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Contains fulltext : 225037.pdf (Publisher’s version ) (Closed access) 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.

This study evaluated the arthritogenic effect of lipopolysaccharide (LPS) in a mouse model of periodontal disease. Periodontitis was induced in wild-type CD1 mice by nine LPS injections (10 or 50 ng) into the maxillary mucosa. Untreated mice or injected with LPS at the tail were used as controls. Two weeks after final inoculation, mice were sacrificed to collect blood, maxilla, and paw samples. Development and progression of periodontitis and arthritis were monitored using clinical assessment, micro-computed tomography (micro-CT), ultrasound (US), and histological analysis. CXCL1, IL-1β, IL-6, TNF-α, and anti-citrullinated peptide antibodies (ACPA) serum levels were determined by enzyme immunoassay. Ankle swelling and inflammation manifested after the 5th periodontal injection of 50 ng of LPS and progressed until the end of experiments. Periodontal injection of 10 ng of LPS and LPS tail injection did not induce paw changes. Therefore, the subsequent assessments were conducted only in mice periodontally injected with 50 ng of LPS. Maxillary micro-CT and histological analysis showed that LPS-induced alveolar bone resorption and vascular proliferation in periodontal tissue, but not inflammation. US and histology revealed increased joint space, leukocyte infiltration, synovial proliferation, and mild cartilage and bone destruction in the paws of mice orally injected. Cytokines and ACPA showed a trend towards an increase in LPS mice. This study shows that arthritis and periodontal disease can co-occur in wild-type mice after periodontal injection of LPS at optimal dose. Our model may be useful to improve the understanding of the mechanisms linking periodontitis and arthritis.

ObjectiveTo evaluate the discriminatory ability of ultrasound in calcium pyrophosphate deposition disease (CPPD), using microscopic analysis of menisci and knee hyaline cartilage (HC) as reference standard.MethodsConsecutive patients scheduled for knee replacement surgery, due to osteoarthritis (OA), were enrolled. Each patient underwent ultrasound examination of the menisci and HC of the knee, scoring each site for presence/absence of CPPD. Ultrasound signs of inflammation (effusion, synovial proliferation and power Doppler) were assessed semiquantitatively (0–3). The menisci and condyles, retrieved during surgery, were examined microscopically by optical light microscopy and by compensated polarised microscopy. CPPs were scored as present/absent in six different samples from the surface and from the internal part of menisci and cartilage. Ultrasound and microscopic analysis were performed by different operators, blinded to each other’s findings.Results11 researchers from seven countries participated in the study. Of 101 enrolled patients, 68 were included in the analysis. In 38 patients, the surgical specimens were insufficient. The overall diagnostic accuracy of ultrasound for CPPD was of 75%—sensitivity of 91% (range 71%–87% in single sites) and specificity of 59% (range 68%–92%). The best sensitivity and specificity were obtained by assessing in combination by ultrasound the medial meniscus and the medial condyle HC (88% and 76%, respectively). No differences were found between patients with and without CPPD regarding ultrasound signs of inflammation.ConclusionUltrasound demonstrated to be an accurate tool for discriminating CPPD. No differences were found between patents with OA alone and CPPD plus OA regarding inflammation.

Purpose To evaluate cytokine production in vitro by different types of leukocytes stimulated with monosodium urate (MSU), calcium pyrophosphate (CPP) and basic calcium phosphate (BCP) crystals. Material and methods Polymorphonuclear cells (PMN), monocytes and lymphocytes, isolated from healthy volunteer blood, were stimulated for different time periods with increasing MSU, CPP or BCP crystal concentrations. IL-1β, IL-8, IL-6, CCL2, IL-1Ra and TGFβ1 were determined by ELISA. Results Exposure of PMN to different crystals resulted in a moderate IL-8 and IL-1Ra release. Stimulation of monocytes induced a significant production of all the cytokines evaluated. The highest levels of IL-1β, IL-6, CCL2 and IL-8 were observed with MSU at 0.5 mg/ml, CPP at 0.01–0.05 mg/ml and BCP at 1 mg/ml after 18–48 h and then decreased. At the same crystal concentrations, IL-1Ra and TGFβ1 increased until the end of the experiment. Treatment of lymphocytes with different crystals did not induce cytokine release. Conclusion This study demonstrates that PMN, monocytes and lymphocytes from the same donor respond differently after stimulation with MSU, CPP or BCP crystals, depending on the dose and the time of exposure. Crystals induce a rapid increase of pro-inflammatory cytokines, whereas longer time is required to release high levels of anti-inflammatory cytokines.

Background NKG2D ligands (NKG2DLs) are stress-inducible molecules involved in multiple inflammatory settings. In this work, we quantified MICA, an NKG2DL, in the synovial fluid of patients suffering various arthritides and measured Nkg2dLs gene expression in murine models of acute joint inflammation. Methods Soluble MICA (sMICA) was quantified by ELISA is synovial fluids harvested from patients suffering osteoarthritis, rheumatoid arthritis, psoriatic arthritis, calcium pyrophosphate crystal arthritis, urate crystal arthritis and reactive arthritis. Transcripts encoding murine NKG2DLs were quantified by RT-qPCR in the joints of mouse models of rheumatoid arthritis, urate crystal arthritis and osteoarthritis. Results Marked overproduction of sMICA was observed in the synovial fluid of RA patients. Mouse studies highlighted the complex transcriptional regulation of Nkg2d ligands encoding genes depending on the inflammatory setting and microenvironment Conclusions sMICA quantification could be an interesting biomarker to identify acute inflammation in RA patients in which classical markers (ie, anti-citrullinated protein antibodies, ACPA) are undetectable.

Polyphenols have been extensively investigated with regard to their antioxidant, anti-inflammatory, and immunomodulant properties in many inflammatory chronic conditions. The aim of this review is to summarise how these compounds can modulate the inflammatory pathways which characterise the most prevalent arthropathies including osteoarthritis, rheumatoid arthritis and crystal-induced arthritis. Among polyphenols, epigallocatechin gallate, carnosol, hydroxytyrosol, curcumin, resveratrol, kaempferol and genistein have been the most widely investigated in arthritis. The most important results of the studies outlined in this article show how polyphenolic compounds are able to inhibit the expression and the release of a number of pro-inflammatory mediators and proteolytic enzymes, the activity of different transcriptional factors and the production of reactive oxygen species in vitro. Studies on animal models of rheumatoid arthritis, osteoarthritis and gout show interesting results in terms of reduced tissue damage, restored cartilage homeostasis, and decreased levels of uric acid, respectively. Despite the multiple protective effects of polyphenols, there are no dietary recommendations for patients affected by rheumatic diseases. Future studies, including intervention trials, should be conducted to determine the relevance of polyphenols consumption or supplementation in arthritis. © 2017 Society of Chemical Industry.

Background:Only few case reports and case series have analysed the efficacy of IL-1 inhibitors in the treatment of calcium pyrophosphate deposition disease (CPPD), reporting conflicting results.Objectives:The main aim of this systematic literature review (SLR) was to summarize the evidence in the use of biological therapies in CPPD.Methods:PRISMA-IPD guidelines were used for this review. Published articles reporting the use of TNFα and/or IL-1 inhibitors in the treatment of CPPD were reviewed. We performed a SLR using PubMed, Embase and Cochrane databases. The search resulted in 83 articles; 11 were further evaluated in the SLR.Results:Seventy-six patients were included: 2 received infliximab, whereas 74 anakinra. The main data of included studies are reported in table 1.Table 1.Studies evaluating biological therapies in patients with CPPD.AuthorsYear of publicationPopulation of interestNumber of CPPD patientsDiagnostic criteriaClinical presentationMcGonagle D. et al.2008CPPD1SFAChronicAnnoun N. et al.2009CPPD1SFAAcuteCouderc M. et al.2012CPPD3ImagingAcute and chronicDiamantopoulos A.P. et al.2012CPPD1SFAChronicMoltó A. et al.2012CPPD5SFAAcute and chronicOttaviani S. et al.2013CPPD16SFA and/or imagingAcuteVerhoeven F. et al.2013G and CPPD2NRAcute and chronicBruges-Armas J. et al.2014CPPD2NRChronicAouba A. et al.2015G, CPPD and HADD1ImagingAcuteDesmarais J. et al.2018G, CPPD11SFA and/or imagingAcuteThomas M. et al.2018CPPD32SFA and/or imagingAcuteLegend.G: gout,HADD: hydroxyapatite deposition disease,NR: not reported,SFA: synovial fluid analysisTable 2.Efficacy of anakinra in the treatment of CPPDAcute CPPD (n=67)Chronic CPPD (n=7)Clinical efficacy (%)54 (80.6)3 (42.9)Pre TJC6.3±2.43.8±2.4Post TJC1.2±0.61.3±1.5Mean reduction5.1±2.3*2.5±1.9+Pre SJC4.8±2.23.8±2.4Post SJC1.1±0.61.3±1.5Mean reduction3.7±2.2*2.5±1.9+Pre VAS pain (0-100 mm)68.5±9.5/Post VAS pain (0-100 mm)24.2±10.4/Mean reduction44.2±10.9*/Pre CRP (mg/l)40.9±50.950.0±66.5Post CRP (mg/l)22.2±8.63.2±2.5Mean reduction18.6±54.1*46.7±64.0+Legend. CRP: C-reactive protein,SJC: swollen joint count,TJC: tender joint count,VAS: visual analogue scale.+p values were not calculated because of a too small sample size. * p values were Sixty-seven (88.2%) patients presented with an acute CPPD (mean disease duration: 2.7±6.9 months; polyarticular involvement in 61.2%, oligoarticular in 31.3% and monoarticular in 7.5%), whereas 9 (11.8%) patients with a chronic CPPD (mean disease duration: 130.1±133.6 months; polyarticular involvement in 66.7% and oligoarticular in 33.3%).Anakinra was used in refractory disease (85.1%) or in patients with contraindications to standard treatments such as colchicine, oral glucocorticoids and/or non-steroidal anti-inflammatory drugs (23.0%). Clinical response to anakinra was reported in table 2.Duration of anakinra treatment prior to complete resolution of symptoms was associated with the clinical phenotype of chronic CPPD (Rpb: 0.67, pConclusion:This SLR provides evidence in favour of the use of anakinra as a therapeutic option in patients with CPPD, especially in acute refractory CPPD or when standard treatments are contraindicated.Disclosure of Interests: :Edoardo Cipolletta: None declared, Andrea Di Matteo Grant/research support from: the publication was conducted while Dr. Di Matteo was an ARTICULUM fellow, Anna Scanu: None declared, Martina Isidori: None declared, Jacopo Di Battista: None declared, Leonardo Punzi: None declared, Walter Grassi Speakers bureau: Prof. Grassi reports personal fees from AbbVie, personal fees from Celgene, personal fees from Grünenthal, personal fees from Pfizer, personal fees from Union Chimique Belge Pharma, outside the submitted work., Emilio Filippucci Speakers bureau: Dr. Filippucci reports personal fees from AbbVie, personal fees from Bristol-Myers Squibb, personal fees from Celgene, personal fees from Roche, personal fees from Union Chimique Belge Pharma, personal fees from Pfizer, outside the submitted work.

Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy involving synovial and entheseal structures, associated with psoriasis or similar conditions. The etiopathogenetic mechanisms underlying PsA remain unclarified. The most accredited hypothesis involves a complex interaction among genetic, environmental, and immunological factors. Environmental agents, particularly trauma, mechanical stress, and smoke have been cited as possible factors in triggering the disease in genetically predisposed subjects. Like other forms of spondyloarthropathies, PsA shows several genetic associations with the major histocompatibility complex (MHC) class I alleles located on chromosome 6p21.3, particularly the human leukocyte antigen (HLA)-B27 in axial phenotypes. Recent studies have demonstrated that the most common epigenetic mechanisms that regulate gene expression in PsA are represented by DNA methylation, parent of origin effect or genomic imprinting, expression or activity of epigenetic modifying enzymes, and RNA interference (RNAi) by microRNAs (miRNAs). The mechanisms underlying PsA pathogenesis activate the innate and adaptive immune system and overexpression of TNF associated with amplification of the IL-23/IL-17 axis. In recent years, more PsA susceptibility genes and epigenetic mechanisms have been identified. Advances in the knowledge of innate and adaptive immune mechanisms underlying PsA have contributed to a better understanding of the heterogeneous clinical expression of the disease and, thus, to therapy strategies. The complexity of the pathogenetic aspects involving multiple cytokines, cell lines, and molecules needs to be further investigated to advance personalized therapeutic strategies and to improve outcomes of patients affected by PsA.

Osteoarthritis is characterized by articular cartilage breakdown, and emerging evidence suggests that dysregulated innate immunity is likely involved. Here, we performed proteomic, transcriptomic, and electron microscopic analyses to demonstrate that mast cells are aberrantly activated in human and murine osteoarthritic joint tissues. Using genetic models of mast cell deficiency, we demonstrate that lack of mast cells attenuates osteoarthritis in mice. Using genetic and pharmacologic approaches, we show that the IgE/FcεRI/Syk signaling axis is critical for the development of osteoarthritis. We find that mast cell-derived tryptase induces inflammation, chondrocyte apoptosis, and cartilage breakdown. Our findings demonstrate a central role for IgE-dependent mast cell activation in the pathogenesis of osteoarthritis, suggesting that targeting mast cells could provide therapeutic benefit in human osteoarthritis.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Calprotectin is a heterodimer formed by two proteins, S100A8 and S100A9, which are mainly produced by activated monocytes and neutrophils in the circulation and in inflamed tissues. The implication of calprotectin in the inflammatory process has already been demonstrated, but its role in the pathogenesis, diagnosis, and monitoring of rheumatic diseases has gained great attention in recent years. Calprotectin, being stable at room temperature, is a candidate biomarker for the follow-up of disease activity in many autoimmune disorders, where it can predict response to treatment or disease relapse. There is evidence that a number of immunomodulators, including TNF-α inhibitors, may reduce calprotectin expression. S100A8 and S100A9 have a potential role as a target of treatment in murine models of autoimmune disorders, since the direct or indirect blockade of these proteins results in amelioration of the disease process. In this review, we will go over the biologic functions of calprotectin which might be involved in the etiology of rheumatic disorders. We will also report evidence of its potential use as a disease biomarker.Impact statementCalprotectin is an acute-phase protein produced by monocytes and neutrophils in the circulation and inflamed tissues. Calprotectin seems to be more sensitive than CRP, being able to detect minimal residual inflammation and is a candidate biomarker in inflammatory diseases. High serum levels are associated with some severe manifestations of rheumatic diseases, such as glomerulonephritis and lung fibrosis. Calprotectin levels in other fluids, such as saliva and synovial fluid, might be helpful in the diagnosis of rheumatic diseases. Of interest is also the potential role of calprotectin as a target of treatment.

Objective To investigate effectiveness and safety of belimumab in patients with active systemic lupus erythematosus (SLE) in a clinical practice setting. Methods Sixty-seven patients with active SLE, mean ± SD age 39.3 ± 10.2 years, from 2 Italian prospective cohorts were treated with belimumab (10 mg/kg on day 0, 14, 28, and then every 28 days) added to background therapy. The Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, the Disease Activity Score in 28 joints (DAS28), 24-hour proteinuria, the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity score, anti–double-stranded DNA (anti-dsDNA), C3 and C4 levels, and prednisone daily dose were recorded at baseline, month 3, 6, 9, 12, 18, and 24. Arthritis was subdivided into “classical” (CLP) and “rheumatoid-like”; skin manifestations into acute (ACLE), subacute (SCLE), and chronic. SLE flares, defined according to the SLEDAI Flare Index, were calculated before and after belimumab initiation. Adverse events were carefully evaluated during treatment. Statistics were performed by the SPSS package (version 21.0). Results Mean ± SD followup was 16.2 ± 9.5 months. Main refractory manifestations treated with belimumab were musculoskeletal (37.3%), mucocutaneous (22.4%), and renal (23.9%). SLEDAI-2K, prednisone daily dose, anti-dsDNA, DAS28, CLASI, and 24-hour proteinuria decreased during treatment. DAS28 score decreased in patients with polyarthritis (P

Patients affected with systemic lupus erythematosus (SLE) still display increased mortality and decreased quality of life in respect to general population. The major determinant of poor long term prognosis is organ damage, which is predictive of more damage and death. Damage is in turn triggered by uncontrolled disease activity and especially by the long-standing corticosteroid use which often accompanies SLE patients over their disease course, owing both to the need of reaching disease remission and to the habit of keeping patients on a small steroid dose for an indefinite period of time. Hence, the need for new drugs and therapeutic strategies aiming at minimizing damage accrual through a better control of disease activity and a steroid-sparing potential is paramount. So far, however, the therapeutic strategy in SLE requires a multitarget approach which is not devoid of widespread immunesuppression. In fact, several studies have been carried out in recent years targeting both the adaptive and the innate immune system, the majority of which did not achieve their primary endpoint, being often divergent from successful clinical experience and thereby committing physician to off-label use of targeted therapies in face of refractory SLE manifestations. The study designs and the chosen endpoints were often blamed for inadequacy, being at least in part responsible for study failures. In this review, we go over major clinical trials conducted in SLE by analyzing any critical aspects related to study design, predefined endpoints and biological activity of novel compounds that may have hampered study outcome, despite the great effort of providing less toxic drugs within a targeted, pathogenic-based approach.

Anti-pentraxin 3 (PTX3) antibodies were associated with the absence of lupus glomerulonephritis in humans.To explore the effects of anti-PTX3 antibodies in New Zealand Black/White (NZB/NZW F1) mice and their inherent mechanisms of action.30 NZB/NZW F1 mice were subdivided into 3 groups of 10 mice each and subcutaneously injected with PTX3, alum and PBS (group 1), alum and PBS (group 2) or PBS alone (group 3), 3 times 3 weeks apart, before development of renal disease. Mice were followed until natural death. Histological analysis and immunohistochemistry were performed on harvested kidneys. Effects of anti-PTX3 antibodies on C1q binding to immobilized PTX3-anti-PTX3 immune complexes were evaluated in vitro using human SLE sera. Qualitative characterization of human IgG anti-PTX3 was performed.Only group 1 mice developed anti-PTX3 antibodies. Anti-dsDNA and anti-C1q antibodies appeared significantly later and at lower levels in group 1 mice vs. controls (p 0.0001). Proteinuria-free and overall survival were significantly increased in group 1 mice vs. controls (p 0.05 and p = 0.03, respectively). Histopathological analysis showed that glomerular and tubular PTX3 staining and renal lesions were increased in controls compared with immunized mice. Addition of human SLE sera positive for anti-PTX3 antibodies to C1q and fixed PTX3 interfered with C1q binding to PTX3-anti-PTX3 immune complexes. Qualitative characterization of human IgG anti-PTX3 showed an increased proportion of IgG4.Anti-PTX3 antibodies delay lupus-like nephritis and prolong survival of NZB/NZW F1 mice. In vitro observations suggest anti-PTX3 antibodies may dampen complement activation via their Fc fragment, likely hindering renal inflammation.

Background:The OMERACT Ultrasound (US) in calcium pyrophosphate deposition disease (CPPD) sub-task force has been working on the use of US in CPPD since 2014 first creating definitions for CPPD identification and then assessing the reliability[1].Objectives:Objective of this study is to assess the diagnostic accuracy (truth) of US in CPPD.Methods:Consecutive patients waiting to undergo knee replacement surgery due to osteoarthritis were enrolled in 12 centres from 6 countries. Each patient underwent US examination of the knee, focusing on the menisci and the hyaline cartilage, the day prior to surgery, scoring each site for presence/absence of CPP as defined previously[1]. After surgery, the menisci and the condyles were retrieved and examined microscopically. Six samples were collected, both from the surface and from the internal part of menisci and cartilage trying to cover a large part of it. All slides were observed under transmitted light microscopy and by compensated polarised microscopy. A dichotomous score was given for the presence/absence of CPP. US and microscopic analysis were performed by different operators, blind to each other’s findings. Sensitivity and specificity of US were calculated using microscopic findings as the gold standard.Results:101 patients have been enrolled in the study. 33 patients have been excluded due to loss of anatomical pieces at surgery. The mean age of the remaining 68 pts was 71yo (±8), 44 women, 34 were affected by CPPD according to microscopy. Overall and per site diagnostic US accuracy results are presented in table 1Diagnostic accuracySensitivitySpecificityPositive Predictive valueNegative Predictive valueGlobal0.750.910.590.690.87Medial meniscus0.820.870.770.770.87Lateral meniscus0.750.830.680.680.83Medial cartilage0.860.790.920.880.85Lateral cartilage0.820.710.880.770.84Medial side (combined cartilage and meniscus)0.820.880.760.790.87Lateral side (combined cartilage and meniscus)0.780.880.690.730.86Conclusion:Our results demonstrate that US is an accurate exam for identification of CPPD. The best combination of sensitivity and specificity is achieved by examining the medial aspect of the knee.References:[1]Filippou G, Scirè CA, Adinolfi A,et al.Identification of calcium pyrophosphate deposition disease (CPPD) by ultrasound: reliability of the OMERACT definitions in an extended set of joints—an international multiobserver study by the OMERACT Calcium Pyrophosphate Deposition Disease Ultrasound Subtask Force.Ann Rheum Dis2018;:annrheumdis-2017-212542. doi:10.1136/annrheumdis-2017-212542Disclosure of Interests:Georgios Filippou: None declared, Anna Scanu: None declared, Antonella Adinolfi: None declared, Carmela Toscano: None declared, Dario Gambera: None declared, Raquel Largo: None declared, Esperanza Naredo: None declared, Emilio Calvo: None declared, Gabriel Herrero-Beaumont: None declared, Pascal Zufferey: None declared, Christel Madelaine-Bonjour: None declared, Daryl MacCarter: None declared, Stanley Makman: None declared, Zachary Weber: None declared, Fabiana Figus: None declared, Ingrid Möller: None declared, Marwin Gutierrez: None declared, Carlos Pineda: None declared, Denise Clavijo Cornejo: None declared, Héctor García: None declared, Victor Ilizaliturri: None declared, Jaime Mendoza Torres: None declared, Raul Pichardo: None declared, Luis Carlos Rodriguez Delgado: None declared, Emilio Filippucci Speakers bureau: Dr. Filippucci reports personal fees from AbbVie, personal fees from Bristol-Myers Squibb, personal fees from Celgene, personal fees from Roche, personal fees from Union Chimique Belge Pharma, personal fees from Pfizer, outside the submitted work., Edoardo Cipolletta: None declared, Teodora Serban: None declared, Catalin Cirstoiu: None declared, Florentin Ananu Vreju: None declared, Dun Grecu: None declared, Gael Mouterde: None declared, Marcello Govoni: None declared, Leonardo Punzi: None declared, Nemanja Damjanov Grant/research support from: from AbbVie, Pfizer, and Roche, Consultant of: AbbVie, Gedeon Richter, Merck, Novartis, Pfizer, and Roche, Speakers bureau: AbbVie, Gedeon Richter, Merck, Novartis, Pfizer, and Roche, Lene Terslev Speakers bureau: LT declares speakers fees from Roche, MSD, BMS, Pfizer, AbbVie, Novartis, and Janssen., Carlo Alberto Scirè: None declared, Annamaria Iagnocco Grant/research support from: Abbvie, MSD and Alfasigma, Consultant of: AbbVie, Abiogen, Alfasigma, Biogen, BMS, Celgene, Eli-Lilly, Janssen, MSD, Novartis, Sanofi and Sanofi Genzyme, Speakers bureau: AbbVie, Alfasigma, BMS, Eli-Lilly, Janssen, MSD, Novartis, Sanofi

Background:Acute calcium pyrophosphate (CPP) crystal-induced inflammation is characterized by the massive release of cytokines and pro-inflammatory mediators and, from a clinical point of view, pain and limited joint function. Contrary to the precipitation of urate crystals that can be prevented through the use of hypouricemic drugs, there is no pharmacological therapy that can prevent the formation of pyrophosphate crystals.Polydatin (PD),a natural precursor of resveratrol, is a stilbenoid mainly contained in grape juice and bark of Polygonum Cuspidate. Its antioxidant, anti-inflammatory and immunomodulating properties have been demonstrated in several experimental models. We have recently shown that this compound is able to prevent the inflammatory response to pathogenic crystals in vitro (1).Objectives:The aim of this study was to assess the anti-inflammatory preventing effect of polydatin in the mouse model of acute crystal-induced arthritis.Methods:A suspension of sterile CPP crystals (0.3 mg/20 μL PBS) have been injected intra-articularly (i.a.) into one ankle joint of Balb/c mice under isoflurane anesthesia. Animals were randomized in 5 groups: 1- CPP injection, 2- CPP + PD, 3- CPP + colchicine (control drug), 4- CPP + vehicle (control. N 1), 5- PBS injection (control N. 2). Polydatin and colchicine were administered by gavage (respectively 40 mg/kg and 1mg/kg in 200 μL PBS/EtOH/glucose) at 24, 15 and 1 h before and 1, 6 and 24 h after (prophylactic model) or 1, 6 and 24 h after (therapeutic model) i.a. injection of CPP crystals.Ankle swelling was measured at different time points using a precision caliper. After 48h (peak of the acute phase) mice were euthanized and blood and ankle joints were collected for inflammatory cytokine (IL-1ß and KC) determination and histological analysis, respectively.Results:The mean change in ankle swelling after i.a injection was 0.595±0.434 mm. Prophylactic treatment with PD and colchicine significantly diminished ankle swelling to 0.175±0.115 mm and 0.137±0.100 mm, respectively (Kruskal Wallis p 0.0025; Dunn’s post test p < 0.01 CPP vs PD+CPP). The therapeutic administration of PD did not have significant effects on delta swelling (0.468±0.372 mm - PD vs 0.243±0.152 mm - colchicine). In mice treated with CPP crystals, histological analysis revealed areas of edema and increased cell infiltrate in articular and periarticular tissues and the presence of reactive lymphnodes. Tissue necrosis around inflamed tissue has been observed. Treatment with PD importantly reduced cell infiltrate in the prophylactic but not in the therapeutic protocol.Serum IL-1ß and KC levels, which increased significantly (pConclusion:PD can effectively prevent acute inflammatory response to crystals in the mouse model of CPP arthritis. Oral PD prophylactic treatment showed a similar effect of colchicine in reducing ankle swelling and cell infiltrate. However, only colchicine showed to be effective in the therapeutic protocol.These results raise the possibility that PD might have utility in the prevention of crystal-induced acute attacks in humans.References:[1]Oliviero F, et al. Polydatin and resveratrol inhibit the inflammatory process induced by urate and pyrophosphate crystals in thp-1 cells.Foods 2019 Nov 7;8(11). pii: E560.Disclosure of Interests:Francesca Oliviero: None declared, Francesca Galuppini: None declared, Anna Scanu: None declared, Paola Galozzi: None declared, Vanni Lazzarin: None declared, Paolo Sfriso: None declared, Gianpietro Ravagnan: None declared, Roberta Ramonda Speakers bureau: Novartis, Celgene, Janssen, Pfizer, Abbvie, Lilly, Paolo Spinella: None declared, LEONARDO PUNZI: None declared, Gianmaria Pennelli: None declared, Roberto Luisetto: None declared

Background MIC-A (Major histocompatibility complex class I chain-related gene A)1 is a transmembrane or soluble protein that interacts with the activating NKG2D receptor. MIC-A stimulates effector responses mediated by NK and CD8 +T cells under cellular stress conditions, like cancer or infections.2 MIC-A is also associated with autoimmune diseases (such as rheumatic disorders) characterised by immune dysregulation triggered by environmental factors, and plays important roles in immune activation and surveillance.3 In mice, various NKG2D ligands were discovered: Rae-1, H60 and MULT1 families.4 Objectives This study aims at investigating the potential pathological relevance of soluble MIC-A (sMIC-A) protein in inflammatory rheumatic diseases involving articular structures in humans. The expression of orthologous NKG2D ligands in mouse models of experimental joint inflammation is also quantified. Methods We collected synovial fluid (SF) from 118 subjects: 22 Rheumatoid Arthritis (RA), 13 Psoriatic Arthritis (PSOA), 12 Gout Disease (GOUT), 18 Calcium Pyrophosphate Deposition Disease (CPPD), 8 Reactive Arthritis (REA) and 45 Osteoarthritis patients. Gout and CPPD diseases were confirmed by the presence of crystals in SF. Clinical data were collected. The concentration of soluble MIC-A (sMIC-A), interleukin (IL)−1, IL-6 and IL-8 was measured by ELISA. Murine Rae-1, H60 and Mult1 transcripts were quantified by real-time quantitative PCR (RT-qPCR) in 3 models of joint inflammation: Serum Transfer Arthritis (STA), Collagen-induced arthritis (CIA) and Collagenase-Induced Osteoarthritis (CIOA). Results Significantly higher levels of sMIC-A were found in the synovial fluid of RA patients in comparison with all others diseases (p Conclusions Our data identifies synovial sMIC-A as an important player in rheumatoid arthritis compared to other rheumatic diseases and osteoarthritis. Investigations in mouse models are in agreement with this finding References [1] Bahram, Seiamak, et al. A second lineage of mammalian major histocompatibility complex class I genes. Proceedings of the National Academy of Sciences1994;91(14):6259–6263. [2] Groh, Veronika, et al. Costimulation of CD8αβ T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nature immunology2001;2(3):255. [3] Spear, Paul, et al. NKG2D ligands as therapeutic targets. Cancer Immunity Archive2013;13(2):8. [4] Carapito, Raphael, Seiamak, Bahram. Genetics, genomics, and evolutionary biology of NKG2D ligands. Immunological reviews2015;267(1):88–116. Disclosure of Interest None declared

ObjectiveHand osteoarthritis is a prevalent disease with limited treatment options. Since joint inflammation is often present, we investigated tumour necrosis factor (TNF) as treatment target in patients with proven joint inflammation in a proof-of-concept study.MethodsThis 1-year, double-blind, randomised, multicentre trial (NTR1192) enrolled patients with symptomatic erosive inflammatory hand osteoarthritis. Patients flaring after non-steroidal anti-inflammatory drug washout were randomised to etanercept (24 weeks 50 mg/week, thereafter 25 mg/week) or placebo. The primary outcome was Visual Analogue Scale (VAS) pain at 24 weeks. Secondary outcomes included clinical and imaging outcomes (radiographs scored using Ghent University Scoring System (GUSS, n=54) and MRIs (n=20)).ResultsOf 90 patients randomised to etanercept (n=45) or placebo (n=45), respectively, 12 and 10 discontinued prematurely. More patients on placebo discontinued due to inefficacy (6 vs 3), but fewer due to adverse effects (1 vs 6). The mean between-group difference (MD) in VAS pain was not statistically significantly different (−5.7 (95% CI −15.9 to 4.5), p=0.27 at 24 weeks; − 8.5 (95% CI −18.6 to 1.6), p=0.10 at 1 year; favouring etanercept). In prespecified per-protocol analyses of completers with pain and inflammation at baseline (n=61), MD was −11.8 (95% CI −23.0 to −0.5) (p=0.04) at 1 year. Etanercept-treated joints showed more radiographic remodelling (delta GUSS: MD 2.9 (95% CI 0.5 to 5.4), p=0.02) and less MRI bone marrow lesions (MD −0.22 (95% CI −0.35 to −0.09), p = 0.001); this was more pronounced in joints with baseline inflammation.ConclusionAnti-TNF did not relieve pain effectively after 24 weeks in erosive osteoarthritis. Small subgroup analyses showed a signal for effects on subchondral bone in actively inflamed joints, but future studies to confirm this are warranted.

ObjectiveTo evaluate the prevalence, duration and effect on damage accrual of the ‘Lupus Low Disease Activity State’ (LLDAS) in a monocentric cohort of patients with systemic lupus erythematosus (SLE).MethodsWe studied 293 Caucasian patients with SLE during a 7-year follow-up period. Disease activity was assessed by SLE Disease Activity Index 2000 (SLEDAI-2K) and SELENA-SLEDAI physician global assessment (PGA), and damage by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). We considered the following definition of LLDAS: SLEDAI-2K ≤4 without major organ activity, no new disease activity, PGA (0–3)≤1, prednisone ≤7.5 mg/day and well-tolerated immunosuppressant dosages. The effect of LLDAS on SDI was evaluated by multivariate regression analysis. We also evaluated remission defined as clinical SLEDAI-2K=0 and prednisone ≤5 mg/day in patients treated with/without stable immunosuppressants and/or antimalarials.ResultsLLDAS lasting 1, 2, 3, 4 or ≥5 consecutive years was achieved by 33 (11.3%), 43 (14.7%), 39 (13.3%), 31 (10.6%) and 109 (37.2%) patients, respectively. Patients who spent at least two consecutive years in LLDAS had significantly less damage accrual compared with patients never in LLDAS (p=0.001), and they were significantly less likely to have an increase in SDI (OR 0.160, 95% CI 0.060 to 0.426, pConclusionsLLDAS was associated with a decrease in damage progression in Caucasian patients with SLE. The majority of patients in LLDAS were in remission, which can largely contribute to the protective effect of LLDAS on damage accrual.

Objectives Because it has been suggested that the IgM isotype of antiphospholipid (aPL) antibodies should no longer be included in the laboratory criteria for antiphospholipid syndrome (APS) classification, we assess the clinical relevance of IgM isotype of aPL in a cohort of patients with vascular APS. Patients/methods Mean age, sex, the presence of autoimmune diseases other than systemic lupus erythematosus, risk factors for thrombosis, the type/s and site/s of thromboembolic events, the levels of C3 and C4, and autoantibody profile were evaluated in a large cohort of persistently aPL positive patients fulfilling the Sydney criteria for APS. Patients with isolated IgM isotype were compared for each variable with those with any other aPL antibody combination. Results One hundred six patients were assessed; of these 55 (51.9%) had venous thromboembolism, 48 (45.3%) arterial thrombosis, and 3 (2.8%) small vessel thrombosis. Positivity to only IgM aPL made possible to classify 13 patients (12.3%) as vascular APS. In all cases the presence of IgM aPL was at medium–high titer, confirmed, and found to be stable in the time. There were four patients with retinal thrombosis (3.8%) and the prevalence of this event was significant in the isolated IgM isotype positive patients (p = 0.005). Conclusions Data from this investigation give clinical value to the IgM isotype of aPL and suggest to consider aCL and anti-β2GPI of IgM class as valid laboratory criteria for APS classification, especially when they are associated and stable overtime.

The aim of this study was to assess the frequency of monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals in synovial fluids (SFs) aspirated from wrist and finger joints of patients with previously diagnosed joint diseases. We reviewed the results of SF analysis of 1593 samples and identified 126 patients with effusions in the small joints of the hands and wrists. We reported from patients' medical files data about sex, age, diagnosis, disease duration and the microscopic SF results. The prevalence of CPP crystals in SF was 85.71% in CPP-crystals arthritis (CPP-CA), 19.35% in rheumatoid arthritis (RA), 13.89% in osteoarthritis (OA) and 0% in psoriatic arthritis (PsA), spondyloarthritis (SpA), gout and miscellanea. The prevalence of MSU crystals in SF was 83.3% in gout, 10% in PsA, 2.8% in OA and 0% in RA, SpA, miscellanea and CPP-CA. Consistent with previously reported data concerning the big joints, microcrystals can be frequently found also in the small joints of patients with previous diagnosis. The finding underlines the importance of analyzing SF from the hand and wrist joints in the attempt to identify comorbidities associated with the presence of crystals and to develop targeted treatment strategies.

Introduction: Risk of developing cardiovascular disease (CVD) is increased in systemic lupus erythematosus (SLE) compared with the general population. Traditional risk factors cannot account for the totality of CV events and adequate prevention may be challenging.Areas covered: This review summarizes traditional and emerging risk factors of CVD in SLE patients and goes over potential pathogenic mechanisms involved in CVD development. Role of commonly used drugs and preventive strategies exploitable in everyday clinical practice are also discussed.Expert opinion: SLE-related risk factors involve both disease- and treatment-related features, including disease activity, disease phenotype, corticosteroid misuse and alterations of innate and adaptive immunity. Primary prevention is mandatory in management of lupus patients through appropriate disease control, corticosteroid tapering, use of antimalarials and eventually vitamin D supplementation.

Galectin-3 (gal-3) is a β-galactoside-binding lectin, which regulates cell–cell and extracellular interactions during self/non-self-antigen recognition and cellular activation, proliferation, differentiation, migration and apoptosis. It plays a significant role in cellular and tissue pathophysiology by organizing niches that drive inflammation and immune responses. Gal-3 has some therapeutic potential in several diseases, including chronic inflammatory disorders, cancer and autoimmune diseases. Gal-3 exerts a broad spectrum of functions which differs according to its intra- or extracellular localization. Recombinant gal-3 strategy has been used to identify potential mode of action of gal-3; however, exogenous gal-3 may not reproduce the functions of the endogenous gal-3. Notably, gal-3 induces monocyte–macrophage differentiation, interferes with dendritic cell fate decision, regulates apoptosis on T lymphocytes and inhibits B-lymphocyte differentiation into immunoglobulin secreting plasma cells. Considering the influence of these cell populations in the pathogenesis of several autoimmune diseases, gal-3 seems to play a role in development of autoimmunity. Gal-3 has been suggested as a potential therapeutic agent in patients affected with some autoimmune disorders. However, the precise role of gal-3 in driving the inflammatory process in autoimmune or immune-mediated disorders remains elusive. Here, we reviewed the involvement of gal-3 in cellular and tissue events during autoimmune and immune-mediated inflammatory diseases.

The introduction of biological therapies has significantly improved the outcome of inflammatory rheumatic diseases. As most of these diseases affect women and men in childbearing age, some concerns have been voiced as to the safety of these drugs in relation to reproduction and pregnancy. Data from many hundreds of pregnancies in patients affected by inflammatory bowel disease and inflammatory arthritis have suggested that exposure to anti-TNF therapies at conception and/or during pregnancy is not associated with adverse pregnancy outcomes or any increase in congenital abnormalities. However, the exposure to anti-TNFα agents, particularly to monoclonal antibodies, in late pregnancy is associated with high drug levels in the newborn and their long-term effects on children remain unknown. Therefore, limiting the use of anti-TNFα to the first 30 weeks of pregnancy is recommended to reduce fetal exposure. Live-virus vaccines should be given only when levels of anti-TNFα drugs are undetectable in the serum of infants. Studies suggest that many of these drugs do enter breast milk in small amounts, but the extent to which the infant absorbs them is less clear. Limited reports have not suggested adverse pregnancy outcomes in women whose partners were exposed to anti-TNF therapies at the time of conception. Pregnancy data for rituximab, abatacept, anakinra, tocilizumab and belimumab are limited and their use in pregnancy cannot currently be recommended.

Objectives To investigate the effects and mechanisms of action of high-density lipoproteins (HDL) in monosodium urate (MSU) crystal-induced inflammation —that is, gouty inflammation, in vivo. Methods Air pouches raised on the backs of mice were injected with MSU crystals or tumour necrosis factor (TNF) in the presence or absence of HDL and/or interleukin (IL)-1 receptor antagonist (IL-1Ra) for 3 h. Leucocyte count and neutrophil percentage in pouch fluids were measured using a haemocytometer and May–Grunwald–Giemsa staining. The cytokine production and expression in the pouch were measured by ELISA and quantitative RT-PCR. Results MSU crystals induced leucocyte infiltration, mostly neutrophils, and the release of IL-1β, IL-6, chemokine (C-X-C motif) ligand 1 (CXCL1), chemokine (C-C motif) ligand 2 (CCL2) and IL-1Ra in pouch fluids. TNF remained under the detection limit. MSU crystals triggered IL-1β, IL-6 and CXCL1 expression in both pouch exudates and membranes, whereas CCL2 and TNF mRNA were not modulated. The co-injection of MSU crystals and HDL inhibited leucocyte influx by 59% and neutrophil infiltration by 83% and, in turn, both protein and mRNA levels of all assessed proinflammatory cytokines were reduced, but not those of IL-1Ra. Similar results were obtained when mice were injected with MSU crystals pretreated with HDL or TNF instead of crystals. When HDL and IL-1Ra were added together they displayed additional inhibition, suggesting different mechanisms of action. Conclusions This study demonstrated that HDL may represent an important factor in the modulation of gouty inflammation by acting on both tissue and infiltrating cells —that is, synovial tissue and synovial fluid cells. HDL display anti-inflammatory activity, in part, by interacting with crystals but also by directly acting on cells.

Objective.To investigate the possibility of achieving partial remission (PR) in patients with nonradiographic axial spondyloarthritis (nr-axSpA) versus ankylosing spondylitis (AS) treated with anti-tumor necrosis factor (TNF)-α antagonists, such as adalimumab (ADA), etanercept (ETN), and infliximab (IFX), in a real clinical practice setting. The Assessment of SpondyloArthritis international Society (ASAS) 20, ASAS40, and Ankylosing Spondylitis Disease Activity Score were also calculated.Methods.A retrospective study was conducted in patients with axSpA treated with ADA, ETN, and IFX from 2000 to 2013. All patients fulfilled the ASAS or the modified New York criteria. PR was reached when the score was < 20 mm (on a visual analog scale of 0–100 mm) in each of these domains: (1) patient global assessment, (2) pain, (3) function, and (4) inflammation.Results.A total of 321 patients with axSpA were treated. Among them, 62 were nr-axSpA while the remaining 259 were AS. Log-rank test to compare survival curves showed that the probability of obtaining PR in nr-axSpA and AS during treatment with anti-TNF-α was not significantly different. At 12 weeks of exposure to the first anti-TNF-α drug, PR was achieved in 7 patients with nr-axSpA (11.3%) and in 68 patients with AS (26.2%).Conclusion.Our results, obtained from clinical practice, showed that PR is an achievable target of anti-TNF-α treatment in nr-axSpA. The PR rate, as a reliable indicator of sustained effectiveness, is similar in nr-axSpA and in AS.

Blau syndrome (BS) and early onset sarcoidosis (EOS) are, respectively, the familial and sporadic forms of the pediatric granulomatous autoinflammatory disease, which belong to the group of monogenic autoinflammatory syndromes. Both of these conditions are caused by mutations in the NOD2 gene, which encodes the cytosolic NOD2 protein, one of the pivotal molecules in the regulation of innate immunity, primarily expressed in the antigen-presenting cells. Clinical onset of BS and EOS is usually in the first years of life with noncaseating epithelioid granulomas mainly affecting joints, skin, and uveal tract, variably associated with heterogeneous systemic features. The dividing line between autoinflammatory and autoimmune mechanisms is probably not so clear-cut, and the relationship existing between BS or EOS and autoimmune phenomena remains unclear. There is no established therapy for the management of BS and EOS, and the main treatment aim is to prevent ocular manifestations entailing the risk of potential blindness and to avoid joint deformities. Nonsteroidal anti-inflammatory drugs, corticosteroids and immunosuppressive drugs, such as methotrexate or azathioprine, may be helpful; when patients are unresponsive to the combination of corticosteroids and immunosuppressant agents, the tumor necrosis factor-α inhibitor infliximab should be considered. Data on anti-interleukin-1 inhibition with anakinra and canakinumab is still limited and further corroboration is required. The aim of this paper is to describe BS and EOS, focusing on their genetic, clinical, and therapeutic issues, with the ultimate goal of increasing clinicians' awareness of both of these rare but serious disorders.

Joint Bone Spine - In Press.Proof corrected by the author Available online since vendredi 9 aout 2013

Background Bactericidal/permeability-increasing protein (BPI) is a cationic protein mainly produced by polymorphonuclear cells (PMN) which exerts an antimicrobial activity by damaging bacterial membranes and interacts with specific cell surface receptors, such as toll-like receptors (TLRs). BPI has been detected in synovial fluid of patients with different arthritis, including crystal-induced arthritis. Objectives To evaluate the effects and mechanisms of action of BPI in in vitro and in vivo models of crystal-induced inflammation. Methods The human monocytic cell line THP-1 was primed for 3 h with phorbole myristate acetate (300 ng/ml), reincubated overnight, and treated with sterile synthetic monosodium urate (MSU) (0.5 mg/ml) or calcium pyrophosphate (CPP) (0.1 mg/ml) crystals for 24 h in presence or absence of BPI (5 μ g/ml). In some experiments, cells or crystals were pretreated with BPI for 2 h before stimulation. BPI inhibition experiments were carried out with antibody against TLR2 or TLR4. Cell supernatants were tested by ELISA for interleukin (IL)-1β and IL-8 production. Chemotactic effect of culture supernatants was evaluated in chemotaxis chamber by the migration of freshly isolated peripheral blood PMN. As regard the study in vivo, air pouches were raised on the backs of CD1 mice (n=7 per condition). 2 mg of MSU crystals in 1 ml of PBS were injected into the pouch in the presence or absence of 0.1 mg of BPI for 3 h. Controls received 1 ml of PBS. After the sacrifice, pouch fluids were recovered by washing with 2 ml of PBS. Leukocyte count in lavage fluids was obtained using a hemocytometer and the percentage of PMN was determined by May-Grunwald-Giemsa staining. IL-1β, chemokine (C-X-C motif) ligand 1 (CXCL1) and IL-6 levels were measured in exudates by ELISA. Results Exposure of THP-1 cells to different types of crystals increased the production of IL-1β (MSU: 406.62±12.00 pg/ml; CPP: 357.07±25.17 pg/ml) and IL-8 (MSU: 3798.56±24.64 pg/ml; CPP: 3427.74±22.33 pg/ml). The release of both cytokines induced by crystals was significantly diminished in the presence of BPI (76% IL-1β, 58% IL-8), and tended to be more pronounced when cells, but not crystals, were pretreated with the protein (90% IL-1β, 65% IL-8). The presence of antibody anti-TLR2 or anti-TLR4 did not affect the BPI inhibitory effect. Supernatants of crystal-stimulated cells increased the migration of PMN cells which was reduced in the presence of BPI. The injection of MSU crystals into the subcutaneous pouches of mice induced leukocyte infiltration (10.2±3.39 x 105 cells/ml) comprising 68.6±8.75% of PMN. IL-1β (32.33±6.35 pg/ml), CXCL1 (467.07±27.47 pg/ml) and IL-6 (624.61±29.41 pg/ml) were measured in lavage fluids. The co-injection of MSU crystals and BPI inhibited leukocyte influx by 60% and PMN infiltration by 87% and, in turn, the levels of all assessed cytokines were reduced (81% IL-1β, 70% CXCL1, 35% IL-6). Conclusions This study shows that BPI reduces the crystal-induced inflammatory process in vitro and in vivo by inhibiting pro-inflammatory cytokine release and PMN recruitment. The mechanism of action of BPI may include the direct interaction with activated cells in a TLR-independent manner. Disclosure of Interest None declared

Background Adult-onset Still9s disease (AOSD) is a systemic inflammatory condition characterized by episodes of spiking fever, evanescent rash, arthralgia, leukocytosis and hyperferritinemia. The inflammatory status of AOSD could result from a deregulation of the NLRP3 inflammasome as Interleukin-1 (IL-1) is pivotal in the pathogenesis of AOSD. Objectives To evaluate IL-1 beta and caspase-1 p45 expression in AOSD patients. Methods 11 AOSD patients with systemic chronic disease (mean age: 44.5±15.6 years; mean disease duration: 3.0±1.7 years) and 5 healthy donors (mean age: 41.8±7.5) were enrolled. Anakinra (in 6 patients) and DMARDs (in 5 patients) adequately controlled the disease. PBMCs (peripheral blood mononuclear cells) obtained by Ficoll centrifugation were stimulated with lipopolysaccharide (LPS) [10 ng/ml] and ATP [1 mM] for 0.5, 1, 6 and 24 hours. IL-1β level was measured in the supernatant by ELISA and the expression of caspase-1 p45 at protein level was detected by Western Blotting. Results In unstimulated PBMCs minimal IL-1β production was found both in AOSD patients and controls. After 6 hours stimulation, IL-1β level was increased whereas we observed a reduced processing of caspase-1 p45 particularly in AOSD patients treated with Anakinra. Conclusions Patients with refractory AOSD, who therefore need Anakinra, seem to have an increased production of IL-1β compared to healthy controls and to AOSD patients who respond to standard therapies. Altered processing of caspase-1 p45 in AOSD patients support the involvement of the NLRP3 inflammasome pathway in the pathogenesis of the disease. Disclosure of Interest None declared

Background Blau Syndrome (BS) is a rare autosomal dominant inflammatory disease characterized by early-onset granulomatous arthritis, dermatitis and recurrent uveitis (1). Mutations in the nucleotide-binding domain (NBD) of CARD15/NOD2 gene (mainly R334W, R334Q and L469F) have been identified in Blau syndrome (2). Despite advances in BS knowledge, patients9 functional prognosis remains uncertain, BS potentially leading to visual impairment or joint deformities. Optimal treatments have not been determinated yet. Objectives To assess the efficacy of several biologic agents in this affection Methods We conduct an observational, international, retrospective cohort of BS collecting clinical, biological and histological data. Results Among the twenty-three patients included in the cohort, 14 patients were treated by one or several lines of biologic agents, mostly by TNF blockers (80%), IL1 blockers (16%) or treatment targeting CTLA-4 (4%). Fifty-seven percent of patients achieved remission after almost two lines of treatment (1.75 lines; [0.8–2.7]). Association with csDMARDs did not significantly improved response to biologics. Considering the 3 mains symptoms independently, TNF blockers were associated with a better response in case of articular or skin features but less effective in case of ocular involvement, a clinical situation in which IL-1 targeting should be preferentially chosen. Conclusions Biologic treatments appeared to be effective in BS but additional data prospectively collected are still needed in order to define their place in the therapeutic strategy in order to minimize functional consequences. References Blau EB. Familial granulomatous arthritis, iritis, and rash. The Journal of pediatrics. 1985 Nov;107(5):689–93. PubMed PMID: 4056967. Epub 1985/11/01. eng. Miceli-Richard C, Lesage S, Rybojad M, Prieur AM, Manouvrier-Hanu S, Hafner R, et al. CARD15 mutations in Blau syndrome. Nature genetics. 2001 Sep;29(1):19–20. PubMed PMID: 11528384. Epub 2001/08/31. eng. Disclosure of Interest None declared

The history of what, in 1979, was called interleukin-1 (IL-1), orchestrator of leukocyte inter-communication, began many years before then, initially by the observation of fever induction via the endogenous pyrogen (EP) (1974) and then in rheumatology on the role in tissue destruction in rheumatoid diseases via the induction of collagenase and PGE2 in human synovial cells by a mononuclear cell factor (MCF) (1977). Since then, the family has exploded to presently 11 members as well as many membrane-bound and soluble receptor forms. The discovery of a natural Interleukin-1 receptor antagonist (IL-1Ra) in human biological fluids has highlighted the importance of IL-1 and IL-1Ra in human diseases. Evidence delineating its role in autoinflammatory syndromes and the elucidation of the macromolecular complex referred to as “inflammasome” have been instrumental to our understanding of the link with IL-1. At present, the IL-1blockade as therapeutic approach is crucial for many hereditary autoinflammatory diseases, as well as for adult-onset Still’s disease, crystal-induced arthropathies, certain skin diseases including neutrophil-triggered skin diseases, Behçet’s disease and deficiency of IL-1Ra and other rare fever syndromes. Its role is only marginally important in rheumatoid arthritis and is still under debate with regard to osteoarthritis, type 2 diabetes mellitus, cardiovascular diseases and cancer. This brief historical review focuses on some aspects of IL-1, mainly IL-1β and IL-Ra, in rheumatology. There are many excellent reviews focusing on the IL-1 family in general or with regard to specific diseases or biological discoveries.

The term spondyloarthritis (SpA) is used to describe a group of multifactorial chronic inflammatory diseases characterized by a predisposing genetic background and clinical manifestations typically involving the sacroiliac joint. The absence of pathognomonic clinical and/or laboratory findings generally results in a delay in diagnosis and, consequently, in treatment. In addition, 20-40% of SpA patients are non-responders to tumor necrosis factor (TNF) inhibitor therapies. Given these considerations, it is important to identify biomarkers that can facilitate the diagnosis and assessment of disease activity. As inflammation plays a key role in the pathogenesis of SpA, inflammatory mediators have been investigated as potential biomarkers for diagnosing the disease and predicting response to therapy. Some investigators have focused their attention on the role of matrix metalloproteinases (MMPs), which are known to be markers of synovial inflammation that is generated in the joint in reaction to inflammatory stimuli. Several studies have been carried out to verify if serum MMPs levels could be useful to diagnose SpA, to assess disease severity, and to predict response to TNF inhibitor therapy. The current review focuses on MMPs' role in SpA pathogenesis, diagnosis and therapeutic implications.

BackgroundNew drugs and new evidence concerning the use of established treatments have become available since the publication of the first European League Against Rheumatism (EULAR) recommendations for the management of gout, in 2006. This situation has prompted a systematic review and update of the 2006 recommendations.MethodsThe EULAR task force consisted of 15 rheumatologists, 1 radiologist, 2 general practitioners, 1 research fellow, 2 patients and 3 experts in epidemiology/methodology from 12 European countries. A systematic review of the literature concerning all aspects of gout treatments was performed. Subsequently, recommendations were formulated by use of a Delphi consensus approach.ResultsThree overarching principles and 11 key recommendations were generated. For the treatment of flare, colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), oral or intra-articular steroids or a combination are recommended. In patients with frequent flare and contraindications to colchicine, NSAIDs and corticosteroids, an interleukin-1 blocker should be considered. In addition to education and a non-pharmacological management approach, urate-lowering therapy (ULT) should be considered from the first presentation of the disease, and serum uric acid (SUA) levels should be maintained at)and )in those with severe gout. Allopurinol is recommended as first-line ULT and its dosage should be adjusted according to renal function. If the SUA target cannot be achieved with allopurinol, then febuxostat, a uricosuric or combining a xanthine oxidase inhibitor with a uricosuric should be considered. For patients with refractory gout, pegloticase is recommended.ConclusionsThese recommendations aim to inform physicians and patients about the non-pharmacological and pharmacological treatments for gout and to provide the best strategies to achieve the predefined urate target to cure the disease.

Galectins are evolutionary conserved β-galactoside binding proteins with a carbohydrate-recognition domain (CRD) of approximately 130 amino acids. In mammals, 15 members of the galectin family have been identified and classified into three subtypes according to CRD organization: prototype, tandem repeat-type and chimera-type galectins. Galectin-3 (gal-3) is the only chimera type galectin in vertebrates containing one CRD linked to an unusual long N-terminal domain which displays non-lectin dependent activities. Although recent studies revealed unique, pleiotropic and context-dependent functions of gal-3 in both extracellular and intracellular space, gal-3 specific pathways and its ligands have not been clearly defined yet. In the kidney gal-3 is involved in later stages of nephrogenesis as well as in renal cell cancer. However, gal-3 has recently been associated with lupus glomerulonephritis, with Familial Mediterranean Fever-induced proteinuria and renal amyloidosis. Gal-3 has been studied in experimental acute kidney damage and in the subsequent regeneration phase as well as in several models of chronic kidney disease, including nephropathies induced by aging, ischemia, hypertension, diabetes, hyperlipidemia, unilateral ureteral obstruction and chronic allograft injury. Because of the pivotal role of gal-3 in the modulation of immune system, wound repair, fibrosis and tumorigenesis, it is not surprising that gal-3 can be an intriguing prognostic biomarker as well as a promising therapeutic target in a great variety of diseases, including chronic kidney disease, chronic heart failure and cardio-renal syndrome. This review summarizes the functions of gal-3 in kidney pathophysiology focusing on the reported role of gal-3 in autoimmune diseases.

ObjectivesWhile various monocyte chemokine systems are increased in expression in osteoarthritis (OA), the hierarchy of chemokines and chemokine receptors in mediating monocyte/macrophage recruitment to the OA joint remains poorly defined. Here, we investigated the relative contributions of the CCL2/CCR2 versus CCL5/CCR5 chemokine axes in OA pathogenesis.MethodsCcl2-, Ccr2-, Ccl5- and Ccr5-deficient and control mice were subjected to destabilisation of medial meniscus surgery to induce OA. The pharmacological utility of blocking CCL2/CCR2 signalling in mouse OA was investigated using bindarit, a CCL2 synthesis inhibitor, and RS-504393, a CCR2 antagonist. Levels of monocyte chemoattractants in synovial tissues and fluids from patients with joint injuries without OA and those with established OA were investigated using a combination of microarray analyses, multiplexed cytokine assays and immunostains.ResultsMice lacking CCL2 or CCR2, but not CCL5 or CCR5, were protected against OA with a concomitant reduction in local monocyte/macrophage numbers in their joints. In synovial fluids from patients with OA, levels of CCR2 ligands (CCL2, CCL7 and CCL8) but not CCR5 ligands (CCL3, CCL4 and CCL5) were elevated. We found that CCR2+ cells are abundant in human OA synovium and that CCR2+ macrophages line, invade and are associated with the erosion of OA cartilage. Further, blockade of CCL2/CCR2 signalling markedly attenuated macrophage accumulation, synovitis and cartilage damage in mouse OA.ConclusionsOur findings demonstrate that monocytes recruited via CCL2/CCR2, rather than by CCL5/CCR5, propagate inflammation and tissue damage in OA. Selective targeting of the CCL2/CCR2 system represents a promising therapeutic approach for OA.

The aim of the study was to evaluate predictors of disease flares during pregnancy and obstetric and fetal complications in a cohort of systemic lupus erythematosus (SLE) patients. One hundred and thirty-two pregnancies in 96 SLE patients were prospectively followed by monthly clinical and laboratory evaluations. Predictors of lupus flares, fetal and obstetric complications during pregnancy were identified performing stepwise logistic regression analysis. Maternal lupus flares occurred in 57 % of pregnancies and were being best predicted by the number of flares before conception. Manifestations during flares were best predicted by the same features occurred before conception: dermatological flares by skin rash, renal flares by nephritis, and hematological flares by hematological abnormalities. There were 110 live births and 22 fetal losses. Among live newborns, 22 % were premature. Fetal loss was best predicted by hypertension at conception; miscarriages by the amount of steroids taken during the last year before conception; stillbirth by the number of flares during the last year before conception; preterm birth by the coexistence of anti-phospholipid antibody syndrome and anti-double-stranded DNA antibody levels before conception; premature rupture of membranes by high ECLAM score during the 6 months before conception, small for gestation age by hypertension at conception; and preeclampsia by positive lupus anticoagulant. Some independent predictors of lupus flares and fetal and obstetric complications were identified, which can help the risk assessment of pregnancy in SLE patients.

The aim of our study was to analyze olfactory function in patients with idiopathic inflammatory myopathies (IIM). We performed a case–control study on 60 IIM patients (48 females and 12 males) and 60 healthy controls (HC) recruited by the best friend method, matched for age, sex and lifestyle. Olfactory function was analyzed by “Sniffin’ sticks test” and expressed through a score (TDI), indicating normosmia (TDI > 30), hyposmia (TDI 15–30) and anosmia (TDI

Microcrystals are responsible for some of the most common and complex arthropathies which are often accompanied by intense, severe pain and inflammatory reactions. The main pathogens are crystals of monosodium urate (MSU), responsible for the gout, calcium pyrophosphate (CPP), which deposits also in various clinical forms of arthopathies, and basic calcium phosphate associated with osteoarthritis. In this context, the microcrystal arthritis is characterized by multiple, acute attacks followed by chronic pain, disability, impaired quality of life, and increased mortality. Given their chronic nature, they represent an ever more urgent public health problem. MSU and CPP crystals are also able to activate nociceptors. The pain in mycrocrystalline arthritis (MCA) is an expression of the inflammatory process. In the course of these diseases there is an abundant release of inflammatory molecules, including prostaglandins 2 and kinins. Interleukin-1 represents the most important cytokine released during the crystal-induced inflammatory process. Therefore, clinically, pain is the most important component of MCA, which lead to functional impairment and disability in a large proportion of the population. It is fundamental to diagnose these diseases as early as possible, and to this aim, to identify appropriate and specific targets for a timely therapeutic intervention.

Serine protease inhibitors (serpins) are evolutionary old, structurally conserved molecules which encompass nearly all branches of life. More than 1,000 serpins were characterized to date which are subdivided into 16 subgroups (A-P) according to their common ancestry; among them, 37 are found in humans. Serpins were termed after their capability to inhibit serine proteases, but mounting evidence suggests that they may achieve a greater deal of functions, ranging from embryological growth to synaptic plasticity, development of both myeloid and lymphoid immune cells, and modulation of apoptosis. Serpins are mainly extracellular molecules, although some of them (namely, ov-serpins or clade B serpins) mostly act inside the cells, being either ubiquitously or tissue-specifically expressed. Among newly characterized serpin functions, regulation of cellular proliferation through apoptosis modulation and proteasome disturbance seems to play a major role. Accordingly, several serpins were found to be hyperexpressed in tumor cells. Indeed, apoptosis dysregulation is likely to be a cornerstone in both tumorigenesis and autoimmunity, since uncontrolled cellular viability results in tumor proliferation, while inefficient disposal of apoptotic debris may favor the rescue of autoreactive immune cells. Such a process was widely documented in systemic lupus erythematosus (SLE). Interestingly, alterations in the expression of some serpins, e.g., the ov-serpin SERPINB3, are being unraveled in patients affected with SLE and other autoimmune disorders, suggesting that a failure in serpin function might affect immune homeostasis and self-tolerance, thereby contributing to autoimmunity. Here, we provide an overview of serpin origin, function, and dysfunction, focusing on human serpins and ov-serpins, with a hub on SERPINB3.

Background Spondyloarthritis often affects young people, typically in their working years. The aim of our study was to investigate work productivity and its relationship with disease activity and physical functioning in Italian patients with axial spondyloarthritis (axSpA) with chronic back pain (CBP) for ≥3 months and ≤2 years, and onset

Objectives: To update the EULAR recommendations for management of knee osteoarthritis (OA) by an evidence based medicine and expert opinion approach. Methods: The literature search and guidelines were restricted to treatments for knee OA pertaining to clinical and/or radiological OA of any compartment of the knee. Papers for combined treatment of knee and other types of OA were excluded. Medline and Embase were searched using a combination of subject headings and key words. Searches for those treatments previously investigated were conducted for January 1999 to February 2002 and for those treatments not previously investigated for 1966 to February 2002. The level of evidence found for each treatment was documented. Quality scores were determined for each paper, an effect size comparing the treatment with placebo was calculated, where possible, and a toxicity profile was determined for each treatment modality. Results: 497 new publications were identified by the search. Of these, 103 were intervention trials and included in the overall analysis, and 33 treatment modalities were identified. Previously identified publications which were not exclusively knee OA in the initial analysis were rejected. In total, 545 publications were included. Based on the results of the literature search and expert opinion, 10 recommendations for the treatment of knee OA were devised using a five stage Delphi technique. Based on expert opinion, a further set of 10 items was identified by a five stage Delphi technique as important for future research. Conclusion: The updated recommendations support some of the previous propositions published in 2000 but also include modified statements and new propositions. Although a large number of treatment options for knee OA exist, the evidence based format of the EULAR Recommendations continues to identify key clinical questions that currently are unanswered.

Systemic lupus erythematosus (SLE) is the prototype of systemic autoimmune diseases. Patients with SLE display a wide spectrum of clinical and serological findings that can mislead and delay the diagnosis. Diagnostic criteria have not been developed yet, whereas several sets of classification criteria are available; however, none of them has 100% sensitivity and 100% specificity, i.e. the hallmark of diagnostic criteria. Nevertheless, classification criteria are often misused as diagnostic criteria, which may affect earliness of diagnosis and lead to more misdiagnosed cases. Areas covered: In this review, we compare old and new classification criteria, discussing their application and pinpointing their limitations in the management of patients. Moreover, we will focus on current and novel biomarkers for SLE diagnosis, highlighting their predictive value and applicability in clinical practice. Expert commentary: SLE diagnosis still represents a challenge, remaining largely based on a clinical judgment. Besides SLE diagnosis, even its classification is still challenging to date. Indeed, although classification of SLE seems to be achieved more frequently with the 2012 SLICC criteria than with the previous 1997 ACR criteria, this last-updated 2012 set might be improved. Notably, diagnostic and classification criteria should be applied to any subject in the world, and consequently they should include immunological variables validated in different populations, which is still an unmet need.

AimTo identify the shortest duration of remission associated with improved outcomes in systemic lupus erythematosus (SLE).MethodsWe studied 293 Caucasian patients with SLE during 7-year follow-up. Disease activity was assessed by SLE Disease Activity Index 2000 and damage by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). We defined three remission levels: complete, clinical off-corticosteroids, clinical on-corticosteroids (prednisone 1–5 mg/day). The effect of different durations of remission (1, 2, 3, 4 and ≥5 consecutive years) on damage was evaluated by multivariate logistic regression analysis.ResultsAmong patients achieving 1-year (27 patients), 2-year (47 patients), 3-year (45 patients), 4-year (26 patients) remission, damage was similar irrespective of the level of remission achieved, whereas, among patients achieving ≥5-year remission (113 patients), damage was higher in those in clinical remission on-corticosteroids (pIn multivariate analysis, ≥2 consecutive year remission was protective against damage (OR (95% CI)): 2 years 0.228 (0.061 to 0.850); 3 years 0.116 (0.031 to 0.436); 4 years 0.118 (0.027 to 0.519) and ≥5 years 0.044 (0.012 to 0.159). Predictors of damage were cumulative prednisone dose ≥180 mg/month (3.136 (1.276 to 7.707)), antiphospholipid antibody syndrome (5.517 (2.092 to 14.546)), vasculitis (3.107 (1.030 to 9.307)) and number of flare/year (8.769 (1.692 to 45.449)).ConclusionsTwo consecutive years is the shortest duration of remission associated with a decrease in damage progression in Caucasian patients with SLE.

Looking to the sustained psoriatic arthritis (PsA) joint as a model of local human inflammation, this study was designed to assess the T lymphocyte signal transduction pathways potentially involved in this chronic immune-mediated inflammatory process, as characterized by direct ex vivo analysis of T helper (Th)-17 T effector (Teff) cell phenotypes in synovial fluid (SF) and peripheral blood (PB) of clinically active PsA patients. The reverse-phase protein arrays (RPPA) technique was employed to identify STAT3, STAT1, JAK1, JAK2, PKCδ and ERK1/2 phosphoprotein levels on total T cell lysates in SF samples of PsA patients. Frequencies of T CD4(+)IL-17A-F(+) and T CD4(+)IL-23R(+) Th17 cells were quantified in SF and matched PB of PsA patients by flow cytometry and compared with PB of healthy controls (HC). Increased levels of JAK1, STAT3, STAT1 and PKCδ phosphoproteins were found in SF T cells of PsA patients, compared with PB of HC. The expansion of T CD4(+)IL-17A-F(+) cells, as well as of T CD4(+) cells expressing IL-23Rp19 (T CD4(+) IL-23R(+)), considered as the pathogenic phenotype of effector Th17 cells, was found to be confined to the joints of PsA patients, as the frequencies of both populations were significantly higher in SF than in matched PB, or in PB of HC. In conclusion, T lymphocyte signal transduction pathway mapping revealed an enhanced activation of JAK1/STAT3/STAT1 and PKCδ phosphoproteins that may drive the local inflammatory process, characterized by the in vivo expansion of T CD4(+)IL-17A-F(+) and T CD4(+)IL-23R(+) Th17 Teff cells in SF of clinically active joints of PsA patients.

Autoantibodies are key mediators in determining the clinical manifestations of systemic lupus erythematosus (SLE). The mechanisms by which antibodies may be harmful to self tissues encompass complement mediated inflammation, cell apoptosis and immune-complexes mediated damage, however the precise cooperation of antibodies in SLE have not been unravelled so far. Lupus nephritis (LN) is a protean feature of SLE resulting in wide variety of symptoms including asymptomatic proteinuria, mild renal disease until end-stage renal failure which are triggered by complex autoantibody interactions. Novel clues concerning development and self-maintenance of LN have come to light in recent times, pointing straight to a multistep inflammatory process which is incited by anti-chromatin antibodies, the best known being anti-DNA and anti-nucleosome antibodies, culminating in a self-maintaining inflammatory loop with spreading of glomerular inflammation. In the maintenance of the inflammatory process pro-inflammatory antibodies are involved, among which anti-C1q are thought to play a major role, whereas hindrance of the nephritic process could be actively mediated by protective autoantibodies. Despite being so relevant in occurrence of LN, nor anti-chromatin neither anti-C1q antibodies have been precisely characterized in terms of origin, antigen specificity and mechanisms of action. Moreover, novel autoantibodies are emerging in LN which can modify disease course, whereas the pathogenic value of a myriad of cross-reactive antibodies has been progressively challenged. The aim of this review is to give a comprehensive view of known and emerging autoantibody reactivities involved in renal inflammation and damage going over their origin, mechanisms of action and interactions in determining LN course.

Objective.The aim of this study was to evaluate rate and predictive factors of loss of remission and disease flare in patients with axial spondyloarthritis (axSpA) receiving antitumor necrosis factor (anti-TNF) treatment.Methods.In this retrospective multicenter study, patients with axSpA, according to the Assessment of Spondyloarthritis international Society (ASAS) criteria, treated with adalimumab, etanercept, or infliximab with a minimum followup of 12 months and satisfying the ASAS partial remission criteria and/or Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease were studied. Disease flare was defined as a Bath Ankylosing Spondylitis Disease Activity Index score > 4.5 or ASDAS score > 2.5 on at least 1 occasion.Results.One hundred seventy-four patients with axSpA were studied. After a median [interquartile range (IQR)] followup of 4 years (2–6), 37 patients (21.2%) experienced a loss of remission and 28 (16.1% of the whole study group) a disease flare. Median (IQR) duration of remission in patients who lost this status was 1 year (0.625–2). Higher median erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values, continuous nonsteroidal antiinflammatory drug (NSAID) use, and an ASDAS-CRP ≥ 0.8 during the remission period were significantly associated with both loss of remission and disease flare. At the multivariate analysis, continuous NSAID intake (OR 4.05, 95% CI 1.4–11.74, p = 0.010) and ESR > 15 (OR 2.90, 95% CI 1.23–6.82, p = 0.015) were the only factors predictive of disease reactivation.Conclusion.In this study, loss of remission and disease flares occurred, respectively, in about 21% and 16% of the patients with axSpA who achieved a state of remission while receiving anti-TNF therapy. Residual disease activity was associated with disease reactivation.