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Objective: To investigate the association of the lipidomic profile with osteoarthritis (OA) severity, considering the outcomes radiographic knee and hand OA, pain and function. Design: We used baseline data from the Applied Public-Private Research enabling OsteoArthritis Clinical Headway (APPROACH) cohort, comprising persons with knee OA fulfilling the clinical American College of Rheumatology classification criteria. Radiographic knee and hand OA severity was quantified with Kellgren-Lawrence sum scores. Knee and hand pain and function were assessed with validated questionnaires. We quantified fasted plasma higher order lipids and oxylipins with liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based platforms. Using penalised linear regression, we assessed the variance in OA severity explained by lipidomics, with adjustment for clinical covariates (age, sex, body mass index (BMI) and lipid lowering medication), measurement batch and clinical centre. Results: In 216 participants (mean age 66 years, mean BMI 27.3 kg/m2, 75% women) we quantified 603 higher order lipids (triacylglycerols, diacylglycerols, cholesteryl esters, ceramides, free fatty acids, sphingomyelins, phospholipids) and 28 oxylipins. Lipidomics explained 3% and 2% of the variance in radiographic knee and hand OA severity, respectively. Lipids were not associated with knee pain or function. Lipidomics accounted for 12% and 6% of variance in hand pain and function, respectively. The investigated OA severity outcomes were associated with the lipidomic fraction of bound and free arachidonic acid, bound palmitoleic acid, oleic acid, linoleic acid and docosapentaenoic acid. Conclusions: Within the APPROACH cohort lipidomics explained a minor portion of the variation in OA severity, which was most evident for the outcome hand pain. Our results suggest that eicosanoids may be involved in OA severity. (c) 2022 Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International.

[Abstract] Background: There are multiple measures for assessment of physical function in knee osteoarthritis (OA), but each has its strengths and limitations. The GaitSmart® system, which uses inertial measurement units (IMUs), might be a user-friendly and objective method to assess function. This study evaluates the validity and responsiveness of GaitSmart® motion analysis as a function measurement in knee OA and compares this to Knee Injury and Osteoarthritis Outcome Score (KOOS), Short Form 36 Health Survey (SF-36), 30s chair stand test, and 40m self-paced walk test. Methods: The 2-year Innovative Medicines Initiative-Applied Public-Private Research enabling OsteoArthritis Clinical Headway (IMI-APPROACH) knee OA cohort was conducted between January 2018 and April 2021. For this study, available baseline and 6 months follow-up data (n = 262) was used. Principal component analysis was used to investigate whether above mentioned function instruments could represent one or more function domains. Subsequently, linear regression was used to explore the association between GaitSmart® parameters and those function domains. In addition, standardized response means, effect sizes and t-tests were calculated to evaluate the ability of GaitSmart® to differentiate between good and poor general health (based on SF-36). Lastly, the responsiveness of GaitSmart® to detect changes in function was determined. Results: KOOS, SF-36, 30s chair test and 40m self-paced walk test were first combined into one function domain (total function). Thereafter, two function domains were substracted related to either performance based (objective function) or self-reported (subjective function) function. Linear regression resulted in the highest R2 for the total function domain: 0.314 (R2 for objective and subjective function were 0.252 and 0.142, respectively.). Furthermore, GaitSmart® was able to distinguish a difference in general health status, and is responsive to changes in the different aspects of objective function (Standardized response mean (SRMs) up to 0.74). Conclusion: GaitSmart® analysis can reflect performance based and self-reported function and may be of value in the evaluation of function in knee OA. Future studies are warranted to validate whether GaitSmart® can be used as clinical outcome measure in OA research and clinical practice. The research leading to these results have received support from the Innovative Medicines Initiative Joint Undertaking under Grant Agreement n° 115770, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. See www.imi.europa.eu and www.approachproject.eu. SM and FL are supported by the Dutch Arthritis Society This communication reflects the views of the authors and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.

We used data from the AutoImmunity and Rituximab (AIR) registry to investigate the safety of surgery for patients with rheumatoid arthritis receiving rituximab (RTX) in routine care.Data for patients included in the AIR registry and undergoing surgery during the year following an infusion of RTX were reviewed to describe the frequency of postsurgical complications, compare patients with and without complications, and identify factors associated with complications.We examined data for 133 patients with a known date of surgery and at least 1 followup visit, corresponding to 140 procedures, including 94 orthopedic surgeries (67%) and 23 abdominal surgeries (16.5%). The median delay between surgery and the last RTX infusion was 6.4 months (interquartile range 4.3– 8.7 months), without any difference between patients with and without complications. Nine patients (6.7%) experienced 12 complications (8.5%), including 8 surgical site infections (5.7%) and 1 death due to septic shock. Postoperative complications occurred after 4.3% of abdominal surgeries (1 of 23) and 7.4% of orthopedic surgeries (7 of 95). On univariate analysis, spine surgery was associated with postoperative complications (P = 0.048).In common practice, the risk of complications may be more important in case of spine surgery, but does not seem to be linked to the time between the last RTX infusion and surgery.

To compare the efficacy and safety of a 'medium' molecular weight (MW) hyaluronan product (F60027, Structovial) with a 'high' MW (Hylan G-F20, Synvisc).Prospective, randomised, multicentre, double-blind, active controlled, parallel-group study with a non-inferiority design. Patients with symptomatic KOA, global pain ≥ 40 mm (VAS, 0-100), Lequesne index (LFI, 0-24) score7 and radiological Kellgren-Lawrence grade 2/3 were centrally randomised to receive F60027 or Hylan G-F20, administered via three weekly injections, with regular follow-up evaluations up to week 24 (W24). The primary outcome was LFI score change over 24 weeks. Secondary outcomes comprised pain VAS, quality of life, patient's and physician's global assessments, rescue medication consumption and OMERACT-OARSI responders rate.276 patients were analysed in the full analysis dataset (FAS), 236 in the Per Protocol dataset (PP). In the main efficacy analysis (PP), the difference of the LFI score change over 24 weeks between F60027 (-4.67 (0.27)) and Hylan G-F20 (-4.54 (0.28)) was 0.132 [95%CI: -0.598, 0.861] which met the predefined non-inferiority margin. Analyses of secondary efficacy criteria showed clinically relevant improvements of all outcomes at W24 for each treatment on both PP/FAS populations. Changes of LFI score between baseline and W24 were -5.73 in the F60027 and -5.57 in the Hylan G-F20 group (PP dataset). Few local reactions were reported: 3.6% of patients in each group.F60027 and Hylan G-F20 were equally effective in reducing functional impairment and relieving pain in KOA patients, and well-tolerated.

AA amyloidosis is a complication of chronic inflam- ine level, albumin concentration at 1.79 g/dl, heavy matory diseases including Crohn’s disease, rheumatoid proteinuria (3 g/day), no haematuria, antinuclear antiarthritis, ankylosing spondylitis, and juvenile rheumat- body titres of 1/500, no anti-DNA antibodies, no oid arthritis. In contrast to the past, today it is less monoclonal gammopathy, and normal levels of comfrequently associated with chronic infectious diseases plement factors. The CRP level was high (6.7 mg/dl ) such as tuberculosis. AA amyloidosis has also been despite the presence of a nephrotic syndrome. No reported in cancer, Muckle‐Wells disease and familial infectious disease was found. Although there were no Mediteranean fever (FMT ) where the incidence diVers signs of active SLE, a diagnosis of membranous between less than 10% for Armeniens and Arabs and glomerulopathy was entertained and renal biopsy was over 30% among Turks and Sephardic Jews. performed which revealed massive glomerular and Conversely, AA amyloidosis is not a classic com- vascular Congo-red-positive areas exhibiting green plication of SLE, and fewer than 20 cases have been birefringence under polarized light, staining with reported in English worldwide, although cases of SLE anti-AA antibodies but not with other sera ( Figure 1). with monoclonal gammopathy may be complicated by Optic microscopy and immunofluorescence study AL amyloidosis. detected no SLE nephritis. Electron-microscopic

Several types of colitis can be NSAID-induced, but whether chronic use of NSAIDs alters colonic mucosa in patients without diarrhoea is not known.Biopsy specimens of rectal mucosa were taken in six patients with rheumatoid arthritis without diarrhoea receiving NSAIDs (group 1, n=6). Patients with rheumatoid arthritis without diarrhoea not receiving NSAIDs (group 2, n=9), and patients undergoing surveillance colonoscopy (group 3, n=23) served as controls. In all patients from the three study groups, intraepithelial lymphocyte count and apoptotic cell count were assessed, and sub-epithelial collagen band thickness was measured. Leucocyte population of lamina propria was evaluated semi-quantitatively. HLA-DR and CD25 expression of mucosal cells was appreciated by immunohistochemistry.Intraepithelial lymphocyte count was in the normal range in all three group patients, and not statistically different between groups. Apoptotic epithelial cell count was not different between groups. Sub-epithelial collagen band thickness was normal in all the patients. No patient had a marked infiltration of lamina propria by leucocytes, and HLA-DR and CD25 were normally expressed in all patients.These results from a small sample of patients suggest that patients without diarrhoea receiving NSAIDs on a long-term basis do not develop microscopic or inflammatory colitis.

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare syndrome of undetermined etiology occurring in the elderly. We describe the first case of RS3PE in a HLA-B27 positive 65-year-old man following intravesical bacillus Calmette-Guérin (BCG) instillation for bladder carcinoma. He developed symmetrical arthritis and synovitis involving wrists, knees, ankles, and metatarsophalangeal joints, with marked pitting edema of the dorsa of both hands and feet, fever, and elevated acute phase reactants. Right knee effusion revealed nonspecific sterile inflammatory fluid. He responded dramatically to nonsteroidal antiinflammatory drugs. BCG instillation may have triggered active symmetrical synovitis via local T cell activation and a T-helper-1 (Th-1)/Th-2 inflammatory profile.

To look for a systemic inflammatory response in patients with disk-related lumbosciatic syndrome by using an ultrasensitive (US) plasma C-reactive protein (CRP) assay, and to determine whether plasma CRP-US levels correlated with clinical and/or laboratory features.Plasma CRP was assayed using an enzyme-linked immunosorbent assay (ELISA) (detection limit, 5 microg/L) in patients with sciatica shown by computed tomography to be due to a disk herniation. Levels in 35 patients aged 23 to 64 years were compared to those in age- and sex-matched controls.Mean CRP-US levels measured by ELISA were significantly higher in the patients than in the controls (1.68 vs 0.74 mg/L; P = 0.002). There was a trend toward higher CRP-US levels in the patients with more severe nerve root symptoms.The significantly higher plasma CRP-US levels by ELISA in our patients with disk-related lumbosciatic syndrome is consistent with a systemic inflammatory response to the local nerve root impingement.

Rheumatoid arthritis and insulin-dependent diabetes mellitus are both autoimmune disorders of unknown etiology. We report the case of a patient who developed the two diseases simultaneously.A 64-year-old man with no remarkable medical history developed insulin-dependent diabetes disclosed by ketoacidosis that occurred 3 weeks after onset of a bilateral symmetrical polyarthritic syndrome characteristic of rheumatoid arthritis.These two disorders share common susceptibility of subjects with MHC class II molecules HLA DRB1*04. Immunological studies have also shown a common Th1 type cytokine-secretion pattern in both diseases. Epidemiological studies have not however clearly demonstrated a link between them.

The activity of the [-831; +103] promoter of the human cyclooxygenase-2 gene in cultured rabbit chondrocytes is stimulated 2.9 +/- 0.3-fold by interleukin-1beta and this stimulation depends on [-132; -124] C/EBP binding-and [-223; -214] NF-kappaB binding-sites. The C/EBPbeta and C/EBPdelta factors bind to the [-132; -124] sequence. The [-61; -53] sequence is also recognized by C/EBPbeta and C/EBPdelta as well as USF. Mutation of the whole [-61; -53] sequence abolished the stimulation of transcription but single mutations of the C/EBP or USF site did not alter the activity of the promoter, suggesting that the factors bound to the proximal [-61; -53] sequence interact with different members of the general transcription machinery. The [-223; -214] site binds only the p50/p50 homodimer and a non-rel-related protein, but not the transcriptionally active heterodimer p50/p65. The p50/p50 homodimer could interact with the C/EBP family members bound to the [-132; -124] sequence for full stimulation of the COX-2 transcription by interleukin-1beta in chondrocytes. By contrast, the [-448; -449] sequence binds with a low affinity both the p50/p50 homodimeric and p50/p65 heterodimeric forms of NF-kappaB but has no role in the regulation of the human COX-2 promoter in chondrocytes.

To develop a reproducible immortalized human chondrocyte culture model for studying the regulation of chondrocyte functions relevant to arthritic diseases in adult humans.Primary adult articular chondrocytes were immortalized with a retrovirus expressing a temperature-sensitive mutant of SV40-large T antigen (tsTAg). The established tsT/AC62 chondrocyte cell line was examined in monolayer and alginate culture systems. The levels of messenger RNA (mRNA) encoding cartilage matrix proteins and interleukin-1beta (IL-1beta)-inducible mRNA were analyzed by reverse transcriptase-polymerase chain reaction. Matrix protein synthesis was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of 35S-sulfate-labeled proteoglycans and Western blotting of type II collagen and aggrecan. Type II collagen (COL2A1)-luciferase reporter gene expression was analyzed by transient transfection. Phosphorylated stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), p38 mitogen-activated protein kinase (p38 MAPK), and activating transcription factor 2 (ATF-2) were detected by Western blotting.The tsT/AC62 cells expressed TAg at the permissive temperature (32degrees C), and the loss of TAg at 37 degrees C and 39 degrees C correlated with decreased cell proliferation. Cells in alginate culture deposited abundant alcian blue-stainable matrix and continued to proliferate at 32 degrees C. Preferential retention of aggrecan was observed in the cell-associated matrix, while biglycan and decorin were secreted into the medium of monolayer and alginate cultures. The levels of COL2A1 and aggrecan mRNA were increased after transfer from monolayer to alginate culture at 32 degrees C. Treatment with IL-1beta decreased COL2A1 and aggrecan mRNA levels and increased the levels of matrix metalloproteinases 1, 3, and 13 mRNA, as well as those of cyclooxygenase 2, type I collagen, and secretory phospholipase A2 type IIA mRNA, but not those of inducible nitric oxide synthase mRNA. IL-1beta also stimulated phosphorylation of p38 MAPK, SAPK/JNK, and ATF-2. The p38 MAPK-selective inhibitor, SB203580, partially reversed IL-1beta-induced inhibition of COL2A1 mRNA levels and COL2A1-luciferase reporter gene expression.The tsT/AC62 cells provide a reproducible model that mimics the adult articular chondrocyte phenotype, particularly in alginate culture, and demonstrates characteristic responses to IL-1beta. These studies also show, for the first time, that p38 MAPK is one of the signals required for IL-1beta-induced inhibition of COL2A1 gene expression. Availability of this model will permit identification of signals that regulate cytokine responses, and will also provide rational strategies for targeting these pathways.

The use of non steroidal anti-inflammatory drugs as analgesic or anti-inflammatory agents is primarily limited by their toxicity to the gastrointestinal tract. Two strategies have been developed recently in order to improve the safety of these drugs. The first approach is the linking of a nitric oxide-releasing moiety to the available compounds. The rationale is that nitric oxide may prevent non steroidal anti-inflammatory drugs-induced ulcerations by preventing mucosal ischemia. The second approach is based on the discovery of two isoforms (COX-1 and COX-2) of the cyclo-oxygenase enzyme. It was hypothesized that the constitutively expressed COX-1 isoenzyme leads to the synthesis of prostaglandins with homeostatic functions whereas COX-2 is merely responsible for the production of prostaglandins mediating pain, fever and inflammation. Accordingly, selective COX-2 inhibitors have been developed. Clinical trials indicate that these compounds are roughly as effective as the available non steroidal anti-inflammatory agents without causing acute gastrointestinal damage. There is some evidence that both COX-1 and COX-2 isoforms are involved in the production of prostaglandins associated with inflammation and homeostatic functions. Finally, the true benefit/risk ratio of these new non steroidal anti-inflammatory drugs remains to be assessed.

A NEW CLASS OF NSAID: All non-steroidal antiinflammatory drugs (NSAID) inhibit cyclooxygenase (COX) and prostaglandin synthesis implicated in inflammatory processes and also participate in protecting the gastric mucosa. The discovery of two isoforms of COX, called COX-1 and COX-2 has led to further research into dissociating NSAID efficacy and intolerance. COX-1 AND COX-2: It appears that the antiinflammatory and antalgesic effects of NSAID is related to COX-2 inhibition while the undesirable effects on the gastric mucosa would be related to COX-1 inhibition. A COX-2 specific inhibitor would thus provide the same efficacy as classic NSAID but without the digestive disadvantages.Celecoxib and rofecoxib are two COX-2 specific inhibitors. They have been found to have an effect comparable to classical NSAID.The fact that healthy gastric mucosa tolerates COX-2 specific inhibitors better does not necessarily mean that the same would be true for ulcerated mucosa, poorly repaired mucosa or simple areas of erosion.

Spondyloarthropathies constitute a group of autoimmune diseases of special interest because of their tight association with the MHC class I molecule HLA-B27 and the bacterial triggering of some clinical forms called reactive arthritis (ReA). One current hypothesis is the presentation by HLA-B27 of a so-called arthritogenic peptide to T cells. To better focus on the relevant T cell populations within the joint, we performed an extensive beta-chain T cell repertoire analysis of synovial fluid compared with PBL in seven patients, four of whom were characterized as having ReA triggered by Yersinia enterocolitica, Chlamydia trachomatis, or Shigella sonnei. Analysis of the size diversity of the beta-chain complementarity-determining region 3 (CDR3) allowed us to evaluate the degree of T cell clonality in the samples. Oligoclonal T cell expansions were frequently observed in the joint. In one patient, CDR3 amino acid sequences of major expansions using two different BV genes were identical. One dominant T cell expansion and several CDR3 amino acid sequences were identical in two different patients. Furthermore, one sequence was identical with a sequence reported independently in a Salmonella-induced ReA patient. Together, these data indicate a surprisingly high degree of conservation in the T cell responses in recent-onset ReA triggered by different micro-organisms. A CD8+ synovial line expressing shared clonotypes was established and reacted toward several B*2705 lymphoblastoid cell lines, therefore supporting a molecular mimicry phenomenon at the T cell level in the disease mechanism.

Kaposi's sarcoma in its sporadic or HIV-related form is due to a gamma herpesvirus, the human herpes virus 8 (HHV8). No data have been published on the potential role of the HHV8 in Kaposi's sarcoma occurring in multiple myeloma patients. A case is reported of a patient in whom four serum samples taken between the diagnosis of multiple myeloma and the occurrence of a Kaposi's sarcoma one year later tested positive for antibody to the HHV8. Similar findings have been reported in patients with other types of Kaposi's sarcoma. PCR studies for HHV8 DNA were positive on a Kaposi's sarcoma biopsy but negative on a bone biopsy, militating against a role for the HHV8 in the genesis of multiple myeloma.

Osteoarthritis is mainly characterized by cartilage degradation as a result of series of pathological processus still not well understood. In recent years much interest has centered on the contribution of cytokines to cartilage degradation: characterization of cytokines extracted from normal and pathological articulation, site of production (synoviocytes, chondrocytes, osteoblasts) and their role on the production of proteases, protease inhibitors or other types of molecules implicated in osteoarthritis. Several types of cytokines such as IL 1 beta and TNF alpha, known as proinflammatory factors in rheumatoid arthritis, have been shown to be present in the synovial fluid from osteoarthritic patients. Recent experimental data allow us to better understand the cellular and molecular mechanisms of the cytokines respectively involved into rheumatoid arthritis and osteo-arthritis.

Secreted phospholipase A2 has been detected in numerous inflammatory and infectious diseases. Since the cloning of the type II sPLA2 in 1989 from rheumatoid arthritis synovial fluid, a direct or indirect participation of type II sPLA2 in the production of lipid mediators has been purposed. This paper reviews the different studies from the literature alleging that type II sPLA2 participates to inflammatory processes and lipid mediators synthesis.

Granulocyte macrophage colony stimulating factor (GM-CSF) is one of the main cytokines involved in tissue damage during rheumatoid arthritis (RA). To investigate the expression of the GM-CSF receptor (GM-CSF-R) in the synovial tissue of osteoarthritic (OA) and RA patients, biopsy specimens were obtained ex vivo during therapeutic arthroscopy. A semi-quantitative polymerase chain reaction (PCR) technique was performed using specific primers for the alpha chain of the GM-CSF-R and for beta-actin. The PCR products were analyzed after slot-blotting and hybridization with specific cDNA probes. Both RA (n = 11) and OA (n = 7) samples were positive. No significant overexpression correlating with the clinical or histological disease status of the patients was observed. In conclusion, GM-CSF-R could be detected in the synovial tissue where it can mediate the effects of this cytokine locally produced during RA inflammation.

An unusual clinical presentation of hyperparathyroidism is reported. The 73-year-old patient was unable to maintain her head upright after ten minutes of walking or standing. Parathyroid adenoma was diagnosed on the basis of ultrasound and pathological findings and parathyroid hormone assays. Following surgery the forward sagging of the head no longer occurred and serum levels of calcium and phosphorus returned to normal. Pathophysiological hypotheses are discussed. No similar cases with isolated weakness of the cervical and dorsal paravertebral muscles has been reported to date.

Bone and joint infections due to Haemophilus parainfluenzae are unusual. We describe a case of hematogenous vertebral osteomyelitis caused by this commensal microorganism of nose and oropharynx. Early diagnosis and therapy were possible within a week using sensitive radiologic methods: technetium bone scanning, computed tomography and magnetic resonance imaging.

The case reported concerns an obese patient suffering from lumbo-radicular intermittent claudication due to lumbar epidural lipomatosis. Compression was revealed by magnetic resonance imaging which showed the existence of a hypersignal in weighted sequences in T1 situated in the epidural space and narrowing the dural sheath. Three cases of lumbar epidural lipomatosis related to obesity have already been described. Treatment in all three was surgical with the result assessed as good in one case and poor in two. The interest of the present case is demonstration of the cause and effect relationship between epidural lipomatosis and obesity as shown by complete restoration of the epidural space after a calorie-controlled diet, and the possibility of successful treatment by this technique.

Objective To compare the characteristics of traditional cardiovascular risk factors for untreated patients with early arthritis (EA) and healthy subjects, and to look for a link between cardiovascular risk factors and inflammation in EA patients. Methods This multicenter case–control study enrolled 607 patients with EA (ESPOIR cohort) and 1,821 age- and sex-matched controls (World Health Organization MONICA survey). Lipid levels, blood pressure, glucose levels, and exposure to smoking were characterized in patients and controls. Systemic inflammation was quantified in EA patients. Traditional cardiovascular risk factor characteristics were compared between patients with EA and controls. The link between cardiovascular risk factors and inflammation was assessed in EA patients. Results Mean ± SEM total cholesterol (2.14 ± 0.022 versus 2.34 ± 0.017 gm/liter; P < 0.001), high-density lipoprotein (HDL) cholesterol (0.60 ± 0.011 versus 0.63 ± 0.007 gm/liter; P = 0.020), and low-density lipoprotein (LDL) cholesterol (1.28 ± 0.025 versus 1.51 ± 0.016 gm/liter; P < 0.001) were lower in EA patients than in controls. Triglycerides, triglycerides/HDL ratio, and pulse pressure were higher in patients with EA. Diastolic blood pressure and glucose levels were lower in EA patients. Former or current smokers were more frequent in patients with EA. Total and HDL cholesterol levels were negatively associated with C-reactive protein or serum interleukin-6 levels. Conclusion Total, HDL, and LDL cholesterol, triglycerides, diastolic blood pressure, pulse pressure, glucose, and triglycerides/HDL ratio differ between patients with EA and controls. Some of these risk factors appear to be linked to systemic inflammation. Such initial differences could modulate the risk of cardiovascular events later in the course of arthritis.