What Is Allopurinol Failure and What Should We Do About It?

Allopurinol is the most widely used urate-lowering medication worldwide. However, allopurinol failure is frequently observed in clinical practice. In this review, we provide a framework for assessing allopurinol failure, which includes failure of allopurinol to control serum urate concentrations, failure of allopurinol to control clinical symptoms, and failure of allopurinol due to an adverse drug reaction. Understanding the causes of allopurinol failure underpins the approach required to turn failure into success in gout management.

The development and evaluation of dose-prediction tools for allopurinol therapy (Easy-Allo tools).

AIMS: Dose escalation at the initiation of allopurinol therapy can be protracted and resource intensive. Tools to predict the allopurinol doses required to achieve target serum urate concentrations would facilitate the implementation of more efficient dose-escalation strategies. The aim of this research was to develop and externally evaluate allopurinol dosing tools, one for use when the pre-urate-lowering therapy serum urate is known (Easy-Allo1) and one for when it is not known (Easy-Allo2). METHODS: A revised population pharmacokinetic-pharmacodynamic model was developed using data from 653 people with gout. Maintenance doses to achieve the serum urate target of <0.36 mmol L-1 in >80% of individuals were simulated and evaluated against external data. The predicted and observed allopurinol doses were compared using the mean prediction error (MPE) and root mean square error (RMSE). The proportion of Easy-Allo predicted doses within 100 mg of the observed was quantified. RESULTS: Allopurinol doses were predicted by total body weight, baseline urate, ethnicity and creatinine clearance. Easy-Allo1 produced unbiased and suitably precise dose predictions (MPE 2 mg day-1 95% confidence interval [CI] -13-17, RMSE 91%, 90% within 100 mg of the observed dose). Easy-Allo2 was positively biased by about 70 mg day-1 and slightly less precise (MPE 70 mg day-1 95% CI 52-88, RMSE 131%, 71% within 100 mg of the observed dose). CONCLUSIONS: The Easy-Allo tools provide a guide to the allopurinol maintenance dose requirement to achieve the serum urate target of <0.36 mmol L-1 and will aid in the development of novel dose-escalation strategies for allopurinol therapy.

Relationship Between Adalimumab Concentrations, Antidrug Antibodies, and Disease Activity in Rheumatoid Arthritis: A Cross-Sectional Observational Study.

OBJECTIVES: To determine the influence of patient characteristics and disease activity on adalimumab (ADA) concentrations; to assess the relationships between ADA concentrations, the presence of antidrug antibodies (ADAb), and disease activity in rheumatoid arthritis (RA); and to determine the association between cytokine concentrations and ADA concentrations. METHODS: A cross-sectional study of people with RA receiving ADA for at least 4 weeks was undertaken. Disease activity was assessed by the Disease Activity Score in 28 joints (DAS28), with responders defined as DAS28 ≤ 3.2. Serum and plasma were obtained for ADA concentrations and ADAb, and a panel of cytokines were obtained for a subgroup. ADA concentrations were compared between demographic and clinical subgroups using ANOVA. The independent associations between clinical and demographic features were analyzed using a general linear model. Variables significantly associated with ADA concentrations from the univariate analyses were entered into multivariate analyses. RESULTS: Of the 156 participants, 69.2% were female and the mean age was 57.4 (SD 12.7) years. Multivariate analysis revealed that higher C-reactive protein (P < 0.001) and higher weight (P < 0.004) were independently associated with lower ADA concentrations. ADA concentrations were higher in those with DAS28 ≤ 3.2 compared to those with DAS28 > 3.2 (median 10.8 [IQR 6.4-20.8] mg/L vs 7.1 [IQR 1.5-12.6] mg/L, P < 0.001). There was a significant negative correlation between interleukin 6 (IL-6) and ADA concentrations (r = -0.04, P < 0.01). CONCLUSION: ADA concentration correlates negatively with markers of inflammatory disease activity in RA, including IL-6. ADA concentration in the range 5 to 7 mg/L over the dose interval are associated with better disease control.

Colchicine: the good, the bad, the ugly and how to minimize the risks.

Colchicine has an important role in managing various conditions, including gout, familial Mediterranean fever, amyloidosis, Behçet's syndrome, recurrent pericarditis and calcium pyrophosphate deposition disease. The adverse effect profile of colchicine is well understood. However, due to its narrow therapeutic index, colchicine has been associated with overdose and fatalities. When ingested in toxic amounts, the mainstay of management is supportive care. Strategies to minimize the risk of colchicine poisoning can focus on three broad causes: unauthorized access, intentional overdose and inappropriate dosing. Culturally safe and appropriate education about storage and appropriate use of colchicine is essential to minimize the risk of overdose.

Is colchicine prophylaxis required with start-low go-slow allopurinol dose escalation in gout? A non-inferiority randomised double-blind placebo-controlled trial.

OBJECTIVES: To determine whether placebo is non-inferior to low-dose colchicine for reducing gout flares during the first 6 months of allopurinol using the 'start-low go-slow' dose approach. METHODS: A 12-month double-blind, placebo-controlled non-inferiority trial was undertaken. Adults with at least one gout flare in the preceding 6 months, fulfilling the American College of Rheumatology (ACR) recommendations for starting urate-lowering therapy and serum urate ≥0.36 mmol/L were recruited. Participants were randomised 1:1 to colchicine 0.5 mg daily or placebo for the first 6 months. All participants commenced allopurinol, increasing monthly to achieve target urate <0.36 mmol/L. The primary efficacy outcome was the mean number of gout flares/month between 0 and 6 months, with a prespecified non-inferiority margin of 0.12 gout flares/month. The primary safety outcome was adverse events over the first 6 months. RESULTS: Two hundred participants were randomised. The mean (95% CI) number of gout flares/month between baseline and month 6 was 0.61 (0.47 to 0.74) in the placebo group compared with 0.35 (0.22 to 0.49) in the colchicine group, mean difference 0.25 (0.07 to 0.44), non-inferiority p=0.92. There was no difference in the mean number of gout flares/month between randomised groups over the 12-month period (p=0.68). There were 11 serious adverse events in 7 participants receiving colchicine and 3 in 2 receiving placebo. CONCLUSIONS: Placebo is not non-inferior to colchicine in prevention of gout flares in the first 6 months of starting allopurinol using the 'start-low go-slow' strategy. After stopping colchicine, gout flares rise with no difference in the mean number of gout flares/month between groups over a 12-month period. TRIAL REGISTRATION NUMBER: ACTRN 12618001179224.

The 2023 ACR/EULAR Classification Criteria for Calcium Pyrophosphate Deposition Disease.

OBJECTIVE: Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease. METHODS: Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort. RESULTS: Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score >56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers). CONCLUSION: The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.

The 2023 ACR/EULAR classification criteria for calcium pyrophosphate deposition disease.

OBJECTIVE: Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease. METHODS: Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort. RESULTS: Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score>56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers). CONCLUSION: The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.

Activated CD90/Thy-1 fibroblasts co-express the Δ133p53ß isoform and are associated with highly inflamed rheumatoid arthritis.

BACKGROUND: The p53 isoform Δ133p53ß is known to be associated with cancers driven by inflammation. Many of the features associated with the development of inflammation in rheumatoid arthritis (RA) parallel those evident in cancer progression. However, the role of this isoform in RA has not yet been explored. The aim of this study was to determine whether Δ133p53ß is driving aggressive disease in RA. METHODS: Using RA patient synovia, we carried out RT-qPCR and RNAScope-ISH to determine both protein and mRNA levels of Δ133p53 and p53. We also used IHC to determine the location and type of cells with elevated levels of Δ133p53ß. Plasma cytokines were also measured using a BioPlex cytokine panel and data analysed by the Milliplex Analyst software. RESULTS: Elevated levels of pro-inflammatory plasma cytokines were associated with synovia from RA patients displaying extensive tissue inflammation, increased immune cell infiltration and the highest levels of Δ133TP53 and TP53ß mRNA. Located in perivascular regions of synovial sub-lining and surrounding ectopic lymphoid structures (ELS) were a subset of cells with high levels of CD90, a marker of 'activated fibroblasts' together with elevated levels of Δ133p53ß. CONCLUSIONS: Induction of Δ133p53ß in CD90+ synovial fibroblasts leads to an increase in cytokine and chemokine expression and the recruitment of proinflammatory cells into the synovial joint, creating a persistently inflamed environment. Our results show that dysregulated expression of Δ133p53ß could represent one of the early triggers in the immunopathogenesis of RA and actively perpetuates chronic synovial inflammation. Therefore, Δ133p53ß could be used as a biomarker to identify RA patients more likely to develop aggressive disease who might benefit from targeted therapy to cytokines such as IL-6.

Clinical phenotype and complications of large vessel giant cell arteritis: A systematic review and meta-analysis.

BACKGROUND: Giant Cell Arteritis (GCA) is a heterogenous systemic granulomatous vasculitis involving the aorta and any of its major tributaries. Despite increased awareness of large vessel (LV) involvement, studies reporting incidence, clinical characteristics and complications of large-vessel GCA (LV-GCA) show conflicting results due to inconsistent disease definitions, differences in study methodologies and the broad spectrum of clinical presentations. The aim of this systematic literature review was to better define LV-GCA based on the available literature and identify distinguishing characteristics that may differentiate LV-GCA patients from those with limited cranial disease. METHODS: Published studies indexed in MEDLINE and EMBASE were searched from database inception to 7th May 2021. Studies were included if they presented cohort or cross-sectional data on a minimum of 25 patients with LV-GCA. Control groups were included if data was available on patients with limited cranial GCA (C-GCA). Data was quantitatively synthesised with application of a random effects meta-regression model, using Stata. RESULTS: The search yielded 3488 studies, of which 46 were included. Diagnostic criteria for LV-GCA differed between papers, but was typically dependent on imaging or histopathology. Patients with LV-GCA were generally younger at diagnosis compared to C-GCA patients (mean age difference -4.53 years), had longer delay to diagnosis (mean difference 3.03 months) and lower rates of positive temporal artery biopsy (OR: 0.52 [95% CI: 0.3, 0.91]). Fewer LV-GCA patients presented with cranial manifestations and only 53% met the 1990 ACR Classification Criteria for GCA. Vasculitis was detected most commonly in the thoracic aorta, followed by the subclavian, brachiocephalic trunk and axillary arteries. The mean cumulative prednisolone dose at 12-months was 6056.5mg for LV-GCA patients, relapse rates were similar between LV- and C-GCA patients, and 12% of deaths in LV-GCA patients could be directly attributed to an LV complication. CONCLUSION: Patients with LV-GCA have distinct disease features when compared to C-GCA, and this has implications on diagnosis, treatment strategies and surveillance of long-term sequalae.

Changes in Tophus Composition During Urate-Lowering Therapy: A Dual-Energy Computed Tomography Study.

OBJECTIVE: The gouty tophus is an organized structure composed of monosodium urate (MSU) crystals and chronic inflammatory soft tissue. This dual-energy computed tomography (DECT) study aimed to determine whether the composition of the tophus changes during urate-lowering therapy. METHODS: Serial DECT scans from 32 people with gout were obtained over 2 years of allopurinol therapy, dose-escalated to serum urate of <0.36 mmoles/liter. Up to 5 index tophi were selected for each patient, with 103 separate tophi included in the analysis. Using manual outlining methods of conventional CT and DECT scans, the same index tophi were serially measured for total tophus volume and urate volume. For each tophus, the soft tissue volume was then calculated by subtracting the urate volume from the total tophus volume. RESULTS: The mean ± SD serum urate reduced from 0.43 ± 0.03 mmoles/liter at baseline to 0.31 ± 0.02 mmoles/liter at year 2. The mean ± SD total tophus volume reduced over the 2-year period from 5.17 ± 5.55 cm3 to 2.61 ± 2.73 cm3 (P < 0.0001). Greater reductions in tophus urate volumes than tophus soft tissue volumes were observed; the tophus urate volume decreased by 70.6%, and tophus soft tissue volume decreased by 37.8% (P < 0.0001). The mean tophus urate:soft tissue ratio reduced from 0.15 at baseline to 0.05 at year 2 (P < 0.001). CONCLUSION: The composition of the tophus is dynamic and changes during urate-lowering therapy for gout management. The soft tissue component of the tophus is slower to respond and may persist without measurable MSU crystal deposition.

The impact of genetic variability in urate transporters on oxypurinol pharmacokinetics.

The genetic determinants of the allopurinol dose-concentration relationship have not been extensively studied. We aimed to clarify what factors, including genetic variation in urate transporters, influence oxypurinol pharmacokinetics (PKs). A population PK model for oxypurinol was developed with NONMEM (version 7.3). The influence of urate transporter genetic variants for ABCG2 (rs2231142 and rs10011796), SLC2A9/GLUT9 (rs11942223), SLC17A1/NPT1 (rs1183201), SLC22A12/URAT1 (rs3825018), SLC22A11/OAT4 (rs17300741), and ABCC4/MRP4 (rs4148500), as well as other participant factors on oxypurinol PKs was assessed. Data from 325 people with gout were available. The presence of the T allele for ABCG2 (rs2231142) and SLC17A1/NPT1 (rs1183201) was associated with a 24% and 22% increase in oxypurinol clearance, respectively, in univariate analysis. This effect was not significant in the multivariate analysis. In the final model, oxypurinol PKs were predicted by creatinine clearance, diuretic use, ethnicity, and body weight. We have found that genetic variability in the transporters examined does not appear to influence oxypurinol PKs.

An allopurinol adherence tool using plasma oxypurinol concentrations.

AIMS: This study aimed to develop and evaluate an allopurinol adherence tool based on steady-state oxypurinol plasma concentrations, allopurinol's active metabolite. METHODS: Plasma oxypurinol concentrations were simulated stochastically from an oxypurinol pharmacokinetic model for allopurinol doses of 100-800 mg daily, accounting for differences in renal function, diuretic use and ethnicity. For each scenario, the 20th percentile for peak and trough concentrations defined the adherence threshold, below which imperfect adherence was assumed. Predictive performance was evaluated using both simulated low adherence and against data from 146 individuals with paired oxypurinol plasma concentrations and adherence measures. Sensitivity and specificity (S&S), negative and positive predictive values (NPV, PPV) and receiver operating characteristic (ROC) area under the curve (AUC) were determined. The predictive performance of the tool was evaluated using adherence data from an external study (CKD-FIX). RESULTS: The allopurinol adherence tool produced S&S values for trough thresholds of 89-98% and 76-84%, respectively, and 90%-98% and 76-83% for peak thresholds. PPV and NPV were 79-84% and 88-94%, respectively, for trough and 80-85% and 89-98%, respectively, for peak concentrations. The ROC AUC values ranged from 0.84 to 0.88 and from 0.86 to 0.89 for trough and peak concentrations, respectively. S&S values for the external evaluation were found to be 75.8% and 86.5%, respectively, producing an ROC AUC of 0.8113. CONCLUSION: A tool to identify people with gout who require additional support to maintain adherence using plasma oxypurinol concentrations was developed and evaluated. The predictive performance of the tool is suitable for adherence screening in clinical trials and may have utility in some clinical practice settings.

Multivariate analysis of a missense variant in CREBRF reveals associations with measures of adiposity in people of Polynesian ancestries.

The minor allele of rs373863828, a missense variant in CREB3 Regulatory Factor, is associated with several cardiometabolic phenotypes in Polynesian peoples. To better understand the variant, we tested the association of rs373863828 with a panel of correlated phenotypes (body mass index [BMI], weight, height, HDL cholesterol, triglycerides, and total cholesterol) using multivariate Bayesian association and network analyses in a Samoa cohort (n = 1632), Aotearoa New Zealand cohort (n = 1419), and combined cohort (n = 2976). An expanded set of phenotypes (adding estimated fat and fat-free mass, abdominal circumference, hip circumference, and abdominal-hip ratio) was tested in the Samoa cohort (n = 1496). In the Samoa cohort, we observed significant associations (log10 Bayes Factor [BF] ≥ 5.0) between rs373863828 and the overall phenotype panel (8.81), weight (8.30), and BMI (6.42). In the Aotearoa New Zealand cohort, we observed suggestive associations (1.5 < log10 BF < 5) between rs373863828 and the overall phenotype panel (4.60), weight (3.27), and BMI (1.80). In the combined cohort, we observed concordant signals with larger log10 BFs. In the Samoa-specific expanded phenotype analyses, we also observed significant associations between rs373863828 and fat mass (5.65), abdominal circumference (5.34), and hip circumference (5.09). Bayesian networks provided evidence for a direct association of rs373863828 with weight and indirect associations with height and BMI.

Giant cell arteritis: A population-based retrospective cohort study exploring incidence and clinical presentation in Canterbury, Aotearoa New Zealand.

Background/aim: To determine the epidemiology and clinical features of giant cell arteritis (GCA) in Canterbury, Aotearoa New Zealand, with a particular focus on extra-cranial large vessel disease. Methods: Patients with GCA were identified from radiology and pathology reports, outpatient letters and inpatient hospital admissions in the Canterbury New Zealand from 1 June 2011 to 31 May 2016. Data was collected retrospectively based on review of electronic medical records. Results: There were 142 cases of GCA identified. 65.5% of cases were female with a mean age of 74.2 years. The estimated population incidence for biopsy-proven GCA was 10.5 per 100,000 people over the age of 50 and incidence peaked between 80 and 84 years of age. 10/142 (7%) people were diagnosed with large vessel GCA, often presenting with non-specific symptoms and evidence of vascular insufficiency including limb claudication, vascular bruits, blood pressure and pulse discrepancy, or cerebrovascular accident. Those with limited cranial GCA were more likely to present with the cardinal clinical features of headache and jaw claudication. Patients across the two groups were treated similarly, but those with large vessel disease had greater long-term steroid burden. Rates of aortic complication were low across both groups, although available follow-up data was limited. Conclusion: This study is the first of its kind to describe the clinical characteristics of large vessel GCA in a New Zealand cohort. Despite small case numbers, two distinct subsets of disease were recognized, differentiating patients with cranial and large vessel disease. Our results suggest that utilization of an alternative diagnostic and therapeutic approach may be needed to manage patients with large vessel disease.

Long-Term Follow-up of a Randomized Controlled Trial of Allopurinol Dose Escalation to Achieve Target Serum Urate in People With Gout.

OBJECTIVE: To 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. METHODS: For 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. RESULTS: Over 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. CONCLUSION: Most 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.

Effects of elevated serum urate on cardiometabolic and kidney function markers in a randomised clinical trial of inosine supplementation.

In observational studies, serum urate positively associates with cardiometabolic and kidney diseases. We analyzed data from a randomised placebo-controlled trial to determine whether moderate hyperuricemia induced by inosine affects cardiometabolic and kidney function markers. One hundred and twenty post-menopausal women were recruited into a 6-month randomised, double-blind, placebo-controlled trial of inosine for bone health. Change from baseline in the following pre-specified endpoints was analyzed: body mass index; blood pressure; lipid profile; C-reactive protein; fasting glucose; insulin; HbA1c; serum creatinine; and estimated glomerular filtration rate (eGFR). Despite increases in serum urate levels (+ 0.17 mmol/L at week 6, P < 0.0001), no significant between-group differences were observed in cardiometabolic markers, with the exception of lower fasting glucose concentrations with inosine at week 19. In the inosine group, change in serum urate correlated with change in serum creatinine (r = 0.41, P = 0.0012). However, there was no between-group difference in serum creatinine values. Over the entire study period, there was no significant difference in eGFR (ANCOVA P = 0.13). Reduction in eGFR was greater in the inosine group at Week 13 (mean difference - 4.6 mL/min/1.73 m2, false detection rate P = 0.025), with no between-group difference in eGFR at other time points. These data indicate that increased serum urate does not negatively influence body mass index, blood pressure, lipid profile, or glycaemic control. Serum urate changes associated with inosine intake correlate with changes in serum creatinine, but this does not lead to clinically important reduction in kidney function over 6 months.Clinical trial registration number: Australia and New Zealand Clinical Trials Registry (ACTRN12617000940370), registered 30/06/2017.

A Polynesian-specific copy number variant encompassing the MICA gene associates with gout.

Gout is of particularly high prevalence in the Maori and Pacific (Polynesian) populations of Aotearoa New Zealand (NZ). Here, we investigated the contribution of common population-specific copy number variation (CNV) to gout in the Aotearoa NZ Polynesian population. Microarray-generated genome-wide genotype data from Aotearoa NZ Polynesian individuals with (n = 1196) and without (n = 1249) gout were analyzed. Comparator population groups were 552 individuals of European ancestry and 1962 of Han Chinese ancestry. Levels of circulating major histocompatibility complex (MHC) class I polypeptide-related sequence A (MICA) were measured by enzyme-linked immunosorbent assay. Fifty-four CNV regions (CNVRs) appearing in at least 10 individuals were detected, of which seven common (>2%) CNVRs were specific to or amplified in Polynesian people. A burden test of these seven revealed associations of insertion/deletion with gout (odds ratio (OR) 95% confidence interval [CI] = 1.80 [1.01; 3.22], P = 0.046). Individually testing of the seven CNVRs for association with gout revealed nominal association of CNVR1 with gout in Western Polynesian (Chr6: 31.36-31.45 Mb, OR = 1.72 [1.03; 2.92], P = 0.04), CNVR6 in the meta-analyzed Polynesian sample sets (Chr1: 196.75-196.92 Mb, OR = 1.86 [1.16; 3.00], P = 0.01) and CNVR9 in Western Polynesian (Chr1: 189.35-189.54 Mb, OR = 2.75 [1.15; 7.13], P = 0.03). Analysis of European gout genetic association data demonstrated a signal of association at the CNVR1 locus that was an expression quantitative trait locus for MICA. The most common CNVR (CNVR1) includes deletion of the MICA gene, encoding an immunomodulatory protein. Expression of MICA was reduced in the serum of individuals with the deletion. In summary, we provide evidence for the association of CNVR1 containing MICA with gout in Polynesian people, implicating class I MHC-mediated antigen presentation in gout.

Plasma interleukin-23 and circulating IL-17A+IFNγ+ ex-Th17 cells predict opposing outcomes of anti-TNF therapy in rheumatoid arthritis.

OBJECTIVES: TNF-α inhibitors are widely used in rheumatoid arthritis (RA) with varying success. Response to TNF-α inhibition may reflect the evolution of rheumatoid inflammation through fluctuating stages of TNF-α dependence. Our aim was to assess plasma concentrations of Th-17-related cytokines and the presence of circulating effector T-cells to identify predictors of response to TNF-α inhibitors. METHODS: Ninety-three people with RA were seen prior to and 4-6 months after commencing etanercept or adalimumab. Plasma concentrations of Th17-related cytokines, circulating effector T-cells, their production of relevant transcription factors and intracellular cytokines were measured at baseline. EULAR response criteria were used to define poor (ΔDAS28 ≤ 1.2 and/or DAS28 > 3.2) and good (ΔDAS28 > 1.2 and DAS28 ≤ 3.2) responders. Multivariate logistic regression was used to identify predictors of response. RESULTS: Participants with plasma IL-23 present at baseline were more likely to be poor responders [15/20 (75%) of IL-23+ versus 36/73 (49.3%) of IL-23-; p = 0.041]. While frequencies of Th1, Th17, ex-Th17 and Treg cell populations were similar between good and poor responders to anti-TNF therapy, IL-17A+IFNγ+ ex-Th17 cells were more prevalent in good responders (0.83% of ex-TH17 cells) compared to poor responders (0.24% of ex-Th17 cells), p = 0.023. Both plasma IL-23 cytokine status (OR = 0.17 (95% CI 0.04-0.73)) and IL-17A+IFNγ+ ex-Th17 cell frequency (OR = 1.64 (95% CI 1.06 to 2.54)) were independently associated with a good response to anti-TNF therapy. Receiver operator characteristic (ROC) analysis, including both parameters, demonstrated an area under the ROC curve (AUC) of 0.70 (95% CI 0.60-0.82; p = 0.001). CONCLUSIONS: Plasma IL-23 and circulating IL-17A+IFNγ+ ex-Th17 cells are independently associated with response to anti-TNF therapy. In combination, plasma IL-23 and circulating IL-17A+IFNγ+ ex-Th17 cells provide additive value to the prediction of response to anti-TNF therapy in RA.