Systemic inflammatory cytokine profiles in patients with gout during flare, intercritical and treat-to-target phases: TNFSF14 as new biomarker.

INTRODUCTION: Untreated gout is characterised by monosodium urate (MSU) crystal accumulation responsible for recurrent flares that are commonly separated by asymptomatic phases. Both phases are inflammatory conditions of variable intensity. Gout flares are self-limited inflammatory reactions involving multiple mediators. This study aimed to characterise the inflammatory profiles of gout at different phases. METHODS: Using the Olink targeted proteomics, levels of 92 inflammation-related proteins were measured in plasma samples of a prospective gout population (GOUTROS), collected at gout flare (T1), the intercritical phase (T2) and after reaching the target serum urate level under urate-lowering therapy (T3). Results were validated in an independent cohort (OLT1177-05) with plasmas collected at T1 and T2. Ex vivo and in vitro experiments were performed to assess the inflammatory properties of new biomarkers. RESULTS: In total, 21 inflammatory new biomarkers were differentially expressed during the three time-points of gout disease. The levels of four of these proteins (interleukin 6 (IL-6), colony-stimulating factor 1, vascular endothelial growth factor A and tumour necrosis factor superfamily 14 (TNFSF14)) were increased during gout flare in an independent cohort. IL-6 and TNFSF14 had the highest fold change in expression during T1 versus T2 or T3. TNFSF14 was produced at the inflamed joint and enhanced the inflammatory response induced by lipopolysaccharide and MSU crystal stimulation. Conversely, TNFSF14 blockade reduced the inflammatory response. Additionally, single nucleotide polymorphisms of TNFSF14 affected the ability of myeloid cells to produce inflammatory cytokines. CONCLUSION: Gout flare involves multiple inflammatory mediators that may be used as potential therapeutic targets.

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.

Evaluating the safety and short-term equivalence of colchicine versus prednisone in older patients with acute calcium pyrophosphate crystal arthritis (COLCHICORT): an open-label, multicentre, randomised trial.

BACKGROUND: Acute calcium pyrophosphate crystal arthritis causes intense joint pain mainly affecting older people. Because guidance and evidence remain scarce, management of this disease relies on expert opinion. We therefore aimed to compare the safety and short-term equivalence of low-dose colchicine with oral prednisone in older patients with acute calcium pyrophosphate crystal arthritis. METHODS: We did an open-label, multicentre, randomised, trial (COLCHICORT) at six hospitals in Paris and northern France. We enrolled patients who were admitted to hospital who were 65 years or older and who presented with acute calcium pyrophosphate crystal arthritis with a symptom duration of less than 36 h. Diagnosis of calcium pyrophosphate crystal arthritis was made by the identification of calcium pyrophosphate crystals on synovial fluid analysis or typical clinical presentation (onset of joint pain and swelling). Key exclusion criteria included absence of calcium pyrophosphate crystals on synovial fluid analysis or a history of gout. Participants were randomly allocated (1:1), using a centralised electronic treatment group allocation module, to receive either colchicine 1·5 mg on day 1 and 1 mg on day 2 (ie, the colchicine group) or oral prednisone 30 mg on days 1 and 2 (ie, the prednisone group). The primary outcome was change in joint pain (measured by visual analogue scale [VAS] from 0 mm to 100 mm) at 24 h. Equivalence was determined whether the 95% CI of the between-group difference at 24 h was within the -13 mm to +13 mm margin in the per-protocol analysis. Adverse events were recorded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). This trial is completed and is registered with ClinicalTrials.gov, NCT03128905. FINDINGS: Between Feb 5, 2018, and May 7, 2022, 111 patients who were admitted to hospital were randomly assigned (57 [51%] to the colchicine group and 54 [49%] to the prednisone group). 95 (86%) of 111 patients were included in the per-protocol analysis (49 [52%] in the colchicine group and 46 [48%] in the prednisone group). The median age was 88·0 years (IQR 82·0-91·0) and 69 (73%) of 95 participants were women and 26 (27%) were men. Acute calcium pyrophosphate crystal arthritis affected mainly the knee in 46 (48%) of 95 participants, the wrist in 19 (20%), and the ankle in 12 (13%). Pain VAS at baseline was 68 mm (SD 17). At 24 h, change in pain VAS was -36 mm (SD 32) in the colchicine group and -38 mm (SD 23) in the prednisone group. The between-group difference in change in pain VAS at 24 h was -1 mm (95% CI -12 to 10), showing equivalence between the two drugs. In the colchicine group, 12 (22%) of 55 patients had diarrhoea, one (2%) had hypertension, and none had hyperglycaemia. In the prednisone group, three (6%) of 54 had diarrhoea, six (11%) had hypertension, and three (6%) had hyperglycaemia. No deaths occurred in the colchicine group; two deaths occurred in the prednisone group, which were deemed unrelated to prednisone (one due to infectious valvular endocarditis leading to heart failure, and one due to a stroke). INTERPRETATION: Colchicine and prednisone exhibit equivalent short-term efficacy for the treatment of acute calcium pyrophosphate crystal arthritis, with different safety profiles in the older population. FUNDING: French Inter-regional Hospital Program of Clinical Research.

Risk factors for cutaneous reactions to allopurinol in Kinh Vietnamese: results from a case-control study.

OBJECTIVE: The aim of this study was to investigate risk factors for cutaneous adverse reactions (CARs) in Kinh Vietnamese. METHODS: All patients were prospectively recruited in Ho Chi Minh City. Presence of the HLA-B*58:01 allele was determined by real-time PCR-sequence-specific amplification by using the PG5801 Detection Kit (Pharmigene, Taipei). Patients with severe (SCARs) and mild (MCARs) CARs and controls were compared for differences in features prospectively collected, and odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. RESULTS: On comparing 32 patients with SCARs and 395 tolerant controls, we identified eight strong risk factors: increased age (OR 15.1 [95% CI 5.8-40.1], P < 0.0001), female sex (OR 333 [40-43,453], P < 0.0001), allopurinol for asymptomatic hyperuricemia (OR 955 [120-125,847], P < 0.0001), allopurinol starting dose > 150 mg (OR 316 [101-122], P < 0.0001), diuretics intake (OR 304 [35-40,018], P < 0.0001), eGFR < 60 ml/min/1.73 m2 (OR 100 [32-353], P < 0.0001), history of allopurinol-induced skin reaction (OR 78 [6-10,808], P = 0.004), and HLA-B*58:01 carriage (OR 147 [45-746], P < 0.0001). HLA-B*58:01 allele frequency in controls was 7.3%. For MCARs (n = 74), risk factors were eGFR < 60 ml/min/1.73 m2 (OR 4.9 [1.61-14.6], P = 0.006), history of allopurinol-induced skin reaction (OR 27 [2-3777], P = 0.01), and asymptomatic hyperuricemia (OR 27 [2-3777], P = 0.01). CONCLUSION: This study confirmed 8 risk factors, including HLA-B*58:01, for SCARs and identified 3 risk factors for MCARs in Kinh Vietnamese. HLA-B*58:01 genotyping could guide the indication for allopurinol in Kinh Vietnamese patients with gout.

Gout and pseudo-gout-related crystals promote GLUT1-mediated glycolysis that governs NLRP3 and interleukin-1ß activation on macrophages.

OBJECTIVE: Macrophage activation by monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals mediates an interleukin (IL)-1ß-dependent inflammation during gout and pseudo-gout flare, respectively. Since metabolic reprogramming of macrophages goes along with inflammatory responses dependently on stimuli and tissue environment, we aimed to decipher the role of glycolysis and oxidative phosphorylation in the IL-1ß-induced microcrystal response. METHODS: Briefly, an in vitro study (metabolomics and real-time extracellular flux analysis) on MSU and CPP crystal-stimulated macrophages was performed to demonstrate the metabolic phenotype of macrophages. Then, the role of aerobic glycolysis in IL-1ß production was evaluated, as well in vitro as in vivo using 18F-fluorodeoxyglucose positron emission tomography imaging and glucose uptake assay, and molecular approach of glucose transporter 1 (GLUT1) inhibition. RESULTS: We observed that MSU and CPP crystals led to a metabolic rewiring toward the aerobic glycolysis pathway explained by an increase in GLUT1 plasma membrane expression and glucose uptake on macrophages. Also, neutrophils isolated from human synovial fluid during gout flare expressed GLUT1 at their plasma membrane more frequently than neutrophils isolated from bloodstream. Both glucose deprivation and treatment with either 2-deoxyglucose or GLUT1 inhibitor suppressed crystal-induced NLRP3 activation and IL-1ß production, and microcrystal inflammation in vivo. CONCLUSION: In conclusion, we demonstrated that GLUT1-mediated glucose uptake is instrumental during the inflammatory IL-1ß response induced by MSU and CPP crystals. These findings open new therapeutic paths to modulate crystal-related inflammation.

2020 recommendations from the French Society of Rheumatology for the management of gout: Urate-lowering therapy.

OBJECTIVE: To develop French Society of Rheumatology-endorsed recommendations for the management of urate-lowering therapy (ULT). METHODS: Evidence-based recommendations were developed by 9 rheumatologists (academic or community-based), 3 general practitioners, 1 cardiologist, 1 nephrologist and 1 patient, using a systematic literature search, one physical meeting to draft recommendations and two Delphi rounds to finalize them. RESULTS: A set of 3 overarching principles and 5 recommendations was elaborated. The overarching principles emphasize the importance of patient education, especially the need for explaining the objective of lowering serum urate (SU) level to obtain crystal dissolution, clinical symptoms disappearance and avoidance of complications. ULT is indicated as soon as the diagnosis of gout is established. SU level must be decreased below 300µmol/l (50mg/l) in all gout patients or at least below 360µmol/l (60ml/l) when the 300µmol/l target cannot be reached, and must be maintained at these targets and monitored life-long. The choice of the ULT primarily relies on renal function: in patients whose estimated glomerular filtration rate (eGFR) is above 60ml/min/1.73m2, first-line ULT is allopurinol; in those with eGFR between 30 and 60ml/min/1.73m2, allopurinol use must be cautious and febuxostat can be considered as an alternative; and in those whose eGFR is below 30ml/min/1.73m2, allopurinol must be avoided and febuxostat should be preferred. Prophylaxis of ULT-induced gout flares involves progressive increase of ULT dosage and low-dose colchicine for at least 6 months. Cardiovascular risk factors and diseases, the metabolic syndrome and chronic kidney disease must be screened and managed. CONCLUSION: These recommendations aim to provide simple and clear guidance for the management of ULT in France.

Comparative effectiveness of rituximab, abatacept, and tocilizumab in adults with rheumatoid arthritis and inadequate response to TNF inhibitors: prospective cohort study.

OBJECTIVE: To compare the effectiveness and safety of three non-tumour necrosis factor (TNF) α inhibitors (rituximab, abatacept, and tocilizumab) in the treatment of rheumatoid arthritis. DESIGN: Population based prospective study. SETTING: 53 university and 54 non-university clinical centres in France. PARTICIPANTS: 3162 adults (>18 years) with rheumatoid arthritis according to 1987 American College of Rheumatology criteria, enrolled in one of the three French Society of Rheumatology registries; who had no severe cardiovascular disease, active or severe infections, or severe immunodeficiency, with follow-up of at least 24 months. INTERVENTION: Initiation of intravenous rituximab, abatacept, or tocilizumab for rheumatoid arthritis. MAIN OUTCOME MEASURE: The primary outcome was drug retention without failure at 24 months. Failure was defined as all cause death; discontinuation of rituximab, abatacept, or tocilizumab; initiation of a new biologic or a combination of conventional disease modifying antirheumatic drugs; or increase in corticosteroid dose >10 mg/d compared with baseline at two successive visits. Because of non-proportional hazards, treatment effects are presented as life expectancy difference without failure (LEDwf), which measures the difference between average duration of survival without failure. RESULTS: Average durations of survival without failure were 19.8 months for rituximab, 15.6 months for abatacept, and 19.1 months for tocilizumab. Average durations were greater with rituximab (LEDwf 4.1, 95% confidence interval 3.1 to 5.2) and tocilizumab (3.5, 2.1 to 5.0) than with abatacept, and uncertainty about tocilizumab compared with rituximab was substantial (-0.7, -1.9 to 0.5). No evidence was found of difference between treatments for mean duration of survival without death, presence of cancer or serious infections, or major adverse cardiovascular events. CONCLUSION: Among adults with refractory rheumatoid arthritis followed-up in routine practice, rituximab and tocilizumab were associated with greater improvements in outcomes at two years compared with abatacept.

Tendon thickening in dialysis-related joint arthritis is due to amyloid deposits at the surface of the tendon.

OBJECTIVES: Beta-2-microglobulin (ß2M) dialysis-related amyloidosis (DRA), a disabiliting joint disease, has been initially reported in patients under long-term dialysis. The incidence and prevalence has significantly decreased with the improvement in dialysis techniques. Here, we attempted to clarify the clinical and MRI features to improve the diagnosis. METHODS: We retrospectively reviewed the files of 19 patients under dialysis treatment referred for suspicion of ß2M DRA. The diagnosis was based on MRI criteria (low signal intensity on both T1- and T2-weighted MR sequences). MRI analysis included a scoring of the several joint lesions. Scores were quantified according to a severity scale (0 to 3). RESULTS: Patients had a mean age of 66.0 ± 10.5 years and mean dialysis duration of 23.7 ± 10.5 years. DRA affected mainly large joints (shoulder in 73.7%, hip in 47.3%) and spine (36.8%). MRI images for 8 shoulders, 8 hips, and 3 spines were analysed. Amyloid synovitis was present in all cases, with high mean scores in the three sites. In all joints, the most common lesions were tendon thickening (68.4%) and bone erosions (68.4%). The mean tendon thickening score was high, particularly at the shoulders and also at the spine. Bone erosions were most frequent in the shoulder and pelvis. CONCLUSION: In patients under long-term dialysis, ß2M DRA involves large joints but also the spine. Special awareness should be drawn by the thickening of the tendon. MRI is required to characterize the pattern of the lesions and to achieve the diagnosis.

Impact of gender on the response and tolerance to abatacept in patients with rheumatoid arthritis: results from the 'ORA' registry.

OBJECTIVE: The impact of gender on the response and tolerance to abatacept was assessed in a large prospective cohort during 2 years of follow-up. METHODS: From the 1017 patients included in the Orencia and Rheumatoid Arthritis registry, disease activity was assessed at baseline, 6, 12 and 24 months. The relationship between the European League Against Rheumatism (EULAR) response, Disease Activity Score 28 (DAS28) remission, rate of adverse events and gender was explored in multivariate analysis. RESULTS: 990 patients, 79.3%female, with at least one follow-up visit were analysed. At baseline, women had longer disease duration, higher disease activity and more often received antitumour necrosis factor (TNF) drugs. The remission was not different between men and women during the follow-up after adjustment on age, disease duration and activity, rheumatoid factor and anti-cyclic citrullinated pyeptide (CCP) positivity, and current disease-modifying antirheumatic drugs (DMARDs), previous TNF blockers and corticosteroids use. The proportion of men and women achieving EULAR good-or-moderate response at any endpoints was similar (52.4% vs 55.5%), as well as time to achieving EULAR response (5.4±4.9 vs 5.6±5.2 months). Moderate EULAR response was more frequent in women at 6 months (OR=1.80, p=0.02) but was no longer significant at 12 or 24 months. During the follow-up, the DAS28, the tender joint count score and the patient global assessment remained higher in women (p=0.001, 0.04 and 0.06, respectively). Drug retention and safety were comparable. CONCLUSION: In this large daily practice cohort of established rheumatoid arthritis treated with abatacept, women achieved similar remission and EULAR response than men despite higher disease activity and tender joint count during the treatment course.

Intravenous sodium thiosulfate for treating tumoral calcinosis associated with systemic disorders: Report of four cases.

Intravenous sodium thiosulfate (ivSTS) is a promising new therapeutic option for calciphylaxis related to end-stage renal disease. However, its effect on tumoral calcinosis (TC) complicating autoimmune connective-tissue diseases has been scarcely described. We report here 4 cases (3 adults and 1 child) of TC treated with ivSTS. TC was secondary to CREST syndrome, dermatomyositis (1 adult and 1 child) and systemic erythematous lupus and involved multiple sites in all cases. In all 4 patients, TC was responsible for joint pain, reduced mobility, inflammatory flares and skin fistulations. One patient experienced difficulty sitting due to the pain induced by calcified lesions on the buttock; another patient had major disability, moved only with wheelchair and was under opioid treatment for pain. For all patients, treatment with several medications before STS was unsuccessful. The 3 adults received at least 6 cycles of ivSTS (20g/d, 5 days/month) and the child received a daily infusion of 17g STS during 1 month then a 9-g/d infusion during 3 months. Two adults and the child showed clinical improvement with STS treatment and the third adult felt disappointed and stopped STS treatment after 6 months. The child also stopped STS after 6 months due to vomiting. In one patient, an intensive regimen of ivSTS (20g every 2 days) controlled recurrent flares and fistulations. Unfortunately, TC remained unchanged. Further studies are needed to decipher how STS modulates ectopic calcification, the optimal regimen and posology.

Lesinurad in combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study).

OBJECTIVES: Determine the efficacy and safety of daily lesinurad (200 or 400 mg orally) added to allopurinol in patients with serum uric acid (sUA) above target in a 12-month, randomised, phase III trial. METHODS: Patients on allopurinol ≥300 mg (≥200 mg in moderate renal impairment) had sUA level of ≥6.5 mg/dL (≥387 µmol/L) at screening and two or more gout flares in the prior year. Primary end point was the proportion of patients achieving sUA level of <6.0 mg/dL (<357 µmol/L) (month 6). Key secondary end points were mean gout flare rate requiring treatment (months 7 through 12) and proportions of patients with complete resolution of one or more target tophi (month 12). Safety assessments included adverse events and laboratory data. RESULTS: Patients (n=610) were predominantly male, with mean (±SD) age 51.2±10.90 years, gout duration 11.5±9.26 years and baseline sUA of 6.9±1.2 mg/dL (410±71 µmol/L). Lesinurad at 200 and 400 mg doses, added to allopurinol, significantly increased proportions of patients achieving sUA target versus allopurinol-alone therapy by month 6 (55.4%, 66.5% and 23.3%, respectively, p<0.0001 both lesinurad+allopurinol groups). In key secondary end points, there were no statistically significant treatment-group differences favouring lesinurad. Lesinurad was generally well tolerated; the 200 mg dose had a safety profile comparable with allopurinol-alone therapy. Renal-related adverse events occurred in 5.9% of lesinurad 200 mg+allopurinol, 15.0% of lesinurad 400 mg+allopurinol and 4.9% of allopurinol-alone groups, with serum creatinine elevation of ≥1.5× baseline in 5.9%, 15.0% and 3.4%, respectively. Serious treatment-emergent adverse events occurred in 4.4% of lesinurad 200 mg+allopurinol, in 9.5% of lesinurad 400 mg+allopurinol and in 3.9% of allopurinol-alone groups, respectively. CONCLUSION: Lesinurad added to allopurinol demonstrated superior sUA lowering versus allopurinol-alone therapy and lesinurad 200 mg was generally well tolerated in patients with gout warranting additional therapy. TRIAL REGISTRATION NUMBER: NCT01493531.

Weight Loss, Xanthine Oxidase, and Serum Urate Levels: A Prospective Longitudinal Study of Obese Patients.

OBJECTIVE: The mechanisms by which weight loss decreases serum uric acid (SUA) levels are poorly known. We aimed to investigate the role played by xanthine oxidase (XOD), metabolic status, and low-grade inflammation in decreased SUA levels induced by weight loss in obese patients. METHODS: Data were from a series of consecutive patients with severe obesity involved in a bariatric surgery program. Measurements of body composition and biologic samples were obtained before surgery and 6 months after surgery. RESULTS: Among the 154 patients (mean ± SD age 41.0 ± 12.3 years, body mass index [BMI] 47.8 ± 7.2 kg/m(2) , 81% female), the mean ± SD weight loss at 6 months was 31.3 ± 7.8 kg. Reduction in SUA levels was modest (-10%): 4.98 ± 1.21 mg/dl at 6 months versus 5.52 ± 1.33 mg/dl at baseline (P < 0.001). The decrease in SUA levels was greatest (-18%) in hyperuricemic patients (n = 48). In these patients, circulating XOD activity decreased with weight loss (P < 0.0001). Multiple linear regression analysis revealed decreased SUA levels associated with decreased triglyceride levels (P = 0.0001) and BMI (P = 0.02) but not XOD activity, adipokine levels (leptin and adiponectin), insulin resistance, or levels of inflammatory variables (interleukin 6, orosomucoid, fibrinogen, and high-sensitivity C-reactive protein). CONCLUSION: In obese patients, weight loss was associated with a decrease in both SUA levels and XOD activity. Our findings suggest that reduced SUA levels are not mediated by decreased XOD activity or improved insulin resistance but could be partly due to a reduction in triglyceride levels.

Risk of cutaneous adverse events with febuxostat treatment in patients with skin reaction to allopurinol. A retrospective, hospital-based study of 101 patients with consecutive allopurinol and febuxostat treatment.

OBJECTIVE: To investigate the cutaneous tolerance of febuxostat in gouty patients with skin intolerance to allopurinol. METHODS: We identified all gouty patients who had sequentially received allopurinol and febuxostat in the rheumatology departments of 4 university hospitals in France and collected data from hospital files using a predefined protocol. Patients who had not visited the prescribing physician during at least 2 months after febuxostat prescription were excluded. The odds ratio (OR) for skin reaction to febuxostat in patients with a cutaneous reaction to allopurinol versus no reaction was calculated. For estimating the 95% confidence interval (95% CI), we used the usual Wald method and a bootstrap method. RESULTS: In total, 113 gouty patients had sequentially received allopurinol and febuxostat; 12 did not visit the prescribing physician after febuxostat prescription and were excluded. Among 101 patients (86 males, mean age 61±13.9 years), 2/22 (9.1%) with a history of cutaneous reactions to allopurinol showed skin reactions to febuxostat. Two of 79 patients (2.5%) without a skin reaction to allopurinol showed skin intolerance to febuxostat. The ORs were not statistically significant with the usual Wald method (3.85 [95% CI 0.51-29.04]) or bootstrap method (3.86 [95% CI 0.80-18.74]). CONCLUSION: The risk of skin reaction with febuxostat seems moderately increased in patients with a history of cutaneous adverse events with allopurinol. This moderate increase does not support the cross-reactivity of the two drugs.

Revisiting comorbidities in gout: a cluster analysis.

OBJECTIVES: The reciprocal links between comorbidities and gout are complex. We used cluster analysis to attempt to identify different phenotypes on the basis of comorbidities in a large cohort of patients with gout. METHODS: This was a cross-sectional multicentre study of 2763 gout patients conducted from November 2010 to May 2011. Cluster analysis was conducted separately for variables and for observations in patients, measuring proximity between variables and identifying homogeneous subgroups of patients. Variables used in both analyses were hypertension, obesity, diabetes, dyslipidaemia, heart failure, coronary heart disease, renal failure, liver disorders and cancer. RESULTS: Comorbidities were common in this large cohort of patients with gout. Abdominal obesity, hypertension, metabolic syndrome and dyslipidaemia increased with gout duration, even after adjustment for age and sex. Five clusters (C1-C5) were found. Cluster C1 (n=332, 12%) consisted of patients with isolated gout and few comorbidities. In C2 (n=483, 17%), all patients were obese, with a high prevalence of hypertension. C3 (n=664, 24%) had the greatest proportion of patients with type 2 diabetes (75%). In C4 (n=782, 28%), almost all patients presented with dyslipidaemia (98%). Finally, C5 (n=502, 18%) consisted of almost all patients with a history of cardiovascular disease and renal failure, with a high rate of patients receiving diuretics. CONCLUSIONS: Cluster analysis of comorbidities in gout allowed us to identify five different clinical phenotypes, which may reflect different pathophysiological processes in gout.

Efficacy and safety of rituximab in elderly patients with rheumatoid arthritis enrolled in a French Society of Rheumatology registry.

OBJECTIVE: The aim of this study was to compare the efficacy and safety of rituximab (RTX) as a function of patient age. METHODS: We included all rheumatoid arthritis patients in the AutoImmunity and Rituximab registry with a 2-year followup. RESULTS: Of the 1,709 patients, 191 were age ≥75 years, 417 were ages 65­74 years, 907 were ages 50­64 years, and 194 were age <50 years. At baseline, the elderly and very elderly patients presented with longer disease duration, a higher incidence of erythrocyte sedimentation rate and C-reactive protein level, a lower incidence of previous tumor necrosis factor α (TNFα) therapy, and a smaller number of previously used TNFα agents. Disease activity, rheumatoid factor (RF), or anti­cyclic citrullinated peptide (anti-CCP) antibodies and corticosteroid therapy were not statistically different among the groups. At 24 months, no significant difference was shown among the groups for RTX discontinuation rates (36.1% if age <50 years, 32.6% if ages 50­64 years, 34.5% if ages 65­74 years, and 32.5% if age >75 years). The reasons for discontinuation (inefficacy, adverse events) were the same in all 4 groups. Infections were more common in the elderly. Patients ages 65­75 years were more likely to be good responders than nonresponders at 1 year of followup than patients age ≥75 years (odds ratio 3.81, 95% confidence interval 1.14­12.79) after adjustment on disease duration, RF/anti-CCP positivity, corticosteroids, anti-TNF use, and baseline Disease Activity Score in 28 joints (DAS28). After the sixth month, the decrease in DAS28 score was less marked in the population age >75 years than in the group age <50 years. CONCLUSION: The efficacy and safety of RTX is affected by age.

Improving cardiovascular and renal outcomes in gout: what should we target?

Epidemiological and experimental studies have shown that hyperuricaemia and gout are intricately linked with hypertension, metabolic syndrome, chronic kidney disease and cardiovascular disease. A number of studies suggest that hyperuricaemia and gout are independent risk factors for the development of these conditions and that these conditions account, in part, for the increased mortality rate of patients with gout. In this Review, we first discuss the links between hyperuricaemia, gout and these comorbidities, and present the mechanisms by which uric acid production and gout might favour the development of cardiovascular and renal diseases. We then emphasize the potential benefit of urate-lowering therapies on cardiovascular and renal outcomes in patients with hyperuricaemia. The mechanisms that link elevated serum uric acid levels and gout with these comorbidities seem to be multifactorial, implicating low-grade systemic inflammation and xanthine oxidase (XO) activity, as well as the deleterious effects of hyperuricaemia itself. Patients with asymptomatic hyperuricaemia should be treated by nonpharmacological means to lower their SUA levels. In patients with gout, long-term pharmacological inhibition of XO is a treatment strategy that might also reduce cardiovascular and renal comorbidities, because of its dual effect of lowering SUA levels as well as reducing free-radical production during uric acid formation.