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.

A prospective survey on therapeutic inertia in psoriatic arthritis (OPTI'PsA).

OBJECTIVES: Clinical inertia, or therapeutic inertia (TI), is the medical behaviour of not initiating or intensifying treatment when recommended by clinical recommendations. To our knowledge, our survey is the first to assess TI around psoriatic arthritis (PsA). METHODS: Eight hundred and twenty-five French rheumatologists were contacted via email between January and March 2021 and invited to complete an online questionnaire consisting of seven clinical vignettes: five cases ('oligoarthritis', 'enthesitis', 'polyarthritis', 'neoplastic history', 'cardiovascular risk') requiring treatment OPTImization, and two 'control' cases (distal interphalangeal arthritis, atypical axial involvement) not requiring any change of treatment-according to the most recent PsA recommendations. Rheumatologists were also questioned about their routine practice, continuing medical education and perception of PsA. RESULTS: One hundred and one rheumatologists completed this OPTI'PsA survey. Almost half the respondents (47%) demonstrated TI on at least one of the five vignettes that warranted treatment optimization. The complex profiles inducing the most TI were 'oligoarthritis' and 'enthesitis' with 20% and 19% of respondents not modifying treatment, respectively. Conversely, clinical profiles for which there was the least uncertainty ('polyarthritis in relapse', 'neoplastic history' and 'cardiovascular risk') generated less TI with 11%, 8% and 6% of respondents, respectively, choosing not to change the current treatment. CONCLUSION: The rate of TI we observed for PsA is similar to published data for other chronic diseases such as diabetes, hypertension, gout or multiple sclerosis. Our study is the first to show marked clinical inertia in PsA, and further research is warranted to ascertain the reasons behind this inertia.

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.

Calcium pyrophosphate crystal deposition in a cohort of 57 patients with Gitelman syndrome.

OBJECTIVE: Gitelman syndrome (GS) is the most frequent salt-wasting genetic tubulopathy and a source of hypokalaemia and hypomagnesemia. Chondrocalcinosis (CC) is a frequent feature of GS. The aim of our study was to determine the prevalence, distribution patterns, clinical phenotypes and risk factors for CC in GS. METHODS: This prospective study of a cohort of 57 patients with GS included a systematic screening for CC by peripheral joint radiography, cervical spine CT and joint US. The prevalence of cervical C1-C2 CC by CT was compared between 33 GS patients and sex- and age-matched controls. Clinical and biochemical features were analysed to identify factors associated with CC. RESULTS: Mean (s.d.) age of patients was 46.5 (12.4) years, 66.7% were women and 93.0% carried SLC12A3 mutations. Mean serum magnesium level was 0.60 (0.30) mmol/l. CC was observed in 79% of patients, with the highest prevalence at the cervical spine (81.8%) followed by the knee (52.6%), wrist (50.9%), ankle (38.6%), TM joint (36.4%), shoulder (33.3%), hip (22.8%), elbow (14.0%) and sclerochoroid (12.1%). Prevalence of CC at the C1-C2 level was higher in the GS cohort than control group (72.7% vs 9.1%) (adjusted odds ratio 21.0, 95% CI 2.8, 156.1, P = 0.003). Independent factors associated with CC were low serum magnesium level and age. CONCLUSION: GS was associated with widespread CC, favoured by aging and hypomagnesemia. The C1-C2 level was the most affected site. Follow-up of this unique cohort will help understanding the clinical consequences of CC, especially the precise characterization of pyrophosphate arthropathy.

2019 EULAR points to consider for the assessment of competences in rheumatology specialty training.

BACKGROUND AND AIM: Striving for harmonisation of specialty training and excellence of care in rheumatology, the European League Against Rheumatism (EULAR) established a task force to develop points to consider (PtCs) for the assessment of competences during rheumatology specialty training. METHODS: A systematic literature review on the performance of methods for the assessment of competences in rheumatology specialty training was conducted. This was followed by focus groups in five selected countries to gather information on assessment practices and priorities. Combining the collected evidence with expert opinion, the PtCs were formulated by the multidisciplinary task force, including rheumatologists, medical educationalists, and people with rheumatic and musculoskeletal diseases. The level of agreement (LoA) for each PtC was anonymously voted online. RESULTS: Four overarching principles and 10 PtCs were formulated. The overarching principles highlighted the importance of assessments being closely linked to the rheumatology training programme and protecting sufficient time and resources to ensure effective implementation. In the PtCs, two were related to overall assessment strategy (PtCs 1 and 5); three focused on formative assessment and portfolio (PtCs 2-4); three focused on the assessment of knowledge, skills or professionalism (PtCs 6-8); one focused on trainees at risk of failure (PtC 9); and one focused on training the trainers (PtC 10). The LoA (0-10) ranged from 8.75 to 9.9. CONCLUSION: These EULAR PtCs provide European guidance on assessment methods throughout rheumatology training programmes. These can be used to benchmark current practices and to develop future strategies, thereby fostering continuous improvement in rheumatology learning and, ultimately, in patient care.

Cut-off value to identify a flare using the Flare Assessment in Rheumatoid Arthritis (FLARE-RA) questionnaire: analysis of the TOSCA study.

OBJECTIVE: The Flare Assessment in RA (FLARE-RA) self-administered questionnaire aims to identify patients who had flare in the interval between two consultations. This study aimed to establish a threshold for FLARE-RA score to identify RA flare. METHODS: The Tocilizumab SubCutAneous study evaluated the efficacy and safety of s.c. tocilizumab (TCZ) to patients with active RA. Disease activity was assessed with the DAS28ESR at baseline and at week 2 (W2), W4, W12 and W24. The FLARE-RA questionnaire was administered at W12 and W24. Patient satisfaction, assessed at baseline and W24 with the Patient Acceptable Symptom State (PASS), was used as a surrogate marker of no flare. A correlation was sought between the FLARE-RA score at W12 and W24 and the area under the receiver operating characteristic (ROC) curve (AUC) for monthly DAS28ESR. The optimal FLARE-RA cut-off below which patient satisfaction reached the PASS was explored with an ROC curve. RESULTS: A total of 139 patients were included (mean age 57.3 ± 13.8 years, 74.1% women, mean RA duration 10.8 ± 9.2 years, mean DAS28ESR 5.8 ± 1.1). The correlation between the FLARE-RA score and DAS28ESR AUC was moderate at all times: ρ = 0.41 at W12 (P < 0.0001) and 0.51 at W24 (P < 0.0001). The optimal cut-off for the FLARE-RA score to identify absence of flare (i.e. an acceptable situation based on the PASS) was 2.3 with an AUC of 0.81. CONCLUSION: FLARE-RA and DAS28ESR assessment differ; we propose a FLARE-RA cut-off of 2.3, below which the situation (i.e. without flare) is acceptable for patients.

BCP crystals promote chondrocyte hypertrophic differentiation in OA cartilage by sequestering Wnt3a.

OBJECTIVE: Calcification of cartilage with basic calcium phosphate (BCP) crystals is a common phenomenon during osteoarthritis (OA). It is directly linked to the severity of the disease and known to be associated to hypertrophic differentiation of chondrocytes. One morphogen regulating hypertrophic chondrocyte differentiation is Wnt3a. METHODS: Calcification and sulfation of extracellular matrix of the cartilage was analysed over a time course from 6 to 22 weeks in mice and different OA grades of human cartilage. Wnt3a and ß-catenin was stained in human and murine cartilage. Expression of sulfation modulating enzymes (HS2St1, HS6St1) was analysed using quantitative reverse transcription PCR (RT-PCR). The influence of BCP crystals on the chondrocyte phenotype was investigated using quantitative RT-PCR for the marker genes Axin2, Sox9, Col2, MMP13, ColX and Aggrecan. Using western blot for ß-catenin and pLRP6 we investigated the activation of Wnt signalling. The binding capacity of BCP for Wnt3a was analysed using immunohistochemical staining and western blot. RESULTS: Here, we report that pericellular matrix sulfation is increased in human and murine OA. Wnt3a co-localised with heparan sulfate proteoglycans in the pericellular matrix of chondrocytes in OA cartilage, in which canonical Wnt signalling was activated. In vitro, BCP crystals physically bound to Wnt3a. Interestingly, BCP crystals were sufficient to induce canonical Wnt signalling as assessed by phosphorylation of LRP6 and stabilisation of ß-catenin, and to induce a hypertrophic shift of the chondrocyte phenotype. CONCLUSION: Consequently, our data identify BCP crystals as a concentrating factor for Wnt3a in the pericellular matrix and an inducer of chondrocyte hypertrophy.

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.

2018 updated European League Against Rheumatism evidence-based recommendations for the diagnosis of gout.

Although gout is the most common inflammatory arthritis, it is still frequently misdiagnosed. New data on imaging and clinical diagnosis have become available since the first EULAR recommendations for the diagnosis of gout in 2006. This prompted a systematic review and update of the 2006 recommendations. A systematic review of the literature concerning all aspects of gout diagnosis was performed. Recommendations were formulated using a Delphi consensus approach. Eight key recommendations were generated. A search for crystals in synovial fluid or tophus aspirates is recommended in every person with suspected gout, because demonstration of monosodium urate (MSU) crystals allows a definite diagnosis of gout. There was consensus that a number of suggestive clinical features support a clinical diagnosis of gout. These are monoarticular involvement of a foot or ankle joint (especially the first metatarsophalangeal joint); previous episodes of similar acute arthritis; rapid onset of severe pain and swelling; erythema; male gender and associated cardiovascular diseases and hyperuricaemia. When crystal identification is not possible, it is recommended that any atypical presentation should be investigated by imaging, in particular with ultrasound to seek features suggestive of MSU crystal deposition (double contour sign and tophi). There was consensus that a diagnosis of gout should not be based on the presence of hyperuricaemia alone. There was also a strong recommendation that all people with gout should be systematically assessed for presence of associated comorbidities and risk factors for cardiovascular disease, as well as for risk factors for chronic hyperuricaemia. Eight updated, evidence-based, expert consensus recommendations for the diagnosis of gout are proposed.

Galectin 3 Deficiency Alters Chondrocyte Primary Cilium Formation and Exacerbates Cartilage Destruction via Mitochondrial Apoptosis.

Mechanical overload and aging are the main risk factors of osteoarthritis (OA). Galectin 3 (GAL3) is important in the formation of primary cilia, organelles that are able to sense mechanical stress. The objectives were to evaluate the role of GAL3 in chondrocyte primary cilium formation and in OA in mice. Chondrocyte primary cilium was detected in vitro by confocal microscopy. OA was induced by aging and partial meniscectomy of wild-type (WT) and Gal3-null 129SvEV mice (Gal3-/-). Primary chondrocytes were isolated from joints of new-born mice. Chondrocyte apoptosis was assessed by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), caspase 3 activity and cytochrome c release. Gene expression was assessed by qRT-PCR. GAL3 was localized at the basal body of the chondrocyte primary cilium. Primary cilia of Gal3-/- chondrocytes were frequently abnormal and misshapen. Deletion of Gal3 triggered premature OA during aging and exacerbated joint instability-induced OA. In both aging and surgery-induced OA cartilage, levels of chondrocyte catabolism and hypertrophy markers and apoptosis were more severe in Gal3-/- than WT samples. In vitro, Gal3 knockout favored chondrocyte apoptosis via the mitochondrial pathway. GAL3 is a key regulator of cartilage homeostasis and chondrocyte primary cilium formation in mice. Gal3 deletion promotes OA development.

Gout, Hyperuricaemia and Crystal-Associated Disease Network (G-CAN) consensus statement regarding labels and definitions of disease states of gout.

OBJECTIVE: There is a lack of standardisation in the terminology used to describe gout. The aim of this project was to develop a consensus statement describing the recommended nomenclature for disease states of gout. METHODS: A content analysis of gout-related articles from rheumatology and general internal medicine journals published over a 5-year period identified potential disease states and the labels commonly assigned to them. Based on these findings, experts in gout were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach agreement on disease state labels and definitions. RESULTS: The content analysis identified 13 unique disease states and a total of 63 unique labels. The Delphi exercise (n=76 respondents) and face-to-face meeting (n=35 attendees) established consensus agreement for eight disease state labels and definitions. The agreed labels were as follows: 'asymptomatic hyperuricaemia', 'asymptomatic monosodium urate crystal deposition', 'asymptomatic hyperuricaemia with monosodium urate crystal deposition', 'gout', 'tophaceous gout', 'erosive gout', 'first gout flare' and 'recurrent gout flares'. There was consensus agreement that the label 'gout' should be restricted to current or prior clinically evident disease caused by monosodium urate crystal deposition (gout flare, chronic gouty arthritis or subcutaneous tophus). CONCLUSION: Consensus agreement has been established for the labels and definitions of eight gout disease states, including 'gout' itself. The Gout, Hyperuricaemia and Crystal-Associated Disease Network recommends the use of these labels when describing disease states of gout in research and clinical practice.

Gout: state of the art after a decade of developments.

This review article summarizes the relevant English literature on gout from 2010 through April 2017. It emphasizes that the current epidemiology of gout indicates a rising prevalence worldwide, not only in Western countries but also in Southeast Asia, in close relationship with the obesity and metabolic syndrome epidemics. New pathogenic mechanisms of chronic hyperuricaemia focus on the gut (microbiota, ABCG2 expression) after the kidney. Cardiovascular and renal comorbidities are the key points to consider in terms of management. New imaging tools are available, including US with key features and dual-energy CT rendering it able to reveal deposits of urate crystals. These deposits are now included in new diagnostic and classification criteria. Overall, half of the patients with gout are readily treated with allopurinol, the recommended xanthine oxidase inhibitor (XOI), with prophylaxis for flares with low-dose daily colchicine. The main management issues are related to patient adherence, because gout patients have the lowest rate of medication possession ratio at 1 year, but they also include clinical inertia by physicians, meaning XOI dosage is not titrated according to regular serum uric acid level measurements for targeting serum uric acid levels for uncomplicated (6.0 mg/dl) and complicated gout, or the British Society for Rheumatology recommended target (5.0 mg/dl). Difficult-to-treat gout encompasses polyarticular flares, and mostly patients with comorbidities, renal or heart failure, leading to contraindications or side effects of standard-of-care drugs (colchicine, NSAIDs, oral steroids) for flares; and tophaceous and/or destructive arthropathies, leading to switching between XOIs (febuxostat) or to combining XOI and uricosurics.

Difficult-to-treat gout flares: eligibility for interleukin-1 inhibition in private practice is uncommon according to current EMA approval.

OBJECTIVE: The objective was to determine the proportion of patients with difficult-to-treat or difficult-to-prevent acute gout attacks eligible for IL-1 inhibition. METHODS: Participants included in the French cross-sectional GOSPEL cohort (n = 1003 gout patients) were examined for contraindications and intolerance to standard of care (SoC) drugs of gout flares (colchicine, non-steroidal anti-inflammatory drugs and systemic glucocorticoids). Patients were classified as definitely eligible for first-line IL-1 inhibition (canakinumab) according to European summary of product characteristics (contraindications/intolerance to SoC and at least three flares per year) without any other anti-inflammatory options (contraindications/intolerance only), or potentially eligible (precaution of use). Eligibility to receive IL-1 during an on-going flare related to insufficient efficacy was assessed (second-line eligibility). RESULTS: Definite first-line eligibility for IL-1 therapy was found in 10 patients (1%) and contraindication to all SoC therapies in nine patients who had presented <3 flares in the past 12 months. At least precaution of use for SoC therapies was noted for 218/1003 patients (21.7%). Of 487 patients experiencing flares at baseline, 114 (23.4%) were still experiencing pain scored ⩾4/10 numeric scale on day 3, one of whom could not receive further SoC drugs. Only nine of them had three or more flares in the past year and were eligible for second-line IL-1 inhibition. CONCLUSION: Despite significant numbers of patients without any SoC anti-inflammatory therapeutic options for gout flares, eligibility for IL-1 inhibition therapy according to current European approval is rare.

Ultrasound evaluation in follow-up of urate-lowering therapy in gout: the USEFUL study.

OBJECTIVES: We aimed to determine the ability of ultrasonography (US) to show disappearance of urate deposits in gouty patients requiring urate-lowering therapy (ULT). METHODS: We performed a 6-month multicentre prospective study including patients with: proven gout; presence of US features of gout (tophus and/or double contour sign) at the knee and/or first metatarsophalangeal joints; and no current ULT. US evaluations were performed at baseline and at months 3 and 6 (M3, M6) after starting ULT. Outcomes were: the change in US features of gout at M6 according to final (M6) serum urate (SU) level (high, > 360 µmol/l, i.e. > 6 mg/dl; low, 300-360 µmol/l, i.e. 5-6 mg/dl; very low, < 300 µmol/l, i.e. < 5 mg/dl); and correlation between changed US features and final SU level. RESULTS: We included 79 gouty patients (mean ± s.d., age 61.8 (14) years, 91% males, disease duration 6.3 (6.1) years). Baseline SU level was 530 ± 97 µmol/l (i.e. 8.9 mg/dl ± 1.6mg/dl). At least one US tophus and double contour sign was observed in 74 (94%) and 68 (86%) patients, respectively. Among the 67 completers at M6, 18 and 39 achieved a very low and low SU level, respectively. We found a significant decrease in US features of gout among patients with the lowest SU level (P < 0.001). Final M6 SU level was positively correlated with decreased size of tophus (r = 0.54 [95% CI: 0.34, 0.70], P < 0.0001), and inversely correlated with proportion of double contour sign disappearance (r=-0.59 [-0.74, -0.40]). CONCLUSION: US can show decreased urate deposition after ULT, which is correlated with decreased SU level. The responsiveness of US in gout is demonstrated and can be useful for gout follow-up and adherence to ULT.

Replication of association of the apolipoprotein A1-C3-A4 gene cluster with the risk of gout.

OBJECTIVE: Gout is associated with dyslipidaemia. Association of the apolipoprotein A1-C3-A4 gene cluster with gout has previously been reported in a small study. To investigate a possible causal role for this locus in gout, we tested the association of genetic variants from APOA1 (rs670) and APOC3 (rs5128) with gout. METHODS: We studied data for 2452 controls and 2690 clinically ascertained gout cases of European and New Zealand Polynesian (Maori and Pacific) ancestry. Data were also used from the publicly available Atherosclerosis Risk in Communities study (n = 5367) and the Framingham Heart Study (n = 2984). Multivariate adjusted logistic and linear regression was used to test the association of single-nucleotide polymorphisms with gout risk, serum urate, triglyceride and high-density lipoprotein cholesterol (HDL-C). RESULTS: In Polynesians, the T-allele of rs670 (APOA1) increased (odds ratio, OR = 1.53, P = 4.9 × 10(-6)) and the G-allele of rs5128 (APOC3) decreased the risk of gout (OR = 0.86, P = 0.026). In Europeans, there was a strong trend to a risk effect of the T-allele for rs670 (OR = 1.11, P = 0.055), with a significant protective effect of the G-allele for rs5128 being observed after adjustment for triglycerides and HDL-C (OR = 0.81, P = 0.039). The effect at rs5128 was specific to males in both Europeans and Polynesians. Association in Polynesians was independent of any effect of rs670 and rs5128 on triglyceride and HDL-C levels. There was no evidence for association of either single-nucleotide polymorphism with serum urate levels (P ⩾ 0.10). CONCLUSION: Our data, replicating a previous study, supports the hypothesis that the apolipoprotein A1-C3-A4 gene cluster plays a causal role in gout.

Body mass index and response to abatacept in rheumatoid arthritis.

BACKGROUND: Previous studies suggested that obesity could negatively affect the response to antitumour necrosis factor-α (TNFα) agents in rheumatoid arthritis (RA). However, data are lacking on whether obesity affects the response to abatacept (ABA). We aimed to determine whether body mass index (BMI) affects the response to ABA in RA. MATERIALS AND METHODS: In this multicenter retrospective study, we included RA patients who received ABA. BMI was calculated at the initiation of treatment. After 6 months of treatment, change from baseline in DAS28, pain on a visual analog scale, erythrocyte sedimentation rate and C-reactive protein level, tender and swollen joint count were analysed. The primary endpoint was decrease in DAS28 ≥ 1·2. Secondary outcomes were good response and remission by EULAR criteria. RESULTS: At baseline, among 141 RA patients included, the median [interquartile range] BMI was 26·0 [22·9-30·8] kg/m². The number of patients with normal weight, overweight and obesity was 64 (45·4%), 38 (27%) and 39 (27·6%), respectively. Baseline characteristics did not differ among the three BMI subgroups. Univariate analysis revealed no difference in BMI between responders and nonresponders: DAS28 decrease ≥ 1·2 (25·0 [23·4-31·3] vs. 26·3 [22·9-30·2], P = 0·95), EULAR good response (26·4 [23·5-30·9] vs. 26·0 [22·9-30·6], P = 0·96) and remission (26·7 [21·7-30·3] vs. 26·0 [23·0-30·1], P = 0·83). CONCLUSION: In our real-life study, BMI did not affect the response to ABA in RA. If confirmed, these results suggest that obesity is not a limitation of ABA use in RA.

Non-TNF-Targeted Biologic vs a Second Anti-TNF Drug to Treat Rheumatoid Arthritis in Patients With Insufficient Response to a First Anti-TNF Drug: A Randomized Clinical Trial.

IMPORTANCE: One-third of patients with rheumatoid arthritis show inadequate response to tumor necrosis factor α (TNF-α) inhibitors; little guidance on choosing the next treatment exists. OBJECTIVE: To compare the efficacy of a non-TNF-targeted biologic (non-TNF) vs a second anti-TNF drug for patients with insufficient response to a TNF inhibitor. DESIGN, SETTING, AND PARTICIPANTS: A total of 300 patients (conducted between 2009-2012) with rheumatoid arthritis, with persistent disease activity (disease activity score in 28 joints-erythrocyte sedimentation rate [DAS28-ESR] ≥ 3.2 [range, 0-9.3]) and an insufficient response to anti-TNF therapy were included in a 52-week multicenter, pragmatic, open-label randomized clinical trial. The final follow-up date was in August 2013. INTERVENTIONS: Patients were randomly assigned (1:1) to receive a non-TNF-targeted biologic agent or an anti-TNF that differed from their previous treatment. The choice of the biologic prescribed within each randomized group was left to the treating clinician. MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of patients with good or moderate response according to the European League Against Rheumatism (EULAR) scale at week 24. Secondary outcomes included the EULAR response at weeks 12 and 52; at weeks 12, 24, and 52; DAS28ESR, low disease activity (DAS28 ≤3.2), remission (DAS28 ≤2.6); serious adverse events; and serious infections. RESULTS: Of the 300 randomized patients (243 [83.2%] women; mean [SD] age, 57.1 [12.2] years; baseline DAS28-ESR, 5.1 [1.1]), 269 (89.7%) completed the study. At week 24, 101 of 146 patients (69%) in the non-TNF group and 76 (52%) in the second anti-TNF group achieved a good or moderate EULAR response (OR, 2.06; 95% CI, 1.27-3.37; P = .004, with imputation of missing data; absolute difference, 17.2%; 95% CI, 6.2% to 28.2%). The DAS28-ESR was lower in the non-TNF group than in the second anti-TNF group (mean difference adjusted for baseline differences, -0.43; 95% CI, -0.72 to -0.14; P = .004). At weeks 24 and 52, more patients in the non-TNF group vs the second anti-TNF group showed low disease activity (45% vs 28% at week 24; OR, 2.09; 95% CI, 1.27 to 3.43; P = .004 and 41% vs 23% at week 52; OR, 2.26; 95% CI, 1.33 to 3.86; P = .003). CONCLUSIONS AND RELEVANCE: Among patients with rheumatoid arthritis previously treated with anti-TNF drugs but with inadequate primary response, a non-TNF biologic agent was more effective in achieving a good or moderate disease activity response at 24 weeks than was the second anti-TNF medication. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01000441.

2015 Gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.

OBJECTIVE: Existing criteria for the classification of gout have suboptimal sensitivity and/or specificity, and were developed at a time when advanced imaging was not available. The current effort was undertaken to develop new classification criteria for gout. METHODS: An international group of investigators, supported by the American College of Rheumatology and the European League Against Rheumatism, conducted a systematic review of the literature on advanced imaging of gout, a diagnostic study in which the presence of monosodium urate monohydrate (MSU) crystals in synovial fluid or tophus was the gold standard, a ranking exercise of paper patient cases, and a multi-criterion decision analysis exercise. These data formed the basis for developing the classification criteria, which were tested in an independent data set. RESULTS: The entry criterion for the new classification criteria requires the occurrence of at least one episode of peripheral joint or bursal swelling, pain, or tenderness. The presence of MSU crystals in a symptomatic joint/bursa (ie, synovial fluid) or in a tophus is a sufficient criterion for classification of the subject as having gout, and does not require further scoring. The domains of the new classification criteria include clinical (pattern of joint/bursa involvement, characteristics and time course of symptomatic episodes), laboratory (serum urate, MSU-negative synovial fluid aspirate), and imaging (double-contour sign on ultrasound or urate on dual-energy CT, radiographic gout-related erosion). The sensitivity and specificity of the criteria are high (92% and 89%, respectively). CONCLUSIONS: The new classification criteria, developed using a data-driven and decision-analytic approach, have excellent performance characteristics and incorporate current state-of-the-art evidence regarding gout.

Clinical implications of pathogenic calcium crystals.

PURPOSE OF REVIEW: The role of intraarticular calcifications has been challenged over the past years, with respect to cartilage destruction, especially in osteoarthritis. RECENT FINDINGS: Main themes reviewed in this article will discuss prevalence of articular cartilage calcifications, mechanisms of cartilage calcifications, and mostly the pathogenic role of both calcium pyrophosphate and basic calcium phosphate crystals. SUMMARY: A direct pathogenic role of both calcium crystals has been depicted, in cartilage as a crystal-induced stress, or via acute or chronic crystal-induced synovitis.