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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Objective

Allopurinol is the most commonly used urate-lowering therapy in gout. Allopurinol hypersensitivity syndrome (AHS) is a rare but potentially fatal adverse event. Dosing guidelines based on creatinine clearance have been proposed based on the recognition that dosages of ≥300 mg/day may be associated with AHS, particularly in patients with renal impairment. However, the relationship between the allopurinol starting dose and AHS is unknown. This study was undertaken to determine the relationship between allopurinol dosing and AHS.

Methods

A retrospective case–control study of patients with gout who developed AHS between January 1998 and September 2010 was undertaken. For each case, 3 controls with gout who were receiving allopurinol but did not develop AHS were identified. Controls were matched with cases for sex, diuretic use at the time of initiating allopurinol, age (±10 years), and estimated glomerular filtration rate (estimated GFR). Starting dose and dose at the time of the reaction in cases were compared between cases and controls.

Results

Fifty-four AHS cases and 157 controls were identified. There was an increase in the risk of AHS as the starting dose of allopurinol corrected for the estimated GFR increased. For the highest quintile of starting dose per estimated GFR, the odds ratio was 23.2 (P < 0.01). Receiver operating characteristic analysis indicated that 91% of AHS cases and 36% of controls received a starting dose of allopurinol of ≥1.5 mg per unit of estimated GFR (mg/ml/minute).

Conclusion

Our findings indicate that starting allopurinol at a dose of 1.5 mg per unit of estimated GFR may be associated with a reduced risk of AHS. In patients who tolerate allopurinol, the dose can be gradually increased to achieve the target serum urate level.

Sustained reduction of the serum urate level to ≤6 mg/dl is the mainstay of gout treatment (1–3). Indications for urate-lowering therapy include ≥2 gout attacks per year, chronic gouty arthropathy, tophi, radiographic changes in gout, and urate nephropathy (4, 5), as well as polyarticular gout. Allopurinol, the most commonly used urate-lowering therapy, is generally well tolerated; approximately 2% of patients develop a mild rash (6) and up to 5% of patients stop allopurinol because of any adverse event.

A rare but potentially fatal adverse event is allopurinol hypersensitivity syndrome (AHS). AHS is characterized by rash (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis), eosinophilia, leukocytosis, fever, hepatitis, and renal failure. The mortality associated with AHS is reported to be as high as 27% (7, 8). There is no cure; early diagnosis and allopurinol withdrawal are important. Supportive care is the mainstay of treatment (7, 9).

Risk factors for the development of AHS include female sex, age, renal impairment, diuretic use, recent initiation of allopurinol therapy, and, in some ethnic groups, the HLA–B*5801 genotype (10–14). The relationship between allopurinol dose and AHS is a subject of controversy (10, 15). Dose reduction in renal impairment is based on a reported relationship between “full- dose” allopurinol (≥300 mg/day) in patients with renal impairment and the development of AHS (16). This observation, along with recognition that excretion of the active metabolite oxypurinol is significantly reduced in patients with impaired renal function, led to the suggestion that allopurinol dose should be determined according to creatinine clearance (16). However, there is no clear evidence that creatinine clearance–based allopurinol dosing reduces the incidence of AHS. In a large case–control study of AHS, there was a trend toward lower allopurinol doses in the AHS group compared to allopurinol-tolerant controls (10). In another study, AHS did not occur more frequently in those taking higher than creatinine clearance–based doses compared with those receiving the creatinine clearance–based dose (15). Furthermore, the current allopurinol dosing guidelines do not differentiate between starting dose and maintenance dose.

The aim of this study was to determine the relationship of the starting dose and the dose of allopurinol at the time of the reaction to the occurrence of AHS in patients with gout.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Study design.

A retrospective case–control study design was used to determine the role of the allopurinol dose in AHS. Ethics approval was obtained from the Multi-Region Ethics Committee, New Zealand. Cases were identified in the 5 major regions of New Zealand (Auckland, Waikato, Wellington, Christchurch, and Dunedin), representing ∼3 million people (three-fourths of the New Zealand population).

Cases.

Patients with gout who developed AHS between January 1, 1998 and September 30, 2010 were identified by physician recall, International Classification of Diseases (ICD) code searches, local area database searches, and via the Centre for Adverse Reactions Monitoring (CARM). We searched for the following ICD codes: from ICD-9, codes 693.0 dermatitis due to drugs and medicines taken internally, 695.1 erythema multiforme, and 974.7 poisoning by uric acid metabolism drugs; and from ICD-10, codes L27.0 general skin eruptions due to drugs, L27.1 local skin eruption due to drugs, L51.0 nonbullous erythema multiforme, L51.1 bullous erythema multiforme, L51.2 toxic epidermal necrolysis, and T50.4 drugs affecting uric acid metabolism.

Clinical notes were reviewed to identify patients in whom a diagnosis of AHS could potentially be made. Patients who were prescribed allopurinol for indications other than gout were excluded. Standardized data were collected for each potential case, including age, sex, ethnicity, height, weight, date of gout diagnosis, starting date and dose of allopurinol, diuretic use and dose at the time of starting allopurinol, time from initiation of allopurinol treatment until reaction, dose of allopurinol at the time of the reaction, clinical features, treatment given, and patient outcome. Laboratory results, including serum urate, creatinine, alanine transaminase (ALT), and aspartate aminotransferase (AST) levels, and eosinophil count prior to starting allopurinol and at the time of the reaction were collected. Estimated glomerular filtration rate (estimated GFR) was determined using the Modification of Diet in Renal Disease study equation (17).

Potential AHS cases were adjudicated by a single investigator (LKS), who was blinded with regard to the allopurinol dose, using the Gutierrez-Macias criteria (18). These criteria consist of a clear history of exposure to allopurinol; lack of exposure to another drug potentially causing the reaction; and 2 of the major criteria (worsening renal function, acute hepatocellular injury, or rash) or 1 of the major criteria and 1 of the minor criteria (fever, eosinophilia, or leukocytosis) (18). While these criteria do not state exact values for deterioration in renal and liver function, we used an increase in creatinine level of >20–25% from baseline and an increase in ALT and/or AST levels of >1.5 times the upper limit of normal.

Controls.

For each AHS case, 3 control subjects who were receiving allopurinol for gout but did not develop AHS were identified. Controls were matched with the cases for age (±10 years) and for the following reported risk associations for AHS: sex, diuretic use at the time of initiating allopurinol treatment, and renal function. Renal function was assessed by estimated GFR according to the following bands: <5, 5–15, 15–30, 30–50, 50–70, 70–90, 90–110, 110–130, and >130 ml/minute/1.73 m2.

Standardized data were collected for each control subject, including ethnicity, date of diagnosis, starting dose of allopurinol, diuretic use at the time allopurinol treatment was started, dose of allopurinol at the matched time from initiation of allopurinol treatment that the reaction occurred in the case, and the maximum allopurinol dose reached.

Statistical analysis.

Analysis of variance and chi-square tests were used to compare demographic and clinical features in cases and controls. Conditional logistic regression analysis was used to determine the association between ethnicity, tophi, and quintile of starting dose per estimated GFR and the development of AHS, allowing for multiple matching of controls to cases (∼3:1). These associations were summarized as odds ratios (ORs) and 95% confidence intervals (95% CIs). Analysis of the dose as a function of the estimated GFR showed that differences in renal function did not explain the observed difference in dose between cases and controls. The optimal allopurinol starting dose for predicting the development of AHS was determined using a receiver operating characteristic (ROC) curve. Expert opinion of the authors was used to determine an appropriate dose for starting allopurinol based on the ROC curve and taking the standard tablet sizes for allopurinol into consideration, to ensure that the proposed doses were clinically practical.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Identification of cases and controls.

A total of 7,551 potential cases were identified for case note review. All 7,551 notes were reviewed, and 70 possible AHS cases were identified. The main reasons for exclusion were that the patient was not receiving allopurinol or allopurinol was used for a nongout indication. All cases identified by physician recall or by the CARM search were also captured in the ICD code searches. After adjudication, 54 cases of AHS were confirmed. The remainder had a reaction to allopurinol but did not fulfill the criteria for AHS. For 49 of the 54 cases, 3 well-matched controls were identified. In the remaining 5 cases, 2 well-matched controls were identified, resulting in a total of 157 controls.

Demographic characteristics of the cases and controls.

The demographic and clinical features are outlined in Table 1, showing good matching between cases and controls. Thirty-six of 54 cases (66.6%) and 108 of 157 controls (68.9%) had an estimated GFR of <60 ml/minute.

Table 1. Demographic characteristics of the AHS cases and matched controls*
 Cases (n = 54)Controls (n = 157)P
  • *

    AHS = allopurinol hypersensitivity syndrome; estimated GFR = estimated glomerular filtration rate; BMI = body mass index.

  • Data were available for 39 cases and 137 controls.

  • Data were available for 19 cases and 46 controls.

  • §

    Data were available for 50 cases and 67 controls.

Age, mean (range) years64.8 (24–87)64.1 (23–92)0.79
Sex, no. (%) male30 (55.6)87 (55.4)1.0
No. (%) receiving diuretic at the time allopurinol was started26 (48.1)77 (49.0)0.91
Baseline creatinine, mean (range) mmoles/liter145 (68–850)134 (70–510)0.37
Baseline estimated GFR, mean (range) ml/minute50.2 (6–112)51.3 (11–115)0.73
% with baseline estimated GFR of ≥60 ml/minute33.330.30.68
Ethnicity, no. (%)  <0.001
 New Zealand European26 (48.1)63 (40.1) 
 Maori and Pacific Islander16 (29.6)75 (47.8) 
 Chinese10 (18.5)1 (0.64) 
 Other2 (3.7)18 (11.5) 
No. (%) with tophi15 (27.8)78 (49.6)0.021
Serum urate level at diagnosis, mean (range) mg/dl9.9 (7.1–18.2)10.1 (3.5–15.9)0.62
BMI, mean ± SD kg/m231.3 ± 6.134.6 ± 6.50.064
Weight, mean ± SD kg§88.6 ± 29.599.9 ± 24.90.04

Cases and controls were not matched for the presence of tophi or for ethnicity, and there was no association between these 2 factors. Multivariate analysis allowing for matching between cases and controls showed that the presence of tophi was associated with a reduced risk of AHS (OR 0.29 [95% CI 0.01–0.83], P < 0.021). Ethnicity was associated with risk of AHS (P < 0.001). Compared with New Zealand Europeans, there was a decreased risk of AHS in patients of Maori or Pacific Island descent (OR 0.24, P = 0.02) and an increased risk of AHS in those of Chinese descent (OR 70.8, P = 0.005).

Clinical features and outcomes of AHS cases.

The median time from starting allopurinol to the occurrence of AHS was 30 days (range 1–1,080 days), and 90% of AHS cases occurred within the first 180 days (Figure 1). The clinical features of AHS and which specific criteria were fulfilled by the cases are outlined in Table 2. Among the patients with renal deterioration, the median increase in creatinine level was 55% from baseline. Among the patients with acute hepatocellular injury, the median increase in ALT level was 2.4 times the upper limit of normal.

thumbnail image

Figure 1. Days from starting allopurinol treatment to the occurrence of allopurinol hypersensitivity syndrome in patients with gout.

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Table 2. Clinical features of the 54 AHS cases*
  • *

    Values are the number (%) of cases. AHS = allopurinol hypersensitivity syndrome.

  • Some patients had more than one type of rash.

Major criteria 
 Worsening renal impairment29 (53.7)
 Acute hepatocellular injury17 (31.5)
 Rash52 (96.3)
  Toxic epidermal necrolysis10 (18.5)
  Erythema multiforme4 (7.4)
  Diffuse maculopapular27 (50)
  Exfoliative13 (24.1)
 All 3 major criteria present9 (16.7)
 Rash plus renal deterioration18 (33.3)
 Rash plus hepatocellular injury8 (14.8)
 Rash only17 (31.5)
 Renal deterioration only2 (3.7)
Minor criteria 
 Fever32 (59.3)
 Eosinophilia26 (48.2)
 Leukocytosis24 (44.4)
 3 minor criteria present14 (25.9)
 2 minor criteria present10 (18.5)
 1 minor criterion present20 (37)
 0 minor criteria present10 (18.5)
Criteria fulfillment 
 At least 2 major criteria35 (64.8)
 1 major and at least 1 minor criteria19 (35.2)
 Rash only17
  Plus 3 minor2
  Plus 2 minor6
  Plus 1 minor9
   Fever5
   Eosinophilia3
   Leukocytosis1
 Renal only2
  Plus 3 minor1
  Plus 1 minor (leukocytosis)1

Of the 54 cases, 43 (79.6%) required hospitalization. Six of these 43 cases were admitted to the intensive care unit. Twenty-five patients received corticosteroids, 2 received cyclosporin A, and 4 received antihistamines. Three of the 54 patients (6%) died, 45 recovered, and the outcome for 6 patients could not be determined.

Relationship between the allopurinol starting dose and AHS.

AHS cases started allopurinol at a significantly higher dosage than controls (mean ± SEM starting dosage 183.5 ± 14.0 mg/day versus 112.2 ± 6.3 mg/day) (P < 0.001). Nineteen percent of the controls and 19% of the cases began allopurinol at the creatinine clearance–based dose, according to the Hande guidelines (16). Cases were more likely to start allopurinol at doses that were higher than the creatinine clearance–based dose than were controls (OR 16.7 [95% CI 5.7–47.6], P < 0.001) (Table 3) and controls were more likely to start allopurinol at doses that were lower than the creatinine clearance–based dose than were cases (OR 6.9 [95% CI 2.9–16.5], P < 0.001).

Table 3. Allopurinol starting doses in cases and controls, stratified by dose recommendation based on creatinine clearance*
 Cases (n = 53)Controls (n = 152)P
  • *

    Values are the number (%) of patients.

Allopurinol starting dose higher than the creatinine clearance–based dose23 (43.4)18 (11.8)<0.001
Allopurinol starting dose the same as or lower than the creatinine clearance–based dose30 (56.6)134 (88.2)<0.001

There was a significant increase in the percentage of patients developing AHS as the allopurinol dose corrected for the estimated GFR increased. The proportion of cases for each quintile of starting allopurinol dose corrected for the estimated GFR is shown in Figure 2. Multivariate analysis, allowing for the effects of ethnicity and tophi with matching between cases and controls, revealed a strong dose-response relationship between the starting dose of allopurinol adjusted for estimated GFR and the risk of AHS (overall dose effect P = 0.001). The risk of AHS in the 2 highest quintiles of allopurinol dose corrected for the estimated GFR remained statistically significant in multivariate analysis.

thumbnail image

Figure 2. Percentage of patients who developed allopurinol hypersensitivity syndrome (AHS) in each quintile of the starting dose of allopurinol corrected for the estimated glomerular filtration rate (estimated GFR). Numbers above the bars are the odds ratio. ∗ = P < 0.05 versus the lowest quintile.

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There was no relationship between allopurinol starting dose and serum urate level in the whole group (cases and controls) or in the cases alone (P > 0.05 for both), but there was a negative correlation for the controls (r = −0.06, P = 0.04). This suggests that the higher starting doses of allopurinol in the cases were not a result of a higher serum urate level.

Repeating the analyses with exclusion of the 20% of cases and controls of Chinese ethnicity resulted in no change in the statistical significance levels in any of the analyses.

Allopurinol dose can be increased in patients who tolerate it.

Cases were receiving a significantly higher allopurinol dosage than controls at the time AHS occurred (mean ± SEM 217.9 ± 9.0 mg/day versus 150.3 ± 5.5 mg/day) (P < 0.001). At the time of the reaction, 11.5% of the cases and 26% of the controls were receiving the creatinine clearance–based allopurinol dose. Cases were more likely to be receiving doses that were higher than the creatinine clearance–based allopurinol dose (29 of 52 cases [55.8%] versus 27 of 150 controls [18%]) (OR 28.5 [95% CI 6.0–47.6], P < 0.001). Controls were more likely than cases to be receiving doses that were lower than the creatinine clearance–based allopurinol dose (84 of 150 controls [56%] versus 17 of 52 cases [32.7%]) (OR 5.3 [95% CI 2.1–13.7], P < 0.001). Only 10 of 53 cases (18.8%) had the dosage of allopurinol increased between the time allopurinol was started and the time the reaction occurred, as compared to 50 of 150 controls (33.3%). In the 10 cases in whom the dosage was increased, the mean increase was 197.5 mg/day between the starting dosage and the dosage at the time of the reaction. In the 50 controls, the mean increase in allopurinol was 110.5 mg/day. Allowing for matching between cases and controls, the mean increase in dosage was significantly larger in the cases (P = 0.002). All controls subsequently had increases in the dosage of allopurinol after the matched time (time at which AHS occurred in cases). The mean increase in allopurinol dosage was 83 mg/day, and the mean ± SEM maximum dosage was 229.3 ± 8.8 mg/day.

Can a safe starting dose of allopurinol be determined?

ROC analysis indicated that the starting dose of allopurinol in 91% of AHS cases and 36% of controls was ≥1.5 mg per unit of estimated GFR (mg/ml/minute). In comparison, 79% of AHS cases and 53% of controls started at a dose of ≥2.0 mg of allopurinol per unit of estimated GFR (mg/ml/minute). A starting dose based on an estimated GFR of 1.5 mg/ml/minute was selected as a reasonable tradeoff between a clinically practicable dose and the absolute risk of AHS (Table 4).

Table 4. Proposed starting dosage of allopurinol based on 1.5 mg per estimated GFR*
Estimated GFR, ml/minute/1.73 m2Allopurinol starting dosage
  • *

    Consideration should be given to starting allopurinol at even lower doses in patients at high risk of developing allopurinol hypersensitivity syndrome, such as those with HLA–B*5801. Estimated GFR = estimated glomerular filtration rate.

<550 mg/week
5–1550 mg twice weekly
16–3050 mg every 2 days
31–4550 mg/day
46–6050 mg and 100 mg on alternate days
61–90100 mg/day
91–130150 mg/day
>130200 mg/day

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

We have shown that the starting dose of allopurinol is a significant risk factor for AHS. However, in those who tolerate allopurinol, the dose can be increased safely, a finding confirmed in a recent dose-escalation study (19).

The mechanisms leading to AHS remain unclear. Three potential factors are genetic background, drug accumulation, and immunologic responses. Recent studies have highlighted a significant association between HLA–B*5801 and AHS in the Han Chinese (10) and Thai (12) populations and a weaker effect in Europeans (13). There is some controversy regarding the effect of HLA–B*5801 in the Japanese population (11, 20). In addition, the incidence of severe cutaneous adverse reactions to allopurinol have been reported to be higher in Korean patients with stage III–V chronic kidney disease and HLA–B*5801 (21). Ethnicity was a strong risk factor for AHS in the present study, where those of Chinese descent were overrepresented among cases, while patients of Maori/Pacific Island ethnicity were less likely to develop AHS compared to Europeans. Part of this ethnic influence may relate to genetic background, although environmental risk factors may also be involved.

Interestingly, patients with tophi were less likely to develop AHS than those without, but the reason for this is unclear, especially since no relationship between the presence of tophi and ethnicity was observed. Of the 10 cases who were of Chinese ethnicity, 8 did not have tophi, which may have contributed to some of the observed negative association. However, our multivariate analysis, which simultaneously included ethnicity and tophi, indicated that each of these was independently associated with the risk of AHS.

There is no clear relationship between plasma oxypurinol level and AHS. There are case reports of AHS occurring well within the reported therapeutic range for plasma oxypurinol levels (30–100 μmoles/liter) (22). Conversely, many patients without AHS have plasma oxypurinol levels of >100 μmoles/liter (22, 23). Immunologic mechanisms seem likely to play an important role. The onset of AHS within weeks after starting allopurinol suggests a delayed-type hypersensitivity reaction. Deposition of IgM in the dermal–epidermal junction of the skin from a patient with severe AHS has been reported (24). Liver biopsy specimens from patients with AHS have shown infiltration of T lymphocytes and neutrophils (25, 26). Lymphocyte studies from patients with AHS have shown that oxypurinol and allopurinol can induce cellular proliferation (25, 27). How the starting dose of allopurinol could influence these factors is unclear. One explanation is that lower starting doses of allopurinol might lead to desensitization in those who are genetically susceptible or at risk of drug accumulation, thereby preventing AHS.

The higher starting dose of allopurinol observed in the cases compared to the controls in the present study was not related to differences in weight, body mass index, or use of furosemide, although it may be a surrogate marker for other biologic factors. In addition, because cases and controls were matched for renal function and age, the relationship of these factors cannot be directly evaluated in this study. A protocol for starting a patient on allopurinol treatment has not been determined, leading to variations in clinical practice. Our results indicate that allopurinol should be started at a low dose in order to reduce the risk of AHS. We suggest a starting dose of 1.5 mg per unit of estimated GFR. This is based on 90% sensitivity for predicting AHS from the ROC analysis. Despite such dosing, AHS may still occur, and patients beginning allopurinol treatment should be advised to discontinue allopurinol and seek medical attention should they develop a rash or fever. Furthermore, in high-risk groups, such as the Han Chinese or patients with the HLA–B*5801 genotype, even the starting doses suggested may be considered too high; clinicians need to consider this when choosing a starting dose of allopurinol.

Effective long-term management of gout requires a “treat-to-target serum urate level” approach. The British Society for Rheumatology guidelines suggest a target serum urate level of <5 mg/dl (28), while the European League Against Rheumatism recommendations suggest a serum urate level of ≤6 mg/dl, perhaps lower in patients with severe or tophaceous gout (5). An important consequence of creatinine clearance–based allopurinol dosing is failure to achieve the target serum urate level in the majority of patients (29). In the present study, we demonstrated that in patients who tolerate allopurinol, the dose can be increased, supporting up-titration to achieve the target serum urate level rather than a “creatinine clearance–based maximum dose” approach. Although the mean maximal dose was relatively low in the present study, a recent study has shown that in patients in whom the creatinine clearance–based allopurinol dose fails to achieve the target serum urate level, higher doses are well tolerated and are effective in lowering the serum urate level to <6 mg/dl (19).

The median time to occurrence of AHS in our cohort was 30 days, with 90% of cases occurring within 180 days after starting allopurinol. The rate of increase of allopurinol has not been formally studied, but gout flares commonly occur during the first 6–12 months of therapy. The risk of gout flare is reduced by starting allopurinol at a low dose with a gradual up-titration and by administration of low-dose colchicine or a nonsteroidal antiinflammatory drug during the first 6 months of urate-lowering therapy (30). Based on the first 30 days being the period of highest risk for AHS and the results of our previous dose-escalation study (19), we advocate increasing the allopurinol dose at monthly intervals until the target serum urate level is achieved. We did not identify an upper limit of allopurinol dose where an increased risk of AHS occurred.

A starting dose of allopurinol of 1.5 mg per unit of estimated GFR with monthly up-titration of the dose is very conservative compared with usual practice, and may seem overly cautious given the low absolute risk of AHS. When treating a chronic condition, it is more important to achieve long-term adherence to therapy than to achieve the target in the shortest time. A “start low, go slow” approach probably results in fewer episodes of acute gout during treatment initiation and improves compliance. For patients in whom allopurinol treatment fails to achieve the target serum urate level due to intolerance or treatment resistance, newer urate-lowering therapies are available. These are more expensive and lack long-term safety and efficacy data. An understanding of the relationship between the allopurinol starting dose and AHS as observed in this study may improve the safe and cost-effective long-term management of gout with allopurinol.

This study has a number of limitations. Although it represents a large study for a rare condition, the number of cases included was small. There is no specific ICD code for AHS; thus, we used the only published definition of AHS and carefully selected cases to fit this definition. Importantly, we excluded 28 potential cases who had presumed adverse drug reactions to allopurinol but did not meet these strict criteria for AHS. We acknowledge the potential pitfalls of case definition, particularly in such a heterogeneous syndrome, but believe that this methodology is robust and that using widely accepted criteria will allow comparison with other studies of AHS.

The ethnicity of the study population, which was not matched between cases and controls, may limit the generalizability of the results. The higher number of Chinese patients among the cases may relate to the known association between AHS and HLA–B*5801 in those of Chinese ethnicity and the higher prevalence of HLA–B*5801 in those of Chinese descent (∼15–20%) compared to those of European descent (∼1–6%) (13). The results, and therefore our conclusion that AHS is related to the starting dose of allopurinol, did not change, however, when the analysis was limited to those of European, Maori, or Pacific Island descent. Due to the retrospective study design, we were unable to determine HLA–B*5801 genotype or plasma oxypurinol concentrations. The rate at which allopurinol was increased, which may influence the risk of AHS, was not standardized. Therefore, the question remains as to whether the rate of increase in combination with the starting dose is important. In the present study, the estimated GFR was used rather than the creatinine clearance, upon which the Hande criteria are based. These methods are not fully interchangeable for the assessment of renal function. Finally, despite careful matching of cases and controls for recognized risk factors for AHS, with the exception of HLA genotype, there may be other unidentified risk factors.

The choice of ROC cutoff for the starting dose was based on clinician opinion and consideration of practical dosing with the available allopurinol tablet strengths. Validation in an independent cohort of patients will be required to confirm our observation of the relationship between the allopurinol starting dose and AHS. To determine whether the proposed dosing strategy results in fewer cases of AHS would require a very large randomized controlled trial to have adequate power and would probably not be feasible.

In summary, we have shown that the starting dose of allopurinol is an important risk factor for the development of AHS. Using ROC analysis, a starting dose of allopurinol of 1.5 mg per unit of estimated GFR is appropriate to minimize the risk of AHS. Progressive up-titration of allopurinol is not associated with an increased risk of AHS, and once allopurinol treatment is established, this strategy should be adopted to achieve the target serum urate level.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Stamp had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Stamp, Taylor, Jones, Dockerty, Drake, Frampton, Dalbeth.

Acquisition of data. Stamp, Jones, Dockerty, Drake, Dalbeth.

Analysis and interpretation of data. Stamp, Taylor, Drake, Frampton, Dalbeth.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

We acknowledge the assistance of Karen Lindsay, Karen Pui, Angela Crowley, Karen Dentener, Sanjib Ghosh, and Philip Robinson with data collection.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES