urate levels are achieved during therapy. Combined therapy may be useful in patients who do not show enough reduction in serum urate levels with single-drug therapy.
The clinical manifestations of gout, such as acute gouty arthritis, chronic gouty arthropathy, and tophi, develop due to the deposition of monosodium urate crystals in articular, periarticular, and subcutaneous tissue (1, 2).
The development of tophaceous, crippling gout can be avoided (3). Urate-lowering therapy (ULT) should be used to initially reduce and finally eliminate tissue deposits in patients with chronic gout. This is especially important in patients with tophi or chronic gouty arthropathy to avoid further progression of crystal deposition-induced tissue damage.
It has been suggested that ULT should be used to reduce serum uric acid levels to less than the threshold for saturation of uric acid in body fluids. Nevertheless, some experts contend that, to prevent further gouty episodes and to enhance mobilization of urate deposits, serum urate should be lowered to <6.0 mg/dl in patients with chronic gout and <5.0 mg/dl in patients with tophaceous gout (4–6). However, there is no consensus as to the optimal level of serum urate during ULT to reduce deposits in gouty patients (7, 8). It is uncertain if there is a relationship between serum uric acid levels during ULT and the velocity of reduction of urate deposition in tissue.
As in other key decisions in gout, an “incredible paucity of evidence-based medicine” has been found to support clinical practice guides (8). Questions for daily clinical practice should include whether the lower serum uric acid level during ULT achieves faster reduction of urate deposits and which is the best ULT schedule to treat chronic tophaceous gout.
PATIENTS AND METHODS
A prospective, observational study was conducted in a gout clinic at a regional reference hospital that serves a population base of 500,000. All included patients had tophaceous gout and were willing to take ULT with long-term followup in our clinic. Diagnosis of gout was confirmed by observation of monosodium urate crystals in synovial fluid samples or material aspirated from tophi under polarizing red-compensated light microscopy.
At the initial physical examination, the number of tophi were recorded as single tophus, up to 4 tophi but with diameter <40 mm, or more than 4 tophi or diameter >40 mm. The largest tophus at examination was considered the target tophus for evaluation during followup. The largest diameter of the target tophus was measured with a caliper calibrated in millimeters. Soft collections at olecranon bursa with urate milk were excluded as target tophi because local inflammation with synovial effusion may contribute to enlargement of the mass. Also, plain radiographs were used to detect the presence of involvement of affected joints suggesting gouty arthropathy. Concomitant diuretic therapy, previous history of renal stones, time from the onset of gouty symptoms, and age at the onset of ULT were also recorded.
Laboratory evaluation was performed prior to ULT at least 2 weeks before baseline, and included complete red and white blood cell counts and serum proteinogram, liver function tests, creatinine clearance, uric acid clearance, and 24-hour urinary uric acid. Serum uric acid and creatinine levels were measured before ULT and at each control visit. Serum and urine uric acid levels were measured using an automatic enzymatic (uricase) colorimetric (4-aminophenazone) test (UA plus, Roche-Modular, Roche Diagnostics, Mannheim, Germany).
ULT was prescribed based on clinical grounds. Informed consent was not obtained because prescription was based on daily practice clinical indications at our hospital (9). Allopurinol (100-mg or 300-mg tablets) was prescribed to patients showing normal urinary excretion of uric acid (clearance of uric acid >6 ml/minute); patients with previous history of renal colic; and patients who were taking low doses of allopurinol and preferred to try full allopurinol doses rather than changing to benzbromarone. Maximal doses of allopurinol were corrected for creatinine clearance (10) (100 mg allopurinol per day per each 30 ml/minute of clearance of creatinine), starting at 100 mg/day and increasing to the maximal corrected dosage of 300 mg/day in 2 months, with further elevation of dose when necessary. Dosages of allopurinol ≤300 mg/day were administered in a single dose, and dosages >300 mg/day were divided in a twice-daily schedule (11).
Benzbromarone (100-mg tablets) was prescribed to patients showing underexcretion of uric acid without a history of renal colic; and patients with previous adverse reactions to allopurinol despite showing normal renal excretion of uric acid. Benzbromarone therapy was started at 50 mg/day and the dosage was increased up to a maximum of 100 mg/day in 2 months, with further elevation of dosage when necessary up to a maximum dose of 200 mg/day.
Combined allopurinol and benzbromarone therapy was prescribed to patients with massive tophaceous deposits, severe arthropathy, or patients on previous therapy with full doses of allopurinol who did not achieve a serum urate level of <7.0 mg/dl. Patients were prescribed allopurinol at 300 mg/day because uricosuric drugs enhance oxipurinol renal excretion and because toxicity due to oxipurinol accumulation was less probable (12). After the first 2 months with allopurinol, benzbromarone at 50 mg/day was added.
All but 2 patients were receiving oral colchicine prophylaxis: 1 mg/day if creatinine clearance was >50 ml/minute, and 0.5 mg/day if creatinine clearance was <50 ml/minute. The 2 patients intolerant to colchicine were taking prednisone at 5 mg/day. Prophylaxis was maintained until a 6-month period free of attacks was achieved.
From the first 2-month initial evaluation, followup was then made every 4 months. The size of the target tophus was measured with the same caliper until it completely disappeared. Serum urate level during ULT was considered the average of all serum urate measurements during the entire followup period.
The software EPI-INFO version 6.04 (Centers for Disease Control and Prevention, Atlanta, GA), was used for statistical analysis.
Seventy patients entered the study. Seven could not complete the study: 4 died, 2 moved to another city, 1 did not desire further followup because he developed terminal renal and hepatic insufficiency due to liver cirrhosis. Sixty-three patients were available for evaluation from 1995 to 2000: 60 males and 3 females. Mean age at onset of ULT was 57.8 ± 12.8 years (range 35–74 years) and the mean time with gouty symptoms was 12.1 ± 8.3 years. Twenty-one patients showed a single tophus, with a mean diameter of 14.5 ± 7.6 mm; 27 patients showed several small tophi, with a mean diameter of the target tophi of 16.0 ± 6.3 mm; and 15 patients showed large or multiple tophi, with a mean diameter of the target tophi of 29.5 ± 11.7 mm. The overall mean diameter of the target tophi was 18.7 ± 10.2 mm (range 5–61 mm).
Radiographic evidence of chronic gouty arthropathy was observed in 11 of 21 (52.4%) patients who showed a single tophus, 19 of 27 (70.4%) patients with several tophi, and 15 of 15 patients with massive tophaceous deposits (P < 0.01).
Mean serum urate before ULT was 8.98 ± 1.43 mg/dl (range 6.10–12.9). The only patient with serum urate <7.0 mg/dl showed 3 measurements during the previous 10 years <7.0 mg/dl and suffered from severe tophaceous gout. Twelve patients (19%) were on concomitant diuretic therapy. The mean clearance of creatinine was 89 ± 31 ml/minute and the mean clearance of uric acid was 4.58 ± 1.75 ml/minute. Ten patients (16%) showed a creatinine clearance <60 ml/minute. Fifty-one of 63 (81%) patients had a clearance of uric acid <6 ml/minute and were considered to have renal underexcretion of uric acid.
Allopurinol was prescribed to 24 patients, including 7 patients with normal uric acid clearance and 17 patients with underexcretion of uric acid (4 with a history of renal colic, and 13 patients who had been taking low doses of allopurinol and did not wish to change to uricosuric therapy). Benzbromarone was prescribed to 25 patients, including 1 patient with overexcretion of uric acid and a history of Steven–Johnson syndrome secondary to allopurinol, and 4 patients with massive tophaceous gout who had previous adverse reactions to allopurinol (2 rash and 2 altered liver function tests) who were not prescribed combined therapy. Combined allopurinol plus benzbromarone therapy was prescribed to 14 patients, 4 showing overproduction of uric acid and 10 showing underexcretion; 9 patients showed massive tophi, and 5 had severe gouty arthropathy, although they did not show massive tophi. There were no differences in the size of the target tophi in patients taking either allopurinol or benzbromarone in single therapy (data not shown). There were no statistical differences regarding initial serum urate levels, age, or time from onset between groups.
The mean time from onset of ULT to disappearance of the target tophus for the entire series was 20.8 ± 10.2 months (range 6–64 months). It was longer in patients receiving allopurinol alone than in patients receiving benzbromarone or combined therapy, even though this latter group showed the greatest size of tophi (Table 1).
Table 1. Initial serum uric acid levels and outcome measures during followup
Patients taking allopurinol were given a mean dosage of 320 ± 88 mg/day (range 150–600), and a mean dosage corrected for renal function of 321 ± 74 mg/day per 100 ml/minute of clearance of creatinine. Serum urate levels fell from 8.78 ± 1.34 mg/dl to 5.37 ± 0.79 mg/dl (P < 0.001) during followup. The mean velocity of reduction of the target tophus was 0.57 ± 0.18 mm/month.
Patients taking benzbromarone were given a mean dosage of 101 ± 11 mg/day (range 75–150). Serum urate fell from 9.24 ± 1.66 mg/dl to 4.22 ± 1.01 mg/dl (P < 0.001). The mean velocity of reduction of the target tophus was 1.21 ± 0.67 mm/month.
Patients taking combined ULT received allopurinol at 300 mg/day (334 ± 112 mg/day per 100 ml/minute of clearance of creatinine) plus 50 mg/day of benzbromarone. These patients achieved a reduction of serum urate from 8.83 ± 1.11 mg/dl to 3.97 ± 0.76 mg/dl during followup (P < 0.001). The velocity of reduction of tophi was 1.53 ± 0.45 mm/month.
The mean dosage of allopurinol corrected for creatinine clearance was not different in patients with combined therapy or single allopurinol therapy. Although serum urate was the lowest and velocity of reduction was the fastest in patients taking combined therapy, there were no statistical differences in these patients compared with patients taking uricosuric drugs in single therapy.
Mean serum urate during followup was statistically higher (P < 0.001) in patients taking allopurinol than in patients taking benzbromarone or combined therapy; an inverse relationship to that observed with the velocity of reduction of tophi. When mean serum urate during followup was grouped, 5 patients with levels of 6.1–7.0 mg/dl showed a reduction of 0.53 ± 0.59 mm/month, 19 patients with levels of 5.1–6.0 mg/dl achieved a reduction of 0.77 ± 0.41 mm/month, 19 patients with levels of 4.1–5.0 mg/dl had their tophi reduced by 0.99 ± 0.50 mm/month, and 20 patients with mean levels ≤4.0 mg/dl showed a velocity of reduction of tophi of 1.52 ± 0.67 mm/month. There was a linear relationship between mean serum urate levels during ULT and the velocity of reduction of tophi: r = −0.62, r2 = 0.48 (Figure 1).
There were no differences in the mean reduction of serum urate from baseline in patients taking allopurinol despite showing normal renal excretion or underexcretion of uric acid at baseline (serum uric acid level reduction from baseline of 3.33 ± 1.42 versus 3.34 ± 1.29 mg/dl, respectively; P = 0.86).
Twenty one (33%) patients had gouty episodes during ULT. The mean number of attacks per patient was 0.43: 0.41 for the allopurinol group, 0.36 for the benzbromarone group, and 0.57 for the combined therapy (P = 0.664).
Gout is a disease caused by the deposition of monosodium urate crystals in orderly arrays in tissues. This kind of crystallization suggests slow epitaxial formation, which is the way animals form crystalline structures, rather than acute formation (2). Tophaceous gout is characterized by the presence of subcutaneous and periarticular nodules formed by monosodium urate accumulation. Tophaceous gout was reported to develop at 5-year followup in 30% of gouty patients who were not treated with ULT (13).
There is no clear consensus whether ULT should be prescribed to all patients with acute gouty arthritis, but it is clear that ULT should be prescribed to all patients with chronic gouty arthritis or tophi (7, 8, 14, 15). Few studies have assessed the effect of ULT on the progression or reduction of tophaceous deposits. In the 1950s, before allopurinol became available for clinical use, Yü and Gutman (16) reported that up to 70% of patients who were treated with uricosuric drugs for more than 2 years showed reduction of tophaceous deposits. Soon afterward, Goldfarb and Smyth (17) reported the results with allopurinol-uricosuric therapy. Eight patients were treated with up to 800 mg/day of allopurinol, with a mean reduction from 8.6 to 6.0 mg/dl; despite this, 5 of the 8 showed serum urate levels >6.0 mg/dl. When sulfinpyrazone was added, a further reduction of serum urate to 4.7 mg/dl was observed, and all patients showed serum urate levels <6.0 mg/dl. The “most impressive finding … was the dramatic shrinkage of some of the large tophi.” The authors suggested that combined ULT could be considered for patients with extensive urate deposition and poor response to single therapy (17). More recently, McCarthy et al (18) reported a series of patients taking ULT for more than 10 years. Fourteen of 39 patients showed tophi. There was a relationship between serum urate levels during ULT and the clinical outcome of tophi: 7 of 14 patients showed improvement in the size of tophi, their mean serum urate during ULT was 6.2 mg/dl, whereas 7 of 14 patients showed an increased number of tophi, their mean serum urate level being 8.2 mg/dl. Three of 14 showed mean serum urate levels of <6.0 mg/dl. Only 1 of 14 patients cleared of tophi; his mean serum urate level during ULT was 3.4 mg/dl. The results of these 2 later studies suggest that serum urate levels should be maintained at <6.0 mg/dl, and that the lower the serum urate level during ULT, the faster the reduction of tophaceous deposits. Unfortunately, data about the size and extension of the tophi and the velocity of reduction of deposits are not available from these studies.
In the present series, all patients were cleared from tophi, as serum urate levels were maintained under the threshold for saturation of uric acid in body fluids during followup; that is, 7.0 mg/dl at pH 7.4 and 37°C (19). Patients treated with benzbromarone showed a faster reduction of tophaceous deposits than patients taking allopurinol, somehow doubling the velocity of reduction achieved with allopurinol therapy alone. This difference must be related to the difference of reduction of serum urate during ULT with either therapy: patients taking allopurinol showed a reduction of 1.63 mg/dl under the theoretical threshold for urate saturation, and patients taking benzbromarone showed a reduction of 2.78 mg/dl under 7.0 mg/dl. Benzbromarone has been shown in several studies to induce a striking reduction of serum urate levels, from 4–5 mg/dl from baseline (20–24). It is important to highlight that both the reduction of serum urate and the velocity of reduction of tophi was not statistically different in patients treated with allopurinol, despite the presence of either normal or reduced renal excretion of uric acid. So, allopurinol could be a good therapeutic choice for any patient with gout if proper serum urate levels are achieved during therapy (4, 5).
Patients treated with combined allopurinol–benzbromarone therapy showed the fastest reduction of tophi, although there were not statistically significant differences in mean serum urate levels and velocity of reduction of tophi compared with patients treated with benzbromarone alone. Several mechanisms may explain this absence of clear-cut differences. In patients with gout, the body urate pool has been observed to be related to the presence and extent of tophi (25). Thus, patients in the combined therapy group probably would have the highest urate pool and therefore the highest urate offer during ULT. Alternatively, there may be pharmacokinetic interactions reducing the efficacy of combined allopurinol–benzbromarone therapy. First, patients on single allopurinol therapy received similar dosages of allopurinol, even corrected for creatinine clearance, as patients on combined therapy. Second, they received lower benzbromarone dosages than patients taking benzbromarone alone. Finally, uricosuric drugs may enhance renal excretion of oxypurinol, the active metabolite of allopurinol, thus reducing the efficacy of allopurinol (12).
The gold-standard method for evaluating the reduction of the body pool of uric acid is measuring the pool of urate with 14C radioactive uric acid (25–29). Several studies estimated the body uric acid pool in the 1950s and 1960s. Interestingly in one of them (26), determination of the body uric acid pool was also made in one patient after allopurinol therapy. The patient achieved a serum urate level of <4 mg/dl during therapy and the body uric acid pool was normal in a 2-year period. Determination of the body uric acid pool is so complex and expensive that it cannot be made in daily practice. Until another method becomes feasible in clinical practice, clinical studies based on measurement of the size of tophi, such as the present one, may highlight the importance of reducing serum urate levels as much as possible. Serum urate reduction is, of course, limited by the efficacy and safety guidelines for clinical management of the dosages of urate-lowering drugs.
Our results strongly suggest that the lower the serum urate level achieved during ULT, the faster the reduction in tophaceous deposits. Allopurinol may be useful for any gouty patient if proper serum urate is achieved during therapy. Benzbromarone is very useful in reducing serum urate levels and urate deposits at standard dosages, despite moderate reduction of renal function. Combined therapy may be useful in patients who do not achieve optimal serum urate levels during single-drug ULT, but adds nothing to single benzbromarone therapy when indicated. There is much more to the therapy of hyperuricemia than simply prescribing 300 mg/day of allopurinol (30). How much? As much as necessary to obtain low serum urate levels (4).
The authors wish to thank Dr. Naomi Schlesinger (Newark, NJ) for her review and kind criticism. We also thank Dr. Alonso-Ruiz (Chief, Rheumatology Section) and Dr. Jesus Moran (Chief, Investigation Unit) for their support.