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ABSTRACT: OBJECTIVE: Studies in human volunteers have shown that vitamin C reduces serum urate (SU). The aim of this study was to determine effects of vitamin C on SU in patients with gout. METHODS: Patients with gout and SU >0.36mmol/L were recruited. 20 patients already receiving allopurinol were randomised to an increase in allopurinol dose or commenced on vitamin C 500mg/d. 20 patients not receiving allopurinol were randomised to start allopurinol or vitamin C 500mg/d. Plasma ascorbate, creatinine, and SU were measured at day 0 and week 8. RESULTS: There was no significant difference in baseline SU or eGFR between those who received vitamin C and those who did not (SU 0.50±0.11mmol/l vs. 0.50±0.09mmol/l p=0.89; eGFR 65.5±15.7ml/min/1.73m(2) vs. 67.9±20.7 ml/min/1.73m(2) p=0.67). 30% in the vitamin C group and 25% in the no vitamin C group were receiving diuretics (p=0.72). In the patients receiving vitamin C there was a significant increase between week 0 and 8 in plasma ascorbate. The reduction in SU was significantly less in those patients receiving vitamin C compared to those who started or increased the dose of allopurinol (0.014mmol/l vs. 0.118mmol/l p<0.001). CONCLUSION: Modest dose vitamin C (500mg/d) for 8 weeks had no clinically significant urate lowering effect in patients with gout despite increasing plasma ascorbate. These results differ from findings in hyperuricaemic healthy controls. The uricosuric effect of modest dose vitamin C appears less in patients with gout both as monotherapy and in combination with allopurinol. © 2013 American College of Rheumatology.
Arthritis & Rheumatism 05/2013; · 7.87 Impact Factor
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ABSTRACT: Cardiovascular disease is a substantial contributor to increased morbidity and mortality in rheumatoid arthritis (RA). The aim of this audit was to determine the rate of cardiovascular events in a cohort of newly diagnosed RA patients.
The inpatient clinical database from Christchurch Hospital, Christchurch, New Zealand, was searched using the International Classification of Diseases 9th Revision (ICD9) and 10 codes representing RA and cardiovascular disease between 1 January 1999 and 31 December 2008. Notes were reviewed with additional demographic and medication data sought. Outpatient data for RA patients was collated from the Rheumatology Department's letter database.
Four hundred and six patients were identified with combined ICD9 or 10 codes for RA and ischemic heart disease, of whom 194 had a confirmed myocardial event. Of these, 34 were diagnosed with RA between January 1999 and December 2008 prior to their myocardial event. Kaplan-Meier analysis showed risk of a cardiovascular event at 1 and 10 years was 0.64% and 9.4%, respectively. There were 26 confirmed deaths in the study period. The risk of death at 1 and 10 years was 0.48% and 8.16%, respectively.
We have shown a relatively low prevalence of cardiovascular events in this RA population diagnosed within a 10 year period. This is consistent with other reports and likely reflects the short follow-up period. Prospective longer-term studies will be required to further investigate the relative contribution of disease activity and other parameters to cardiovascular events in patients with early RA.
International Journal of Rheumatic Diseases 02/2013; 16(1):19-23. · 0.81 Impact Factor
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ABSTRACT: OBJECTIVE: To compare the performance of the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria with the 1987 American Rheumatism Association (ARA) criteria for rheumatoid arthritis (RA) in an early arthritis cohort. METHODS: The study included 79 patients with early arthritis (symptoms < 12 months) and a minimum of 1 year of followup between January 2004 and August 2010. Case notes were reviewed to determine which criteria were fulfilled at initial, 3-month, 1-year, and 2-year visits. Requirements for disease-modifying antirheumatic drug (DMARD) therapy and presence of joint erosions were compared at 2 years. RESULTS: At the initial visit, twice as many patients fulfilled the 2010 criteria (67%) compared with the 1987 criteria (34%; p < 0.001). Forty-four percent of patients who fulfilled only the 2010 criteria at the initial visit went on to fulfill both 1987 and 2010 criteria at 3 months (p < 0.001). Eight patients did not meet the 1987 RA criteria solely because of short symptom duration. All 17/79 patients who developed joint erosions went on to eventually fulfill both criteria. Of those patients who fulfilled only the 2010 criteria at baseline, 25/27 (93%) ultimately received DMARD therapy compared with 24/26 (92%) of those fulfilling both 1987 and 2010 criteria. CONCLUSION: The 2010 ACR/EULAR RA criteria allowed earlier RA classification compared to the 1987 ARA criteria, although both criteria were equivalent in predicting joint erosions and subsequent need for DMARD (Australian New Zealand Clinical Trials Registry ANZCTR 12608000292370).
The Journal of Rheumatology 09/2012; · 3.69 Impact Factor
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ABSTRACT: To determine the effects of furosemide on serum urate (SU), plasma oxypurinol and urinary urate.
Twenty-three cases with gout receiving furosemide and allopurinol were recruited. Twenty-three controls with gout receiving allopurinol but no diuretics were matched on age, gender, estimated glomerular filtration rate and allopurinol dose. SU, plasma oxypurinol and urinary urate were assessed on a single occasion. The effects of a single dose of furosemide 40 mg were examined in a separate group of 10 patients receiving allopurinol but not diuretic.
Cases had significantly higher SU and plasma oxypurinol compared with controls despite receiving similar doses of allopurinol. There was no difference in urinary urate excretion. There was a significant increase in area under the curve (AUC)(0-24) for oxypurinol after administration of furosemide 40 mg.
The interaction between allopurinol and furosemide results in increased SU and plasma oxypurinol. The exact mechanisms remain unclear but complex interactions that result in attenuation of the hypouricaemic effects of oxypurinol are likely.
Australian New Zealand Clinical Trials Registry, www.anzctr.org.au, 12609000529246.
Rheumatology (Oxford, England) 04/2012; 51(9):1670-6. · 4.24 Impact Factor
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ABSTRACT: To report on the effects of the Canterbury earthquake on rheumatology service provision and identify factors that allowed continuation of patient care. Data was collected on the number of appointments during the period after the earthquake and the effects of the earthquake on service provision. The rheumatology service faced unique challenges in continuing to provide a service and ensure ongoing care for our patients in the community after the earthquake. All outpatient services were cancelled for 2 weeks, resulting in the cancellation of 23 new patient and 145 follow-up patient appointments. Telephone consultation was attempted for all these patients. A total of 113 patients could be contacted, and 15 required acute review. Challenges included difficult access to the hospital, lack of laboratories for blood testing, limited access to clinical records, loss of power, sewerage and waste water and a contaminated drinking water supply. The impact of these on patients with rheumatic diseases was wide ranging. Despite a natural disaster and challenging logistics, the Rheumatology Department was able to provide a service with the use of remote telephone consultations and an electronic patient record backed up by an effective patient and primary practitioner education base and resource access.
Clinical Rheumatology 12/2011; 31(4):723-5. · 2.00 Impact Factor
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ABSTRACT: To determine the effects of changing from oral to subcutaneous (SC) methotrexate (MTX) in patients with rheumatoid arthritis (RA) on red blood cell MTX polyglutamate (RBC MTXGlu(n)) concentrations, disease activity, and adverse effects.
Thirty patients were changed from oral to SC MTX. Trough RBC MTXGlu(n) concentrations were measured for 24 weeks and concentrations fitted to a first-order accumulation model. Disease activity was assessed by 28-joint Disease Activity Score (DAS28).
MTXGlu(3), MTXGlu(4), and MTXGlu(5) concentrations, but not MTXGlu(1) and MTXGlu(2), increased significantly over 24 weeks, reaching 90% of new steady-state concentrations by about 40 weeks. A decrease in DAS28 was associated with increased RBC MTXGlu(5) (p = 0.035) and RBC MTXGlu(3-5) (p = 0.032). No change in adverse effect frequency occurred.
Changing to SC MTX results in increased long-chain MTXGlu(n). However, it takes at least 6 months for RBC steady-state concentrations to be achieved. Increased long-chain MTXGlu(n) concentrations were significantly associated with reduced disease activity.
The Journal of Rheumatology 10/2011; 38(12):2540-7. · 3.69 Impact Factor
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ABSTRACT: To determine the efficacy and safety of increasing the allopurinol dose above the proposed creatinine clearance-based dose in patients with gout.
Patients with gout who had been receiving a stable dose of allopurinol for ≥ 1 month were recruited. The dose of allopurinol was increased to obtain the target serum urate level of <0.36 mmoles/liter (<6 mg/dl). Patients were seen monthly until the serum urate concentration was <0.36 mmoles/liter for 3 consecutive months and then were seen every 3 months for at least 12 months. Data were analyzed using the dosage of allopurinol (mg/day) greater than the recommended dosage, as defined by the Hande criteria.
Ninety patients were enrolled. The mean age of the patients was 58.7 years (range 27-83 years), 87.9% were male, and 81.9% were of European ancestry. Forty-five patients had a serum urate concentration of ≥ 0.36 mmoles/liter, and the dose of allopurinol was increased in these patients. Rashes developed in 3 patients, and either allopurinol was discontinued or dose escalation was ceased in these patients. Seven patients were lost to followup or developed intervening medical problems that precluded dose escalation. In 31 (88.8%) of 35 patients who completed the study, the serum urate level was <0.36 mmoles/liter at 12 months. Two of the 5 patients who had a serum urate level ≥ 0.36 mmoles/liter had undetectable levels of plasma oxypurinol, indicating noncompliance with allopurinol treatment. A significant reduction in the serum urate concentration was observed for all allopurinol doses above the recommended dose. Eighteen of 45 patients were receiving furosemide; those receiving furosemide were just as likely as those not receiving furosemide to achieve a serum urate concentration of <0.36 mmoles/liter (72% versus 88.5%; P = 0.24). Patients receiving furosemide required a higher dose of allopurinol to achieve the target serum urate concentration. No serious adverse events were observed.
Increasing the dose of allopurinol above the proposed creatinine clearance-based dose led to a significant reduction in the serum urate concentration. Approximately 89% of patients achieved a serum urate concentration of <0.36 mmoles/liter. In this cohort, toxicity was not increased in patients receiving higher doses of allopurinol, including those with renal impairment.
Arthritis & Rheumatism 02/2011; 63(2):412-21. · 7.87 Impact Factor
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ABSTRACT: OBJECTIVES:: To determine the efficacy and safety of increasing allopurinol dose above proposed CrCL-based dosing guidelines in patients with gout. METHODS:: Patients with gout on stable dose allopurinol for ≥one month were recruited. Allopurinol dose was increased to obtain the target serum urate (SUA) <0.36mmol/L (6mg/dL). Patients were seen monthly until SUA was <0.36mmol/L for 3 consecutive months, then 3 monthly until at least 12 months. Data were analyzed using allopurinol mg/day above recommended dose, as defined by the Hande criteria. RESULTS:: Ninety patients were enrolled. Mean age 58.3years (range 27-83yrs), 87.8% male, and 78% European. 45 patients had SUA ≥0.36mmol/L and had allopurinol increased. Three patients developed rashes and discontinued allopurinol or ceased dose escalation. Seven patients were lost to follow-up. 31/35 (88%) patients who completed the study achieved a SUA <0.36mmol/L at 12 months. 2/5 patients who had SUA≥0.36mmol/L had undetectable plasma oxypurinol indicating non-compliance. There was a significant reduction in SUA at all allopurinol doses above recommended (p<0.001). 18/45 patients were receiving frusemide or a thiazide diuretic. Patients on frusemide were just as likely to achieve SUA <0.36mmol/L as those not on frusemide (72% vs 88.5% p=0.24). Patients on frusemide required a higher dose to achieve the target SUA. There were no serious adverse events. CONCLUSION:: Increasing allopurinol above the proposed CrCL-based dose led to a significant reduction in serum urate. 88% of patients achieved a SUA <0.36mmol/L. There was no increase in toxicity with higher doses of allopurinol in this cohort, including those with renal impairment.
Arthritis & Rheumatism 10/2010; · 7.87 Impact Factor
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Arthritis & Rheumatism 04/2010; · 7.87 Impact Factor
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ABSTRACT: There are limited data suggesting that methotrexate polyglutamate (MTXGlu) concentrations can guide MTX dosing in patients with rheumatoid arthritis (RA). The aim of this study was to define a therapeutic range of red blood cell (RBC) MTXGlu(n) concentrations (where n refers to the number of glutamate groups), including threshold values for efficacy and adverse effects in patients receiving long-term oral MTX treatment.
A cross-sectional study of 192 patients receiving oral MTX was undertaken. Disease activity was assessed by the swollen and tender joint counts, the C-reactive protein level, and the Disease Activity Score in 28 joints (DAS28). High disease activity was defined as a DAS28 of >3.2. A standardized questionnaire regarding common MTX adverse effects was completed.
The MTX dosage was significantly higher in patients in whom the swollen joint count and DAS28 were higher. The MTXGlu(4), MTXGlu(5), MTXGlu(3-5), and MTXGlu(1-5) concentrations were significantly higher in patients with high disease activity. After correction for age, the estimated glomerular filtration rate, and the MTX dosage, the association remained significant for MTXGlu(5). RBC folate concentrations were significantly higher in the group with high disease activity. There was no association between any MTXGlu(n) concentration and adverse effects.
In contrast to other studies, the results of the present study did not show a relationship between the MTXGlu(n) concentration and reduced disease activity in patients with RA who were receiving long-term MTX therapy. However, disease activity was influenced by the RBC folate level, which may be a more important factor than MTXGlu(n) concentrations for disease control. In accordance with the findings of previous studies, we were unable to show a relationship between MTXGlu(n) concentrations and adverse effects. Prospective studies will be important to determine whether there is a role for measuring MTXGlu(n) concentrations in patients receiving long-term treatment with MTX.
Arthritis & Rheumatism 02/2010; 62(2):359-68. · 7.87 Impact Factor
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ABSTRACT: Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug (DMARD) in the management of rheumatoid arthritis (RA). MTX is transported into cells, where additional glutamate moieties are added and it is retained as MTX polyglutamates (MTXGlu [referred to as a group as MTXGlun]). There is large interpatient variability in MTXGlun concentrations. This study was undertaken to determine nongenetic factors that influence red blood cell (RBC) MTXGlun concentrations in patients receiving long-term stable low-dose oral MTX.
One hundred ninety-two patients receiving long-term oral MTX for the treatment of RA were recruited. Trough MTXGlun concentrations were measured by high-performance liquid chromatography. Univariate analysis was performed to determine variables influencing MTXGlun concentrations. Backward stepwise multivariate regression analysis was done to determine variables that affect individual MTXGlun concentrations; variables with P values of <0.1 in the univariate analysis for any MTXGlun were included.
Univariate analysis revealed that increased age, lower estimated glomerular filtration rate (GFR), higher MTX dosage, longer duration of MTX treatment, and use of prednisone were associated with significantly higher MTXGlun concentrations. Smokers had significantly lower concentrations of MTXGlu3, MTXGlu3-5, and MTXGlu1-5. Sex, rheumatoid factor and anti-cyclic citrullinated peptide status, RBC folate level, and body mass index had no significant effect on MTXGlun levels. Concomitant use of other DMARDs was associated with lower MTXGlu2 levels, and treatment with nonsteroidal antiinflammatory drugs was associated with lower MTXGlu3 and MTXGlu1-5 concentrations. Multivariate regression analysis revealed that age, MTX dosage, and estimated GFR were the major determinants of MTXGlun concentrations.
Large interpatient variability in MTXGlun concentrations can be explained, at least in part, by a combination of factors, particularly age, MTX dosage, and renal function. There are complex interactions between smoking, RBC folate levels, and concentrations of MTXGlun.
Arthritis & Rheumatism 07/2009; 60(8):2248-56. · 7.87 Impact Factor
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ABSTRACT: There is evidence supporting a therapeutic range for methotrexate polyglutamate (MTXGlu) concentrations in the treatment of rheumatoid arthritis (RA). Knowledge of the pharmacokinetics of MTXGlu1-5 is required for optimal timing of blood sampling. The aim of this study was to determine the time to steady state and the half-life of accumulation of red blood cell (RBC) MTXGlu1-5 in patients with RA commencing oral MTX, and the time for RBC MTXGlu1-5 to become undetectable and the half-life of elimination of RBC MTXGlu1-5 in patients ceasing treatment with oral MTX.
Ten patients beginning treatment and 10 patients stopping treatment with low-dose oral MTX were recruited. Blood samples were initially collected weekly, with gradual extension to monthly collection over the study period. RBC MTXGlu1-5 concentrations were assayed by high-performance liquid chromatography. Results were analyzed using a first-order exponential method.
The median times to reach steady state in RBCs (defined as 90% of the maximum concentration) were 6.2, 10.6, 41.2, 149, and 139.8 weeks, respectively, for MTXGlu1, MTXGlu2, MTXGlu3, MTXGlu4, and MTXGlu5. The median half-life of accumulation for RBC MTXGlu1-5 ranged from 1.9 weeks to 45.2 weeks. The median times for MTXGlus to become undetectable in RBCs were 4.5, 5.5, 10, 6, and 4 weeks, respectively, for MTXGlu1, MTXGlu2, MTXGlu3, MTXGlu4, and MTXGlu5. The median half-life of elimination for RBC MTXGlu1-5 ranged from 1.2 weeks to 4.3 weeks.
There is wide interpatient variability of RBC MTXGlu1-5 accumulation and elimination in adults with RA. These data also suggest that after a dose change, >6 months are required for RBC MTXGlu1-5 to reach steady state. Such delays in achieving steady state suggest that more rapid dose escalation or subcutaneous administration from the outset should be considered.
Arthritis & Rheumatism 11/2008; 58(11):3299-308. · 7.87 Impact Factor
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ABSTRACT: To determine the prevalence of severe infections in patients with rheumatoid arthritis (RA) prescribed leflunomide in North Canterbury, New Zealand.
A case-note audit of all Christchurch Hospital patients with RA prescribed leflunomide between 2002 and 2006 was performed. The criterion for severe infection was inpatient hospitalization. Relevant reports to the national Pharmacovigilance Centre were also examined.
Since January 2002, 171 patients with RA have commenced taking leflunomide. Ninety-nine of 171 (57.9%) patients were also prescribed prednisone. Combination disease modifying antirheumatic drug therapy was common, with 82/171 (48.0%) taking methotrexate (MTX), 15/171 (8.8%) hydroxy-chloroquine, 11/171 (6.4%) sulfasalazine, and 8/171 (4.7%) anti-tumor necrosis factor therapy. Eleven patients developed infection requiring hospitalization while taking leflunomide including: lower respiratory tract infections (3), cellulitis (2), disseminated herpes zoster (2), probable TB liver (1), abdominal sepsis (1), mycotic aneurysm (1) and gastroenteritis (1). Nine of the 11 patients were also taking corticosteroids or corticosteroids with MTX. The 171 patients were treated for a total of 4005 months, giving an incidence for severe infection of 3.30/100 patient-years (95% CI 1.65-5.90). Patients at increased risk were those with severe disease and taking concomitant MTX and corticosteroids. The NZ Pharmacovigilance Centre has received 7 additional reports of severe infections in patients with RA taking leflunomide. Reported cases include probable pulmonary TB (1), pneumocystis pneumonia (1), other pulmonary infection (2), and septicemia (3) including a case of infective endocarditis. Four occurred in combination with MTX, one with adalimumab. All 5 patients were also taking -corticosteroids.
We believe this observed rate of serious infection is acceptable in the context of optimally treating active RA. Patients with severe disease and taking combination MTX and corticosteroids are at greatest risk. In our experience, once established, infections may rapidly progress in patients with RA taking leflunomide, and early cholestyramine washout is strongly recommended.
The Journal of Rheumatology 12/2007; 34(11):2201-3. · 3.69 Impact Factor
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ABSTRACT: To compare the performance of a capture proteinase 3 enzyme linked immunosorbent assay (PR3 ELISA) with a direct PR3 ELISA in the measurement of PR3 antineutrophil cytoplasmic antibodies (ANCA).
The performance of both assays systems was compared using two sets of sera. Sera from patients (n = 49) suffering from Wegener's granulomatosis (WG) and fulfilling the American College of Rheumatology classification criteria (or a modification of those criteria that allowed for ANCA positivity) were used along with sera from a group of patients (n = 48) considered to have a clinically false positive PR3 ANCA result when measured by routine direct ELISA.
Using the assay specific cut-offs, the direct ELISA gave a positive result in 92% on repeat testing and the capture ELISA a positive result in 84% of sera from patients with WG. The capture ELISA was negative in 75% of patients considered to have a false positive PR3 ANCA on initial testing by direct ELISA (27% were negative on repeat testing by direct ELISA). The mean concentration of PR3 ANCA in WG patient sera measured by the capture ELISA was significantly higher than that measured by the direct ELISA. The capture PR3 ELISA had a broader analytical range which was also reflected in PR3 ANCA concentrations measured in serial serum samples from WG patients.
In this study the direct PR3 ELISA performed better as a screening test for PR3 ANCA compared with the capture PR3 ELISA, mainly because the cut-off for the capture ELISA needed to be set higher to avoid non-specific binding. In contrast, the improved analytical range of the capture ELISA made it a potentially more useful method for monitoring serial PR3 ANCA concentrations. In specific serum samples the capture ELISA was better able to discriminate 'false positive' PR3 ANCA.
Pathology 05/2007; 39(2):258-63. · 2.38 Impact Factor
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Helen M A Simkins,
Marilyn E Merriman,
John Highton,
Peter T Chapman, John L O'Donnell,
Peter B B Jones,
Peter J Gow,
Lachy McLean,
Violetta Pokorny,
Andrew A Harrison,
Tony R Merriman
Arthritis & Rheumatism 08/2005; 52(7):2222-5. · 7.87 Impact Factor
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ABSTRACT: In 2000 we described a patient with HLA-B27 associated spondyloarthropathy (SpA) and severe ascending aortitis requiring surgical intervention. Despite continued immunosuppressive therapy she developed narrowing of the distal part of the right subclavian artery and proximal axillary artery secondary to active vasculitis. In addition, biopsy-proven amyloid gastroenteropathy developed causing persistent diarrhea and iron deficiency anemia. Treatment with infliximab resulted in resolution of joint symptoms and rapid improvement in laboratory markers of inflammation. Diarrhea settled more gradually, such that her bowel habit had normalized 16 months after therapy commenced.
The Journal of Rheumatology 03/2005; 32(2):382-5. · 3.69 Impact Factor
