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.

2023 EULAR recommendations on imaging in diagnosis and management of crystal-induced arthropathies in clinical practice.

OBJECTIVE: To formulate evidence-based recommendations and overarching principles on the use of imaging in the clinical management of crystal-induced arthropathies (CiAs). METHODS: An international task force of 25 rheumatologists, radiologists, methodologists, healthcare professionals and patient research partners from 11 countries was formed according to the EULAR standard operating procedures. Fourteen key questions on the role of imaging in the most common forms of CiA were generated. The CiA assessed included gout, calcium pyrophosphate deposition disease and basic calcium phosphate deposition disease. Imaging modalities included conventional radiography, ultrasound, CT and MRI. Experts applied research evidence obtained from four systematic literature reviews using MEDLINE, EMBASE and CENTRAL. Task force members provided level of agreement (LoA) anonymously by using a Numerical Rating Scale from 0 to 10. RESULTS: Five overarching principles and 10 recommendations were developed encompassing the role of imaging in various aspects of patient management: making a diagnosis of CiA, monitoring inflammation and damage, predicting outcome, response to treatment, guided interventions and patient education. Overall, the LoA for the recommendations was high (8.46-9.92). CONCLUSIONS: These are the first recommendations that encompass the major forms of CiA and guide the use of common imaging modalities in this disease group in clinical practice.

VEXAS syndrome is characterized by inflammasome activation and monocyte dysregulation.

Acquired mutations in the UBA1 gene were recently identified in patients with severe adult-onset auto-inflammatory syndrome called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). However, the precise physiological and clinical impact of these mutations remains poorly defined. Here we study a unique prospective cohort of VEXAS patients. We show that monocytes from VEXAS are quantitatively and qualitatively impaired and display features of exhaustion with aberrant expression of chemokine receptors. In peripheral blood from VEXAS patients, we identify an increase in circulating levels of many proinflammatory cytokines, including IL-1ß and IL-18 which reflect inflammasome activation and markers of myeloid cells dysregulation. Gene expression analysis of whole blood confirms these findings and also reveals a significant enrichment of TNF-α and NFκB signaling pathways that can mediate cell death and inflammation. This study suggests that the control of the nflammasome activation and inflammatory cell death could be therapeutic targets in VEXAS syndrome.

Retention, safety and efficacy of off-label conventional treatments and biologics for chronic calcium pyrophosphate crystal inflammatory arthritis.

OBJECTIVES: Very little is known on the efficacy and safety of drugs for the management of chronic calcium pyrophosphate (CPP) crystal inflammatory arthritis. The objectives of this work were to describe the drugs used in the management of chronic CPP crystal inflammatory arthritis in expert European centres, and to examine treatment retention. METHODS: This was a retrospective cohort study. Charts from patients with a diagnosis of persistent inflammatory and/or recurrent acute CPP crystal arthritis were reviewed in seven European centres. Baseline characteristics were collected, and visits at months 3, 6, 12 and 24 included an assessment of treatment response and safety. RESULTS: One hundred and ninety-four treatments were initiated in 129 patients. Colchicine (used first-line in n = 73/86), methotrexate (used first-line in n = 14/36), anakinra (n = 27) and tocilizumab (n = 25) were the most prescribed treatments, while long-term corticosteroids, hydroxychloroquine, canakinumab and sarilumab were used occasionally. The 24-month on-drug retention was higher for tocilizumab (40%) than anakinra (18.5%) (P < 0.05), while the difference between colchicine (29.1%) and methotrexate (44.4%) was not statistically significant (P = 0.10). Adverse events led to 14.1% of colchicine discontinuations (100% of diarrhoea), 4.3% for methotrexate, 31.8% for anakinra and 20% for tocilizumab; all other discontinuations were related to insufficient response or losses to follow-up. Efficacy outcomes did not differ significantly between treatments throughout follow-up. CONCLUSION: Daily colchicine is the first-line therapy used in chronic CPP crystal inflammatory arthritis, which is considered efficient in a third to half of cases. Second-line treatments include methotrexate and tocilizumab, which have higher retention than anakinra.

Effectiveness of topical sodium thiosulfate for ectopic calcifications and ossifications. Results of the CATSS-O study.

INTRODUCTION: Ectopic calcifications (ECs) and heterotopic ossifications (HOs) form in non-mineralized tissues, most often in subcutaneous and muscular areas. Local and systemic complications can cause severe disability. Systemic administration of sodium thiosulfate (STS) gives promising results but is difficult to use in clinical practice. OBJECTIVE: Evaluation of the efficacy and safety of topical STS in ECs and HOs. METHODS: Retrospective analysis of the CATSS-O registry that included patients receiving topical STS 25 % prepared by the pharmacy of Limoges hospital during 2014-2020. The efficacy of STS was assessed by imaging (radiography or CT) after at least 6 months' treatment. RESULTS: Among 126 patients who received STS 25 %, 35 had complete clinical and radiographic data for analysis (28 with ECs and 7 with HOs; 18 children [mean age 8.9 years, range 1.5-16], 17 adults [mean age 52.4 years, range 24-90]). Calcifications or ossifications were due to dermatomyositis (8 children, 6 adults), systemic scleroderma (6 adults) or pseudo-hypoparathyroidism 1A (7 children). They were single (37.1 %) or multiple (62.9 %). Treated regions were in the lower limbs (31.4 %), upper limbs (37.1 %) or both (28.6 %) and the axial region (2.9 %). Topical STS was clinically effective in 9/28 (32.1 %) patients with ECs and 2/7 (28.6 %) children with HOs. Three patients experienced complete disappearance of their calcifications. Response for ECs was better in children than adults (54.5% vs 17.6 %, p = 0.035). Topical STS was well tolerated. CONCLUSION: Local STS seems effective for ossifications, particularly pediatric calcifications or ossifications. Randomized and experimental studies are needed to confirm this observation and to identify the underlying mechanisms.

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.

Quantification of cartilage and subchondral bone cysts on knee specimens based on a spectral photon-counting computed tomography.

Spectral photon-counting computed tomography (SPCCT) is a new technique with the capability to provide mono-energetic (monoE) images with high signal to noise ratio. We demonstrate the feasibility of SPCCT to characterize at the same time cartilage and subchondral bone cysts (SBCs) without contrast agent in osteoarthritis (OA). To achieve this goal, 10 human knee specimens (6 normal and 4 with OA) were imaged with a clinical prototype SPCCT. The monoE images at 60 keV with isotropic voxels of 250 × 250 × 250 µm3 were compared with monoE synchrotron radiation CT (SR micro-CT) images at 55 keV with isotropic voxels of 45 × 45 × 45 µm3 used as benchmark for cartilage segmentation. In the two OA knees with SBCs, the volume and density of SBCs were evaluated in SPCCT images. In 25 compartments (lateral tibial (LT), medial tibial, (MT), lateral femoral (LF), medial femoral and patella), the mean bias between SPCCT and SR micro-CT analyses were 101 ± 272 mm3 for cartilage volume and 0.33 mm ± 0.18 for mean cartilage thickness. Between normal and OA knees, mean cartilage thicknesses were found statistically different (0.005 < p < 0.04) for LT, MT and LF compartments. The 2 OA knees displayed different SBCs profiles in terms of volume, density, and distribution according to size and location. SPCCT with fast acquisitions is able to characterize cartilage morphology and SBCs. SPCCT can be used potentially as a new tool in clinical studies in OA.

Early-onset gout and rare deficient variants of the lactate dehydrogenase D gene.

OBJECTIVES: To investigate whether the lactate dehydrogenase D (LDHD) gene deficiency causes juvenile-onset gout. METHODS: We used whole-exome sequencing for two families and a targeted gene-sequencing panel for an isolated patient. d-lactate dosages were analysed using ELISA. RESULTS: We demonstrated linkage of juvenile-onset gout to homozygous carriage of three rare distinct LDHD variants in three different ethnicities. In a Melanesian family, the variant was (NM_153486.3: c.206C>T; rs1035398551) and, as compared with non-homozygotes, homozygotes had higher hyperuricaemia (P = 0.02), lower fractional clearance of urate (P = 0.002), and higher levels of d-lactate in blood (P = 0.04) and urine (P = 0.06). In a second, Vietnamese, family, very severe juvenile-onset gout was linked to homozygote carriage of an undescribed LDHD variant (NM_153486.3: c.1363dupG) leading to a frameshift followed by a stop codon, p.(AlaGly432fsTer58). Finally, a Moroccan man, with early-onset and high d-lactaturia, whose family was unavailable for testing, was homozygous for another rare LDHD variant [NM_153486.3: c.752C>T, p.(Thr251Met)]. CONCLUSION: Rare, damaging LDHD variants can cause autosomal recessive early-onset gout, the diagnosis of which can be suspected by measuring high d-lactate levels in the blood and/or urine.

Simple Application and Adherence to Gout Guidelines Enables Disease Control: An Observational Study in French Referral Centres.

Background: In a context of therapeutic inertia, the French Society of Rheumatology (SFR) published its first recommendations on gout in 2020, which were deliberately simple and concise. The objectives of the study were to determine the profile of patients referred to French gout-expert centres, and to examine the results of their management and the factors leading to those results. Methods: Three hundred patients attending a first visit for gout management in three French referral centres were retrospectively and randomly included in this multicentre observational study. Visits were performed at baseline (M0) and scheduled for month 6 (M6), month 12 (M12), and month 24 (M24). Results: Patients were 81% male and had a mean age 62.2 ± 15.2 years. Management followed French recommendations after the baseline visit in 94.9% of cases. SU levels were below 6.0 mg/dL in 59.4% of patients at M6, 67.9% at M12, and 78.6% at M24, with increasing clinical improvement (i.e., flare decrease) over 2 years of follow-up. At M24, 50% of patients were treated with allopurinol (313 ± 105 mg/d), which exceeded renal restrictions of doses in 61.5% of them, and 48.2% received febuxostat (84 ± 36 mg/d). The need for a sufficient dosage of ULT was the only predictive factor found for successful achievement of SU levels < 6.0 mg/dL at a given visit. Conclusions: Simple application of gout-management guidelines is feasible in clinical practice and is efficient, with a majority of patients achieving SU targets and clinical improvement.

Lin28a induces SOX9 and chondrocyte reprogramming via HMGA2 and blunts cartilage loss in mice.

Articular cartilage has low regenerative capacity despite permanent stress. Irreversible cartilage lesions characterize osteoarthritis (OA); this is not followed by tissue repair. Lin28a, an RNA binding protein, is detected in damaged cartilage in humans and mice. We investigated the role of LIN28a in cartilage physiology and in osteoarthritis. Lin28a-inducible conditional cartilage deletion up-regulated Mmp13 in intact mice and exacerbated the cartilage destruction in OA mice. Lin28a-specific cartilage overexpression protected mice against cartilage breakdown, stimulated chondrocyte proliferation and the expression of Prg4 and Sox9, and down-regulated Mmp13. Lin28a overexpression inhibited Let-7b and Let-7c miRNA levels while RNA-sequencing analysis revealed five genes of transcriptional factors regulated by Let-7. Moreover, Lin28a overexpression up-regulated HMGA2 and activated SOX9 transcription, a factor required for chondrocyte reprogramming. HMGA2 siRNA knockdown inhibited the cartilage protective effect of Lin28a overexpression. This study provides insights into a new pathway including the Lin28a-Let7 axis, thus promoting chondrocyte anabolism in injured cartilage in mice.

Do Glucocorticoid Injections Increase the Risk of Knee Osteoarthritis Progression Over 5 Years?

OBJECTIVE: Recent findings have demonstrated that intraarticular (IA) glucocorticoid injections can be deleterious for knees with osteoarthritis (OA). This study was undertaken to assess, in a real-life setting, the risk of knee OA progression in patients who received IA glucocorticoid injections over a 5-year follow-up period. METHODS: We used marginal structural modeling with inverse probability of treatment weighting to determine the causal association between IA glucocorticoid injections and the 5-year risk of disease progression in patients with symptomatic knee OA from the Knee and Hip Osteoarthritis Long-term Assessment cohort. OA progression was defined as an incident total knee replacement (TKR) and/or radiographic worsening (Kellgren/Lawrence [K/L] grade or joint space narrowing [JSN]). We also examined these outcomes in knees that received IA hyaluronan (IAHA) injections. RESULTS: Among the 564 patients with knee OA included in the study sample, 51 (9.0%) and 99 (17.5%) received IA glucocorticoid or IAHA injections, respectively, and 414 (63.1%) did not receive any injection during follow-up. Compared to untreated knees, those treated with IA glucocorticoid injections had a similar risk of incident TKR (hazard ratio [HR] 0.92 [95% confidence interval (95% CI) 0.20, 4.14]; P = 0.91) or K/L grade worsening (HR 1.33 [95% CI 0.64, 2.79]; P = 0.44). IAHA injections had no effect on the risk of TKR (HR 0.81 [95% CI 0.14, 4.63]; P = 0.81) or K/L grade worsening (HR 1.36 [95% CI 0.85, 2.17]; P = 0.20). Similar results were obtained for JSN, and when TKR and radiographic outcomes were combined. CONCLUSION: In this study, IA glucocorticoid injections for symptomatic knee OA did not significantly increase the 5-year risk of incident TKR or radiographic worsening. These findings should be interpreted cautiously and replicated in other cohorts.

The shrinking toe sign in gout.

OBJECTIVE: To describe the frequency, clinical presentation and understand the pathophysiology of toe shortenings during urate-lowering treatment (ULT) of gout, a feature we called the shrinking toe sign. METHODS: Sequential foot photographs and radiographs of 1141 consecutive gouty patients followed-up for at least 6 months under ULT were retrospectively scrutinized. Features from patients with toe shortenings were extracted from anonymized files. Tophi adjacent to the shortening sites were semi quantified on foot photographs and toe shortenings were measured on radiographs with the Corel draw software (Corel corporation, Canada). Measurement concordance was assessed by concordance correlation coefficients (CCC) and correlation between tophus scores and toe shortenings was analyzed by using linear model with a patient random effect. 97 patients who did not develop toe shortening during ULT were analyzed as controls. RESULTS: Shrinking toes were observed in 10 patients (0.9%) with tophaceous gout at joints with baseline destructive arthropathy. The first and second toes and metatarsophalangeal joints were predominantly involved. The sign was observed after serum urate had been lowered below the 300 and 360 µmol/l targets, in 8 and 2 patients, respectively. Measured shortenings (CCC: 0.99) correlated (p < 10-4) with decreases in tophus score (CCC: 0.91). Sequential radiograph analysis revealed that toe shortening was mainly due to lytic bone collapse during articular tophus dissolution. Comparison with controls showed that the sign developed in severe gout and in joints with more severe erosion score at baseline. CONCLUSION: The shrinking toe appears as rare feature of severe tophaceous gout, triggered by dissolution of bone-replacing tophi. Our findings reinforce the need to treat gout early, before destruction of bone scaffold by extensive tophi, as MSU crystal dissolution by ULT may further weaken these areas and induce their collapse.

Identifying Potential Classification Criteria for Calcium Pyrophosphate Deposition Disease: Item Generation and Item Reduction.

OBJECTIVE: Classification criteria for calcium pyrophosphate deposition (CPPD) disease will facilitate clinical research on this common crystalline arthritis. Our objective was to report on the first 2 phases of a 4-phase process for developing CPPD classification criteria. METHODS: CPPD classification criteria development is overseen by a 12-member steering committee. Item generation (phase I) included a scoping literature review of 5 literature databases and contributions from a 35-member combined expert committee and 2 patient research partners. Item reduction and refinement (phase II) involved a combined expert committee meeting, discussions among clinical, imaging, and laboratory advisory groups, and an item-rating exercise to assess the influence of individual items toward classification. The steering committee reviewed the modal rating score for each item (range -3 [strongly pushes away from CPPD] to +3 [strongly pushes toward CPPD]) to determine items to retain for future phases of criteria development. RESULTS: Item generation yielded 420 items (312 from the literature, 108 from experts/patients). The advisory groups eliminated items that they agreed were unlikely to distinguish between CPPD and other forms of arthritis, yielding 127 items for the item-rating exercise. Fifty-six items, most of which had a modal rating of +/- 2 or 3, were retained for future phases. As numerous imaging items were rated +3, the steering committee recommended focusing on imaging of the knee and wrist and 1 additional affected joint for calcification suggestive of CPP crystal deposition. CONCLUSION: A data- and expert-driven process is underway to develop CPPD classification criteria. Candidate items comprise clinical, imaging, and laboratory features.

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.

Distribution of bony erosions in feet and performance of two bone erosion scores: A dual-energy computed tomography study of 61 patients with gout.

OBJECTIVES: To assess the distribution of bone erosions and two erosion scores in the feet of patients with gout and analyze the association between erosion scores and monosodium urate (MSU) crystal deposition using dual-energy computed tomography (DECT). MATERIALS AND METHODS: We included all patients who underwent DECT of both feet between 2016 and 2019 in our radiology department, with positive detection of MSU deposits. Data on sex, age, treatment, serum urate, and DECT urate volumes were obtained. CT images were analyzed to score bone erosions in 31 sites per foot by using the semi-quantitative method based on the Rheumatoid Arthritis MRI Scoring (RAMRIS) system and the Dalbeth-simplified score. Reproducibility for the two scores was calculated with intraclass correlation coefficients (ICCs). Correlations between clinical features, erosion scores and urate crystal volume were analyzed by the Spearman correlation coefficient (r). RESULTS: We studied 61 patients (mean age 62.0 years); 3,751 bones were scored. The first metatarsophalangeal joint and the midfoot were the most involved in terms of frequency and severity of bone erosions. The distribution of bone erosions was not asymmetrical. The intra- and inter-observer reproducibility was similar for the RAMRIS and Dalbeth-simplified scores (ICC 0.93 vs 0.94 and 0.96 vs 0.90). DECT urate volume was significantly correlated with each of the two erosion scores (r = 0.58-0.63, p < 0.001). There was a high correlation between the two scores (r = 0.96, p < 0.001). CONCLUSIONS: DECT demonstrates that foot erosions are not asymmetric in distribution and predominate at the first ray and midfoot. The two erosion scores are significantly correlated with DECT urate volume. An almost perfect correlation between the RAMRIS and Dalbeth-simplified scores is observed.

Calcium Pyrophosphate Dihydrate Crystal Deposition in Gouty Tophi.

OBJECTIVE: The coexistence of calcium pyrophosphate dihydrate (CPPD) and monosodium urate monohydrate crystals in gouty tophi has rarely been reported. We undertook this study to investigate CPPD crystal deposits in a series of surgically removed gouty tophi and to identify factors associated with these deposits. METHODS: Twenty-five tophi from 22 gout patients were analyzed using polarized light microscopy, field emission scanning electron microscopy (FESEM), and µ Fourier transform infrared (µFTIR) spectroscopy. RESULTS: Tophi consisted of multiple lobules separated by fibrous septa and surrounded by a foreign-body giant cell reaction. CPPD crystal aggregates were identified in 9 of 25 tophi from 6 patients. CPPD crystals were dispersed or highly compacted, localized at the edge or inside the tophus lobules, with some lobules completely filled with crystals. Both monoclinic and triclinic CPPD crystal phases were identified using FESEM and µFTIR. Compared to patients without CPPD, those with CPPD-containing tophi were older (mean 60.5 years versus 47.2 years; P = 0.009), and had longer-term gout duration (mean 17.0 years versus mean 9.0 years; P < 0.05) and tophi duration (mean 10.0 years versus mean 4.6 years; P < 0.01). None of the patients had radiographic chondrocalcinosis of the knee or wrist. CONCLUSION: CPPD crystal formation seems to be a late and frequent event of tophus maturation, occurring more frequently with aging, and could contribute to the speed of tophus dissolution and the apparent persistence of tophus sometimes observed even after effective, long-lasting urate-lowering therapy.

Pain in women with knee and/or hip osteoarthritis is related to systemic inflammation and to adipose tissue dysfunction: Cross-sectional results of the KHOALA cohort.

BACKGROUND: Considering the role of metabolic diseases in osteoarthritis (OA), we investigated whether biomarkers of adipose tissue dysfunction could be associated with OA-related pain. DESIGN: We cross-sectionally analyzed patients with knee and/or hip OA at inclusion in the KHOALA cohort. We used visual analogic scale (VAS) for pain, the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and Osteoarthritis Knee and Hip Quality of Life (OAKHQOL) pain subscores. At inclusion, we measured ultra-sensitive CRP (usCRP), leptin and adiponectin for calculation of leptin:adiponectin ratio (LAR), a marker of adipose tissue dysfunction associated with central adiposity, high-molecular-weight adiponectin, visfatin and apolipoproteins. Univariate and multivariable analyses using stepwise linear regression models were performed to search for correlation between pain assessments and these biomarkers, with systematic adjustment on age. RESULTS: In 596 women with hip and/or knee OA, multivariable analyses indicated that higher pain intensity was associated with higher LAR (VAS pain: ß=0.49; p = 0.0001, OAKHQOL pain: ß=-0.46; p = 0.0002, WOMAC pain: ß=0.30; p = 0.001) in the whole group as well as in hip or knee OA patients considered separately. Pain intensity correlated also with usCRP level (VAS pain: ß= 0.27; p = 0.02, OAKHQOL pain: ß =-0.30; p = 0.01) and Kellgren-Lawrence score. In 267 men, no correlation between biomarkers and pain was found. CONCLUSION: Serum LAR and usCRP level are associated with pain level, independently of radiographic structural severity in women with hip and/or knee OA, emphasizing the role of adipose tissue dysfunction and of meta-inflammation in pain experience in the female population.

EZH2 inhibition reduces cartilage loss and functional impairment related to osteoarthritis.

Histone methyltransferase EZH2 is upregulated during osteoarthritis (OA), which is the most widespread rheumatic disease worldwide, and a leading cause of disability. This study aimed to assess the impact of EZH2 inhibition on cartilage degradation, inflammation and functional disability. In vitro, gain and loss of EZH2 function were performed in human articular OA chondrocytes stimulated with IL-1ß. In vivo, the effects of EZH2 inhibition were investigated on medial meniscectomy (MMX) OA mouse model. The tissue alterations were assayed by histology and the functional disabilities of the mice by actimetry and running wheel. In vitro, EZH2 overexpression exacerbated the action of IL-1ß in chondrocytes increasing the expression of genes involved in inflammation, pain (NO, PGE2, IL6, NGF) and catabolism (MMPs), whereas EZH2 inhibition by a pharmacological inhibitor, EPZ-6438, reduced IL-1ß effects. Ex vivo, EZH2 inhibition decreased IL-1ß-induced degradation of cartilage. In vivo, intra-articular injections of the EZH2 inhibitor reduced cartilage degradation and improved motor functions of OA mice. This study demonstrates that the pharmacological inhibition of the histone methyl-transferase EZH2 slows the progression of osteoarthritis and improves motor functions in an experimental OA model, suggesting that EZH2 could be an effective target for the treatment of OA by reducing catabolism, inflammation and pain.