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ObjectiveThe Māori and Pacific (Polynesian) population of Aotearoa New Zealand has a high prevalence of gout. Our aim was to identify potentially functional missense genetic variants in candidate inflammatory genes amplified in frequency that may underlie the increased prevalence of gout in Polynesian populations.MethodsA list of 712 inflammatory disease-related genes was generated. An in silico targeted exome set was extracted from whole genome sequencing data in people with gout of various ancestral groups (Polynesian, European, East Asian; n = 55, 780, 135, respectively) to identify Polynesian-amplified common missense variants (minor allele frequency > 0.05). Candidate functional variants were tested for association with gout by multivariable-adjusted regression analysis in 2528 individuals of Polynesian ancestry.ResultsWe identified 26 variants common in the Polynesian population and uncommon in the European and East Asian populations. Three of the 26 population-amplified variants were nominally associated with the risk of gout (rs1635712 [KIAA0319], ORmeta = 1.28, Pmeta = 0.03; rs16869924 [CLNK], ORmeta = 1.37, Pmeta = 0.002; rs2070025 [fibrinogen A alpha chain (FGA)], ORmeta = 1.34, Pmeta = 0.02). The CLNK variant, within the established SLC2A9 gout locus, was genetically independent of the association signal at SLC2A9.ConclusionWe provide nominal evidence for the existence of population-amplified genetic variants conferring risk of gout in Polynesian populations. Polymorphisms in CLNK have previously been associated with gout in other populations, supporting our evidence for the association of this gene with gout.

ObjectiveTo determine the long-term use of and adherence to urate-lowering therapy (ULT), serum urate (SU) control, and self-reported flares in participants from a randomized controlled trial of allopurinol dose escalation, in order to achieve target SU concentration (< 0.36 mmol/L) in people with gout.MethodsFor surviving study participants, ULT dispensing and SU testing within the preceding 12 months was obtained by medical record review. A phone interview was conducted to determine self-reported flares and adherence.ResultsOver a mean follow-up of 6.5 (SD 2.5) years since enrollment, 60 out of 183 (33%) participants had died. Review of the 119 surviving participants showed that 98 (82%) were receiving allopurinol, 5 (4%) were receiving febuxostat, and 10 (8%) were not receiving ULT; for the remaining 6 (5.0%), ULT use could not be determined. In those receiving allopurinol, the mean dose was 28.1 (range −600 to 500) mg/day lower than at the last study visit; 49% were receiving the same dose, 18% were on a higher dose, and 33% were on a lower dose than at the last study visit. SU values were available for 86 of the 119 (72%) participants; 50 out of 86 (58%) participants had an SU concentration of < 0.36 mmol/L. Of the 89 participants who participated in the phone interview, 19 (21%) reported a gout flare in the preceding 12 months and 79 (89%) were receiving allopurinol; 71 (90%) of those receiving allopurinol reported 90% or greater adherence.ConclusionMost of the surviving participants in the allopurinol dose escalation study had good real-world persistence with allopurinol, remained at target SU, and had a low number of self-reported flares.

Objective.To determine the relationship between gout flare rate and self-categorization into remission, low disease activity (LDA), and patient acceptable symptom state (PASS).Methods.Patients with gout self-categorized as remission, LDA, and PASS, and reported number of flares over the preceding 6 and 12 months. Multinomial logistic regression was used to determine the association between being in each disease state (LDA and PASS were combined) and flare count, and self-reported current flare. A distribution-based approach and extended Youden index identified possible flare count thresholds for each state.Results.Investigators from 17 countries recruited 512 participants. Remission was associated with a median recalled flare count of zero over both 6 and 12 months. Each recalled flare reduced the likelihood of self-perceived remission compared with being in higher disease activity than LDA/PASS, by 52% for 6 months and 23% for 12 months, and the likelihood of self-perceived LDA/PASS by 15% and 5% for 6 and 12 months, respectively. A threshold of 0 flares in preceding 6 and 12 months was associated with correct classification of self-perceived remission in 58% and 56% of cases, respectively.Conclusion.Flares are significantly associated with perceptions of disease activity in gout, and no flares over the prior 6 or 12 months is necessary for most people to self-categorize as being in remission. However, recalled flare counts alone do not correctly classify all patients into self-categorized disease activity states, suggesting that other factors may also contribute to self-perceived gout disease activity.

ObjectiveThe aim of this study was to determine whether serum urate (SU)–associated genetic variants differ in their influence on gout risk in people taking a diuretic compared to those not taking a diuretic.MethodsThis research was conducted using the UK Biobank Resource (n = 359,876). Ten SU-associated single-nucleotide polymorphisms (SNP) were tested for their association with gout according to diuretic use. Gene-diuretic interactions for gout association were tested using a genetic risk score (GRS) and individual SNP by logistic regression adjusting for relevant confounders.ResultsAfter adjustment, use of a loop diuretic was positively associated with prevalent gout (OR 2.34, 95% CI 2.08–2.63), but thiazide diuretics were inversely associated with prevalent gout (OR 0.60, 95% CI 0.55–0.66). Compared with a lower GRS (< mean), a higher GRS (≥ mean) was positively associated with gout in those not taking diuretics (OR 2.63, 2.49–2.79), in those taking loop diuretics (OR 2.04, 95% CI 1.65–2.53), in those taking thiazide diuretics (OR 2.70, 2.26–3.23), and in those taking thiazide-like diuretics (OR 2.11, 95% CI 1.37–3.25). No nonadditive gene-diuretic interactions were observed.ConclusionIn people taking diuretics, SU-associated genetic variants contribute strongly to gout risk, with a similar effect to that observed in those not taking a diuretic. These findings suggest that the contribution of genetic variants is not restricted to people with “primary” gout, and that genetic variants can play an important role in gout susceptibility in the presence of other risk factors.

Gout is common in people with chronic kidney disease (CKD) and its treatment is frequently suboptimal in this special population due to concerns over adverse events and/or efficacy of medications. There is controversy about the use of urate-lowering therapy (ULT) in those with CKD and lack of agreement about the dosing of allopurinol, the recommended first-line ULT1,2.

Objective.To determine rates of joint replacement for people with rheumatoid arthritis (RA) and osteoarthritis (OA) and to examine the characteristics of those receiving elbow replacements.Methods.Data were extracted from the New Zealand Joint Registry from 1999 to 2015 and annual rates calculated.Results.Rates of joint replacement increased over time for OA but not RA. Elbow replacement was the only procedure performed more commonly in RA.Conclusion.There has been a substantial increase in joint replacement for OA in New Zealand. For RA, where access to biologics has been limited to those with erosions, joint replacement rates have not declined, with the exception of elbow replacements.

Objective.Management of gout is frequently suboptimal. The aim of this study was to determine the proportion of patients presenting to Christchurch Hospital for a gout flare and to determine whether management for both acute flares and urate lowering was in accordance with international recommendations.Methods.A retrospective audit was undertaken of all admissions to Christchurch Hospital from June 1, 2013, to May 31, 2014, in which gout was coded as a primary or secondary discharge diagnosis. Information including demographics, comorbidities, concomitant medications, treatment of acute gout, and urate lowering was collected.Results.A total of 235 acute admissions for gout in 216 individuals were identified. Eleven individuals had 2 admissions and 4 individuals had 3 admissions. In 95/235 admissions (40.4%), gout was the primary diagnosis. Gout accounted for 95/77,321 (0.12%) of acute admissions. The treatment of acute gout was prednisone monotherapy in 170/235 (72.3%) of admissions. Serum urate was measured at some point during 123/235 (52.3%) of admissions, with only 19/123 (15.4%) at target urate level (< 0.36 mmol/l). At 60 of the 235 admissions, urate-lowering therapy was already being prescribed. Nine out of 175 patients (5.1%) not treated with urate-lowering therapy at admission commenced allopurinol and 32/174 (18.4%) had commencement of urate-lowering therapy recommended in the discharge plan.Conclusion.Rates of admission for gout are similar to that observed in other studies. Failure to initiate, change, or recommend alterations in urate-lowering therapy to achieve target urate in people with gout admitted to hospital represents a significant lost opportunity to improve longterm gout management.

Objective.To determine the frequency of adverse events of diagnostic arthrocentesis in patients with possible gout.Methods.Consecutive patients underwent arthrocentesis and were evaluated at 6 weeks to determine adverse events. The 95% CI were obtained by bootstrapping.Results.Arthrocentesis was performed in 910 patients, and 887 (97.5%) were evaluated for adverse events. Any adverse event was observed in 12 participants (1.4%, 95% CI 0.6–2.1). There was 1 case (0.1%, 95% CI 0–0.34) of septic arthritis.Conclusions.Diagnostic arthrocentesis is associated with a low frequency of adverse events. Septic arthritis rarely occurs.

Objective.To identify a comprehensive list of features that might discriminate between gout and other rheumatic musculoskeletal conditions, to be used subsequently for a case-control study to develop and test new classification criteria for gout.Methods.Two Delphi exercises were conducted using Web-based questionnaires: one with physicians from several countries who had an interest in gout and one with patients from New Zealand who had gout. Physicians rated a list of potentially discriminating features that were identified by literature review and expert opinion, and patients rated a list of features that they generated themselves. Agreement was defined by the RAND/UCLA disagreement index.Results.Forty-four experienced physicians and 9 patients responded to all iterations. For physicians, 71 items were identified by literature review and 15 more were suggested by physicians. The physician survey showed agreement for 26 discriminatory features and 15 as not discriminatory. The patients identified 46 features of gout, for which there was agreement on 25 items as being discriminatory and 7 items as not discriminatory.Conclusion.Patients and physicians agreed upon several key features of gout. Physicians emphasized objective findings, imaging, and patterns of symptoms, whereas patients emphasized severity, functional results, and idiographic perception of symptoms.

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).

Objective.To summarize the endorsement of measures of patient-reported outcome (PRO) domains in chronic gout at the 2010 Outcome Measures in Rheumatology Meeting (OMERACT 10).Methods.During the OMERACT 10 gout workshop, validation data were presented for key PRO domains including pain [pain by visual analog scale (VAS)], patient global (patient global VAS), activity limitation [Health Assessment Questionnaire-Disability Index (HAQ-DI)], and a disease-specific measure, the Gout Assessment Questionnaire version 2.0 (GAQ v2.0). Data were presented on all 3 aspects of the OMERACT filters of truth, discrimination, and feasibility. One PRO, health-related quality of life measurement with the Medical Outcomes Study Short-form 36 (SF-36), was previously endorsed at OMERACT 9.Results.One measure for each of the 3 PRO of pain, patient global, and activity limitation was endorsed by > 70% of the OMERACT delegates to have appropriate validation data. Specifically, pain measurement by VAS was endorsed by 85%, patient global assessment by VAS by 73%, and activity limitation by HAQ-DI by 71%. GAQ v2.0 received 30% vote and was not endorsed due to several concerns including low internal consistency and lack of familiarity with the measure. More validation studies are needed for this measure.Conclusion.With the endorsement of one measure each for pain, patient global, SF-36, and activity limitation, all 4 PRO for chronic gout have been endorsed. Future validation studies are needed for the disease-specific measure, GAQ v2.0. Validation for PRO for acute gout will be the focus of the next validation exercise for the OMERACT gout group.

Objective.To determine the epidemiology, clinical features, and microbiology of adult native joint septic arthritis in Canterbury, New Zealand, over a 5-year period in individuals with and without an underlying rheumatic disorder.Methods.Patients with native joint septic arthritis were identified retrospectively and classified by Newman’s criteria. The clinical characteristics were described and comparisons made between those with and without underlying rheumatic disease.Results.Two hundred forty-eight cases of native joint septic arthritis (mean age 60, range 16–97 yrs) were identified with an overall incidence rate of 12.0/100,000/year (95% CI 10.6–13.6). Yearly incidence increased with age to a maximum of 73.4/100,000 in those > 90 years of age. Septic arthritis was iatrogenic in 16.9% of cases while 27% had an underlying inflammatory arthritis including gout (14.9%), calcium pyrophosphate disease (8.5%), and rheumatoid arthritis (4%). Few patients were taking immunosuppressant therapy, with just 1 taking a biological agent.Staphylococcus aureuswas the most commonly identified organism. Those with underlying inflammatory arthritis were significantly older (73.6 yrs vs 55.6 yrs; p < 0.001), more likely to be female (55.2% vs 26.0%; p < 0.001), and to have septic polyarthritis (16.4% vs 4.4%; p = 0.002). The 30-day mortality was 2%, increasing to 6% at 90 days.Conclusion.The incidence of septic arthritis in Canterbury, New Zealand, is higher than in previous studies. Crystal arthropathy commonly coexisted with infection although autoimmune arthritis and immunosuppression was less of a factor than anticipated.

Objective.Inadequate patient information about gout may contribute to poor disease outcomes. We reviewed existing educational resources for gout to identify strengths and weaknesses and compare resources cross-nationally.Methods.Content, readability, and dietary recommendations were reviewed using a sample of 30 resources (print and Web-based) from 6 countries.Results.More than half of the resources were written at a highly complex level. Some content areas were lacking coverage, including comorbidity risks, uric acid target levels, and continuing allopurinol during acute attacks.Conclusion.Our findings suggest significant room for improvement in gout patient educational resources, particularly regarding self-management.

Objective.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 MTXGlun) concentrations, disease activity, and adverse effects.Methods.Thirty patients were changed from oral to SC MTX. Trough RBC MTXGlun 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).Results.MTXGlu3, MTXGlu4, and MTXGlu5 concentrations, but not MTXGlu1 and MTXGlu2, 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 MTXGlu5 (p = 0.035) and RBC MTXGlu3–5 (p = 0.032). No change in adverse effect frequency occurred.Conclusion.Changing to SC MTX results in increased long-chain MTXGlun. However, it takes at least 6 months for RBC steady-state concentrations to be achieved. Increased long-chain MTXGlun concentrations were significantly associated with reduced disease activity.

Objective.To review a novel approach for constructing composite response criteria for use in chronic gout clinical trials that implements a method of multicriteria decision-making.Methods.Preliminary work with paper patient profiles led to a restricted set of core-set domains that were examined using 1000MindsTM by rheumatologists with an interest in gout, and (separately) by OMERACT registrants prior to OMERACT 10. These results and the 1000Minds approach were discussed during OMERACT 10 to help guide next steps in developing composite response criteria.Results.There were differences in how individual indicators of response were weighted between gout experts and OMERACT registrants. Gout experts placed more weight upon changes in uric acid levels, whereas OMERACT registrants placed more weight upon reducing flares. Discussion highlighted the need for a “pain” domain to be included, for “worsening” to be an additional level within each indicator, for a group process to determine the decision-making within a 1000Minds exercise, and for the value of patient involvement.Conclusion.Although there was not unanimous support for the 1000Minds approach to inform the construction of composite response criteria, there is sufficient interest to justify ongoing development of this methodology and its application to real clinical trial data.

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.

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.

T lymphocytes infiltrating rheumatoid synovium may alter the function of resident synoviocytes. We investigated the influence on synoviocyte cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production exerted by soluble factors released by T cells, with particular reference to interleukin 17 (IL-17).Human peripheral blood T cells were stimulated with antibodies directed against CD3 and CD28. Harvested T cell supernatants were applied to cultured human fibroblast-like synoviocytes in culture. The effects of IL-17 alone and in combination with tumor necrosis factor-a (TNF-a) were examined using recombinant cytokines and neutralizing antibodies. Synoviocyte COX-2 expression and PGE2 production were examined.Supernatants from stimulated T cells upregulated COX-2 expression and increased PGE2 production by synoviocytes. The T cell supernatants were found to contain IL-17 and TNF-a. Recombinant IL-17 upregulated synoviocyte COX-2 expression and enhanced TNF-a stimulated synoviocyte COX-2 expression. The upregulation of synoviocyte COX-2 expression by supernatants from stimulated T cells was partially inhibited by addition of neutralizing antibodies against IL-17 or TNF-a or by treatment of T cells with cyclosporin A prior to stimulation.Activated T cells are capable of paracrine upregulation of synoviocyte COX-2 expression and PGE2 production through release of soluble mediators. T cell derived IL-17, especially in combination with TNF-a, may contribute to ongoing inflammation through its effects on COX-2 expression and PGE2 production. These data provide additional evidence for the contribution of T cells in rheumatoid inflammation and highlight the potential of IL-17 as a therapeutic target.

To the Editor: Formal joint counts are an integral part of disease assessment in rheumatology. They form the basis of disease responder indices including Disease Activity Score (DAS), American College of Rheumatology responder criteria, Clinical Disease Activity Index, and Simplified Disease Activity Index. Wide variability among examiners may therefore have a significant effect on outcomes in clinical trials1. In an attempt to reduce examiner variability, the European League Against Rheumatism developed standardized joint assessment criteria for the presence or absence of joint swelling and/or tenderness2. Formal training may improve the degree of variability between examiners. A joint count calibration exercise was organized as part of the New Zealand Treat-to-Target initiative. Twenty-eight tender and swollen joint counts as described by Fuchs, et al 3 were undertaken on 5 separate patients with rheumatoid arthritis (RA) by examiners …

Clopidogrel and ticlopidine are both antiplatelet thienopyridine derivatives that inhibit the binding of adenosine diphosphate to its receptor on platelets. Clopidogrel is more effective than aspirin in reducing the combined risk of ischemic stroke, myocardial infarction, and vascular death1. Dual antiplatelet therapy with aspirin and a thienopyridine reduces the incidence of thrombosis post-stent implantation. Due to its superior safety profile, clopidogrel has replaced ticlopidine as the dominant thienopyridine prescribed, although given the structural similarity between the 2 drugs, cross-reactivity is possible. We describe a case of acute arthritis related to clopidogrel, subsequently resolved when clopidogrel was stopped and replaced with ticlopidine. A 50-year old man presented with 25 minutes of central chest pain. Electrocardiogram showed ST segment depression in leads I and AvL, and he was treated as for acute coronary syndrome with aspirin, s-blocker, and low molecular weight heparin. Cardiac risk factors included previous ischemic heart disease (IHD), a 35-pack-year smoking history, … Address reprint requests to Dr. L.K. Stamp, Department of Medicine, University of Otago, Christchurch, PO Box 4345, Christchurch 8140, New Zealand. E-mail: lisa.stamp{at}cdhb.govt.nz