Emerging Roles of Perivascular Mesenchymal Stem Cells in Synovial Joint Inflammation.

In contrast to the significant advances in our understanding of the mesenchymal stem cell (MSC) populations in bone marrow (BM), little is known about the MSCs that are resident in the synovial joint and their possible roles in the tissue homeostasis, chronic inflammation as well as in repair. Neural crest is a transient embryonic structure, generating multipotential MSC capable of migrating along peripheral nerves and blood vessels to colonize most tissue types. In adult, these MSC can provide functional stromal support as a stem cell niche for lymphocyte progenitors for instance in the BM and the thymus. Critically, MSC have major immunoregulatory activities to control adverse inflammation and infection. These MSC will remain associated to vessels (perivascular (p) MSC) and their unique expression of markers such as myelin P0 and transcription factors (e.g. Gli1 and FoxD1) has been instrumental to develop transgenic mice to trace the fate of these cells in health and disease conditions. Intriguingly, recent investigations of chronic inflammatory diseases argue for an emerging role of pMSC in several pathological processes. In response to tissue injuries and with the release of host cell debris (e.g. alarmins), pMSC can detach from vessels and proliferate to give rise to either lipofibroblasts, osteoblasts involved in the ossification of arteries and myofibroblasts contributing to fibrosis. This review will discuss currently available data that suggest a role of pMSC in tissue homeostasis and pathogenesis of the synovial tissue and joints. Graphical abstract.

Does Training Innate Immunity Confer Broad-spectrum Protection Against Bone and Joint Infection in a Mouse Model?

BACKGROUND: The innate immune system can recall previous immunologic challenges and thus respond more effectively to subsequent unrelated challenges, a phenomenon called trained immunity. Training the innate immune system before surgery might be a potential option to prevent bone and joint infection. QUESTIONS/PURPOSES: (1) Does the training process cause adverse effects such as fever or organ injury? (2) Does training the innate immune system confer broad-spectrum protection against bone and joint infection in a mouse model? (3) Does trained immunity remain effective for up to 8 weeks in this mouse model? METHODS: After randomization and group information blinding, we trained the innate immune system of C57BL/6 mice (n = 20 for each group) by intravenously injecting them with either 0.1 mg of zymosan (a toll-like receptor 2 agonist), 0.1 mg of lipopolysaccharide (a toll-like receptor 4 agonist), or normal saline (control). For assessing the host response and possible organ injury after training and infection challenge, we monitored rectal temperature, collected blood to determine leukocyte counts, and performed biochemical and proinflammatory cytokine analyses. After 2 weeks, we then assessed whether trained immunity could prevent infections in an intraarticular implant model subjected to a local or systemic challenge with a broad spectrum of bacterial species (Staphylococcus aureus, Escherichia coli, Enterococcus faecalis, Streptococcus pyogenes, or Pseudomonas aeruginosa) in terms of culture-positive rate and colony counts. The proportion of culture-positive joint samples from trained and control groups were compared after 4 weeks. Finally, we increased the interval between training and bacterial challenge up to 8 weeks to assess the durability of training efficacies. RESULTS: Training with zymosan and lipopolysaccharide caused mild and transient stress in host animals in terms of elevated rectal temperature and higher blood urea nitrogen, creatinine, alanine aminotransferase, and aspartate aminotransferase levels. Trained mice had fewer culture-positive joint samples after local inoculation with S. aureus (control: 100% [20 of 20]; zymosan: 55% [11 of 20], relative risk 0.55 [95% CI 0.37 to 0.82]; p = 0.001; lipopolysaccharide: 60% [12 of 20], RR 0.60 [95% CI 0.42 to 0.86]; p = 0.003) and systemic challenge with S. aureus (control: 70% [14 of 20]; zymosan: 15% [3 of 20], RR 0.21 [95% CI 0.07 to 0.63]; p = 0.001; lipopolysaccharide: 15% [3 of 20], RR 0.21 [95% CI 0.07 to 0.63]; p = 0.001) than controls. We observed similar patterns of enhanced protection against local and systemic challenge of E. coli, E. faecalis, S. pyogenes, and P. aeruginosa. Zymosan-trained mice were more effectively protected against both local (control: 20 of 20 [100%], zymosan: 14 of 20 [70%], RR 0.70 [95% CI 0.53 to 0.93]; p = 0.02) and systemic (control: 70% [14 of 20]; zymosan: 30% [6 of 20], RR 0.43 [95% CI 0.21 to 0.89]; p = 0.03) challenge with S. aureus for up to 8 weeks than controls. CONCLUSIONS: Trained immunity confers mild stress and broad-spectrum protection against bone and joint infection in a mouse model. The protection conferred by immunity training lasted up to 8 weeks in this mouse model. The results of the current research support further study of this presurgical strategy to mitigate bone and joint infection in other large animal models. CLINICAL RELEVANCE: If large animal models substantiate the efficacy and safety of presurgical immunity training-based strategies, clinical trials would be then warranted to translate this strategy into clinical practice.

Assessment of extraintestinal manifestations in inflammatory bowel diseases: A systematic review and a proposed guide for clinical trials.

BACKGROUND AND AIMS: Extraintestinal manifestations are common in inflammatory bowel disease patients, although there are few data available on their diagnosis, management and follow-up. We systematically reviewed the literature evidence to evaluate tools and investigations used for the diagnosis and for the assessment of the treatment response in inflammatory bowel disease patients with extraintestinal manifestations. METHODS: We searched in PubMed, Embase and Web of Science from January 1999-December 2019 for all interventional and non-interventional studies published in English assessing diagnostic tools and investigations used in inflammatory bowel disease patients with extraintestinal manifestations. RESULTS: Forty-five studies (16 interventional and 29 non-interventional) were included in our systematic review, enrolling 7994 inflammatory bowel disease patients. The diagnostic assessment of extraintestinal manifestations was performed by dedicated specialists in a percentage of cases ranging from 60-100% depending on the specific condition. The clinical examination was the most frequent diagnostic strategy, accounting for 35 studies (77.8%). In patients with primary sclerosing cholangitis or rheumatological symptoms, biochemical and imaging tests were also performed. Anti-TNF agents were the most used biological drugs for the treatment of extraintestinal manifestations (20 studies, 44.4%), and the treatment response varied from 59.1% in axial spondyloarthritis to 88.9% in ocular manifestations. No benefit was detected in primary sclerosing cholangitis patients after treatment with biologics. CONCLUSIONS: In the clinical management of inflammatory bowel disease patients with extraintestinal manifestations the collaboration of dedicated specialists for diagnostic investigations and follow-up is key to ensure the best of care approach. However, international guidelines are needed to homogenise and standardise the assessment of extraintestinal manifestations.

Curcumin: hopeful treatment of hemophilic arthropathy via inhibition of inflammation and angiogenesis.

Introduction: Hemophilic arthropathy (HA) is a serious complication among hemophilic patients causing a wide range of morbidity due to the inflammatory reactions followed by repeated episodes of bleeding. This condition has recently been shown to be accompanied by angiogenesis. The cascade starts with iron accumulation leading to an increase in CD68+ and CD11b+ cells responsible for initiating the inflammation.Areas covered: During inflammation, different factors and cytokines such as interleukin 1 (IL-1), IL-6, and tumor necrosis factor α (TNF-α) actively play parts in the pathogenesis of HA and also angiogenesis. It has been demonstrated that different pro-angiogenic and angiogenic factors such as hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), oxidative stress and matrix metalloproteinases (MMPs) are also important in the pathogenesis of HA. Curcumin is known for its strong anti-inflammatory and anti-angiogenic potentials. This agent is able to inhibit the mentioned inflammatory and angiogenic factors such as IL-1, IL-6, TNF-α, VEGF, MMPs, and HIF-1α. Also, as well as anti-angiogenic and anti-inflammatory activity, curcumin has a strong antioxidant potential and can decrease oxidative stress.Expert opinion: It seems that curcumin could be considered as a possible agent for the treatment of HA through inhibition of inflammation, oxidative stress, and angiogenesis.

Fat Grafting for the Treatment of Scleroderma.

BACKGROUND: Scleroderma is a chronic connective tissue disease that results in fibrosis of the skin and internal organs. Although internal organ involvement corresponds with poor prognosis, systemic agents are effective at improving the effects of scleroderma on internal organs. In contrast, skin manifestations are universally present in all patients diagnosed with scleroderma, yet no systemic agents have been shown to be successful. Fat grafting has been shown to improve skin quality and improve contour irregularities and may be helpful in the treatment of patients with scleroderma. METHODS: The authors performed a thorough review of the pathophysiology of scleroderma and the current treatment options for scleroderma. The efficacy of fat grafting for the treatment of scleroderma and the mechanism by which fat grafting improves outcomes was also discussed. RESULTS: Scleroderma is characterized by chronic inflammation and vascular compromise that leads to fibrosis of the skin and internal organs. Fat grafting has recently been the focus of significant basic science research. It has been shown to reduce inflammation, reduce fibrosis by limiting extracellular matrix proteins and increasing collagenase activity, and provide structural support through stem cell proliferation and differentiation. The adipocytes, adipose stem cells, endothelial cells, and vascular smooth muscle cells in the processed fat likely contribute to the effectiveness of this treatment. CONCLUSIONS: Fat grafting in scleroderma patients likely improves skin manifestations by recreating fullness, correcting contour deformities, and improving skin quality. The injected fat provides a mixture of cells that influences the recipient site, resulting in improved outcomes.

Role of Microparticles in the Pathogenesis of Inflammatory Joint Diseases.

Rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) make up a group of chronic immune-mediated inflammatory diseases (IMIDs). The course of these diseases involves chronic inflammation of joints and enthesopathies, which can result in joint damage and disability. Microparticles (MPs) are a group of small spherical membranous vesicles. The structure and cellular origin of MPs, mechanisms that stimulate their secretion and the place of their production, determine their biological properties, which could become manifest in the pathogenesis of immune-mediated inflammatory diseases. Microparticles can stimulate synovitis with proinflammatory cytokines and chemokines. MPs may also contribute to the pathogenesis of rheumatic diseases by the formation of immune complexes and complement activation, pro-coagulation activity, activation of vascular endothelium cells, and stimulation of metalloproteinase production. It seems that in the future, microparticles can become a modern marker of disease activity, a response to treatment, and, possibly, they can be used in the prognosis of the course of arthritis. The knowledge of the complexity of MPs biology remains incomplete and it requires further comprehensive studies to explain how they affect the development of rheumatic diseases. This review focuses on the immunopathogenic and therapeutic role of MPs in chronic immune-mediated inflammatory joint diseases.

Extraintestinal manifestations in inflammatory bowel disease - epidemiology, genetics, and pathogenesis.

INTRODUCTION: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder, primarily of, but not restricted to the gut. Extraintestinal manifestations (EIMs) are frequently observed and involve the joints, eyes, hepatobiliary tract, and skin. Areas covered: In this review, we discuss classical EIM focusing on epidemiology, genetics, and pathogenesis, highlighting recent advances in the understanding of EIM. We further discuss treatment-induced immunological phenomena, which are increasingly recognized and might challenge IBD-treating physicians in the era of biological treatment. Expert opinion: EIM considerably contributes to morbidity and mortality. Genetic studies have revealed a common genetic background between EIM and IBD and among specific EIM. Identified protein interactions have been shown to cluster in shared biological pathways. However - despite these recent advances - pathogenesis of EIM is at best partially understood. Several pathogenic mechanisms have been proposed such as upregulation of tumor necrosis factor, aberrant lymphocyte homing, and cross-reactive antigen presentation. It still remains unclear whether EIM is a direct result of the inflammatory process in the gut or rather a consequence of a shared genetic background leading to dysfunctional immune responses to environmental stimuli. Exploration and understanding of EIM genetics and pathophysiology will pave the road for better and more efficacious treatment options in the future.

Enriched Cd141+ DCs in the joint are transcriptionally distinct, activated, and contribute to joint pathogenesis.

CD141+ DC are implicated in antiviral and antitumor immunity. However, mechanistic studies in autoimmune disease are limited. This is the first study to our knowledge examining CD141+ DC in autoimmune disease, specifically inflammatory arthritis (IA). We identified significant enrichment of CD141+ DC in the inflamed synovial joint, which were transcriptionally distinct from IA and healthy control (HC) blood CD141+ DC and significantly more activated, and they exhibited increased responsiveness to TLR3. Synovial CD141+ DC represent a bone fide CD141+ DC population that is distinct from CD1c+ DC. Synovial CD141+ DC induced higher levels of CD4+ and CD8+ T cell activation compared with their peripheral blood counterparts, as made evident by expression of IFN-γ, TNF-α, and granulocyte-macrophage CSF (GMCSF). Autologous synovial CD141+ DC cocultures also induce higher levels of these cytokines, further highlighting their contribution to synovial inflammation. Synovial CD141+ DC-T cell interactions had the ability to further activate synovial fibroblasts, inducing adhesive and invasive pathogenic mechanisms. Furthermore, we identify a mechanism in which synovial CD141+ DC are activated, via ligation of the hypoxia-inducible immune-amplification receptor TREM-1, which increased synovial CD141+ DC activation, migratory capacity, and proinflammatory cytokines. Thus, synovial CD141+ DC display unique mechanistic and transcriptomic signatures, which are distinguishable from blood CD141+ DC and can contribute to synovial joint inflammation.

Caspase-1 and Caspase-11 Mediate Pyroptosis, Inflammation, and Control of Brucella Joint Infection.

Brucellosis, caused by the intracellular bacterial pathogen Brucella, is a zoonotic disease for which arthritis is the most common focal complication in humans. Here we investigated the role of inflammasomes and their effectors, including interleukin-1 (IL-1), IL-18, and pyroptosis, on inflammation and control of infection during Brucella-induced arthritis. Early in infection, both caspase-1 and caspase-11 were found to initiate joint inflammation and proinflammatory cytokine production. However, by 1 week postinfection, caspase-1 and caspase-11 also contributed to control of Brucella joint infection. Inflammasome-dependent restriction of Brucella joint burdens did not require AIM2 (absent in melanoma 2) or NLRP3 (NLR family, pyrin domain containing 3). IL-1R had a modest effect on Brucella-induced joint swelling, but mice lacking IL-1R were not impaired in their ability to control infection of the joint by Brucella In contrast, IL-18 contributed to the initiation of joint swelling and control of joint Brucella infection. Caspase1/11-dependent cell death was observed in vivo, and in vitro studies demonstrated that both caspase-1 and caspase-11 induce pyroptosis, which limited Brucella infection in macrophages. Brucella lipopolysaccharide alone was also able to induce caspase-11-dependent pyroptosis. Collectively, these data demonstrate that inflammasomes induce inflammation in an IL-18-dependent manner and that inflammasome-dependent IL-18 and pyroptosis restrict Brucella infection.

Combined mepacrine-hydroxychloroquine treatment in patients with systemic lupus erythematosus and refractory cutaneous and articular activity.

Aim The aim of this study was to evaluate the clinical response to combined therapy with hydroxychloroquine and mepacrine in patients with systemic lupus erythematosus and refractory joint and/or skin disease. Methods Mepacrine was added to 46 systemic lupus erythematosus patients unresponsive to treatment with the following drug combinations: hydroxychloroquine + prednisone + immunosuppressive drugs ( n = 24), hydroxychloroquine + prednisone ( n = 16), hydroxychloroquine + prednisone + retinoids ( n = 2), hydroxychloroquine alone ( n = 1), hydroxychloroquine + one immunosuppressive drug ( n = 1), hydroxychloroquine + prednisone + one immunosuppressive drug + belimumab ( n = 1) or hydroxychloroquine + prednisone + belimumab ( n = 1). The outcome variable was the clinical response, either complete or partial, based on clinical judgement. The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score were additionally used. Results A total of 91% patients showed complete/partial response, with similar rates among those with joint or skin disease. In patients with cutaneous activity, a statistically significant decrease in the CLASI was seen. There also was a statistically significant decrease in the SLEDAI. The mean daily dose of prednisone decreased from 5.8 to 3.4 mg/d ( p = 0.001). Prednisone could be discontinued in 20% of patients. No serious adverse events were seen. Smoking was the only predictor of complete response. Conclusion In the setting of refractory skin and/or joint disease, the addition of mepacrine to previous therapy including hydroxychloroquine was safe and effective in reducing disease activity and decreasing prednisone doses. The fact that smokers responded better opens the door to further studying the combination of mepacrine-hydroxychloroquine as a first-line therapy in such patients.

Anti-alpha-enolase antibodies in Behçet's disease: a marker of mucocutaneous and articular disease activity?

OBJECTIVES: To assess IgM anti-alpha-enolase antibodies (AAEA) in systemic Behçet's disease (BD) and its possible association with clinical manifestations and disease activity. METHODS: Ninety-seven consecutively selected BD patients were compared to 36 enteropathic spondyloarthritis (ESpA) [24 Crohn's disease (CD) and 12 ulcerative colitis (UC)] patients and 87 healthy controls. IgM AAEA was detected by immunoblotting. Disease activity was assessed by standardised indexes, Brazilian BD Current Activity Form (BR-BDCAF) for BD and Harvey-Bradshaw Index (HBI) for CD and UC patients. A second evaluation was performed in BD patients (n=56), regarding IgM AAEA presence, disease activity scores and C-reactive protein (CRP). RESULTS: Higher IgM AAEA prevalence was found in 97 BD (17.7%) compared to ESpA (2.8%) and healthy controls (2.3%), p<0.001. IgM AAEA frequency was higher in active BD compared to inactive BD (30.2% vs. 7.4%, p=0.006), a finding confirmed in the second cross-sectional evaluation of 56 of these BD patients (45.5% vs. 13.3%, p=0.02). Mean BR-BDCAF scores were higher in IgM AAEA positive group on both evaluations (9.1 ± 5.4 vs. 4.9 ± 4.9, p=0.002; 5.0 ± 4.9 vs. 2.2 ± 2.9, p=0.01, respectively). BD patients with mucocutaneous and articular symptoms presented higher IgM AAEA positivity in the first and second evaluations (64.7% vs. 27.5%, p=0.005; 36.4% vs. 7.1%, p=0.039 respectively). CONCLUSIONS: Our data support the notion that alpha-enolase is a target antigen in BD, particularly associated with disease activity, mucocutaneous and articular involvement. In addition, IgM AAEA may distinguish BD from ESpA, especially in patients with high disease activity.

Extracellular vesicles: A new therapeutic strategy for joint conditions.

Extracellular vesicles (EVs) are attracting increasing interest since they might represent a more convenient therapeutic tool with respect to their cells of origin. In the last years much time and effort have been expended to determine the biological properties of EVs from mesenchymal stem cells (MSCs) and other sources. The immunoregulatory, anti-inflammatory and regenerative properties of MSC EVs have been demonstrated in in vitro studies and animal models of rheumatoid arthritis or osteoarthritis. This cell-free approach has been proposed as a possible better alternative to MSC therapy in autoimmune conditions and tissue regeneration. In addition, EVs show great potential as biomarkers of disease or delivery systems for active molecules. The standardization of isolation and characterization methods is a key step for the development of EV research. A better understanding of EV mechanisms of action and efficacy is required to establish the potential therapeutic applications of this new approach in joint conditions.

Cytokines in the pathogenesis of hemophilic arthropathy.

Hemophilic arthropathy (HA) is one of the most common and typical manifestation in the course of recurrent bleeding episodes in patients with hemophilia. Clinical and subclinical joint bleeding episodes gradually lead to irreversible changes manifesting themselves as pain, progressing ankylosis, marked limitation of the range of motion, muscle atrophy and osteoporosis commonly concomitant with joint deformity resulting from chronic proliferative synovitis and both cartilage and bone degeneration leading to the final functional impairment of the joint. In spite of numerous studies, the pathophysiology of HA has not been fully elucidated, especially as regards immunopathological mechanisms which are associated with the subclinical and early stage of the disease and to be more precise, with chronic joint inflammation. It needs to be emphasized that the pathophysiological processes occurring in a joint with HA are most probably highly mediated by interactions within the cytokine network and other inflammatory mediators present in the tissues of affected joint. Among numerous compounds participating in the induction of an inflammatory process in the pathogenesis of HA, cytokines seem to play a leading role. The most important group controlling the disease seems to be well known inflammatory cytokines, including IL-1ß, TNFα and IL-6. The second group with antagonistic effect is formed by anti-inflammatory cytokines such as IL-4 and IL-10. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of HA with respect to cellular and intracellular signaling pathways is still under investigation. This review, summarizes and discusses the current knowledge about cytokine network in the pathogenesis of HA, indicating possible molecular and cellular mechanisms that may provide potential new therapeutic directions.

CT-P13: design, development, and place in therapy.

The introduction of biological agents has revolutionized the management of many life-threatening and debilitating immune-mediated diseases. Because of the high cost of biological drugs and their patent expiration, the market has opened to biosimilar agents, copy versions of the originators, which can lead to reduced health care expenditure and increase treatment access worldwide. CT-P13 is the first biosimilar of infliximab (IFX) and has been approved for the same indications as its originator drug. It obtained regulatory approval by the European Medicines Agency in September 2013 and by the US Food and Drug Administration in April 2016. The Phase I and Phase III clinical trials conducted in ankylosing spondylitis and rheumatoid arthritis have demonstrated pharmacokinetic and efficacy equivalence with comparable safety and immunogenicity to IFX. For these reasons, the use of CT-P13 has been extrapolated also to inflammatory bowel disease. There have been some initial concerns regarding the use of CT-P13 in inflammatory bowel disease patients, because of the lack of randomized controlled trials. However, emerging real-world data have further confirmed the comparability between CT-P13 and its reference product in terms of efficacy, safety, and immunogenicity, in patients naïve to the anti-tumor necrosis factor alpha agents and after switching from IFX, and will be summarized in this review.

Short article: Absence of serological rheumatoid arthritis biomarkers in inflammatory bowel disease patients with arthropathies.

OBJECTIVE: Biomarkers that are associated with future progression to rheumatoid arthritis (RA) and joint destruction have been discovered previously in patients with arthralgia. The present study examined these RA biomarkers in inflammatory bowel disease (IBD) patients with arthropathies. PATIENTS AND METHODS: Sera from 155 IBD patients with and 99 IBD patients without arthropathies were analyzed for immunoglobulin (Ig) M rheumatoid factor (RF), IgA-RF, anti-cyclic citrullinated peptide 2, anti-cyclic citrullinated peptide 3.1, and anti-carbamylated protein antibody positivity using enzyme-linked immunosorbent assays. The prevalence of the autoantibodies in the IBD patients was compared with the prevalence in RA patients. RESULTS: No differences were found in biomarker positivity between IBD patients with and without arthropathies. Significantly more biomarker positivity (P<0.001) was observed in RA patients compared with IBD patients with arthropathies. Also, smoking turned out to be significantly associated with positivity for IgM-RF or IgA-RF. CONCLUSION: Our findings suggest that there is no apparent clinical value in the detection of RA biomarkers in serum of IBD patients to help identify arthropathies.

Osteoarticular manifestations of celiac disease and non-celiac gluten hypersensitivity.

Celiac disease is a chronic inflammatory autoimmune enteropathy based disorder that is triggered by the ingestion of gluten in genetically susceptible individuals. The global prevalence of 1% to 2% represents only the tip of the iceberg. The diagnosis is confirmed by positive specific antibody, anti-transglutaminase or anti-endomysium, specific lesions of the small intestine and a response to strict gluten-free diet. The diagnosis is difficult and often delayed because the clinical variability is very large, ranging from digestive clinical presentation "classic" to "atypical" symptoms, often extra-intestinal, that are sometimes attributed to a concomitant disease or a complication. Among them, there are frequent musculoskeletal manifestations such as osteoporosis and osteomalacia. In the absence of risk factor, osteoporosis, in a premenopausal women or in a man less than 55 years, more is if it is severe and refractory to medications, need to rheumatologists on the track of celiac disease in the absence of digestive symptoms. Osteomalacia is related to secondary hypovitaminosis D malabsorption. Supplementation by calcifediol, water-soluble vitamin D, may be indicated. Celiac disease is associated with an autoimmune disease in almost 1/3 of the cases. Knowing these potential associations allows earlier diagnosis in patients whose only manifestation, a concomitant disease. Anemia, chronic fatigue or unexplained polyarthralgia are symptoms associated with celiac disease to look for specific antibodies. The aim of early diagnosis is to prevent the emergence of other systemic disorders and avoid complications such as bone fractures and cancer, especially intestinal lymphoma. Non-celiac gluten intolerance is a new entity defined by symptomatology similar to that of celiac disease induced by the ingestion of gluten and disappearing after crowding-out, among patients without specific antibodies and without intestinal lesion of celiac disease. This entity is a cause, at least in part, of increasing interest in gluten-free diet in the general population.

Paradoxical articular manifestations in patients with inflammatory bowel diseases treated with infliximab.

INTRODUCTION: Articular involvement is the most common extraintestinal manifestation associated with inflammatory bowel diseases (IBDs). Manifestations are 'paradoxical' when they occur during treatment, notably with anti-tumor necrosis factor (anti-TNF) drugs, which are expected to prevent or treat them. The aim of this study was to assess the frequency, characteristics, and associated factors of paradoxical articular manifestations in patients with IBD treated with anti-TNF. PATIENTS AND METHODS: In this prospective single-center study, an examination by a rheumatologist was systematically offered to all patients with IBD treated with infliximab (IFX) to assess the prevalence of articular manifestations and distinguish between those related to treatment and those associated with intestinal disease. Paradoxical manifestations were defined as the occurrence of articular manifestations (excluding induced lupus and hypersensitivity reactions) during anti-TNF therapy in patients with intestinal remission. Measures of biological inflammatory, immunological markers, HLA-B27 allele, IFX trough levels, and anti-IFX antibody (Ab) were performed for all patients. RESULTS: Between May 2013 and April 2014, 65 patients with Crohn's disease and 15 with patients ulcerative colitis treated with IFX were included. The median duration of anti-TNF therapy was 66 months [quartile (Q)1=23 months-Q3=81 months]. Articular manifestations were observed in 50 (62%) patients treated with IFX. Eleven percent (n=9) were considered to be associated with IBD and 16% (n=13) to be associated with anti-TNF therapy. Among articular manifestations associated with anti-TNF therapy, nine (11%) patients were considered paradoxical, two (2%) as drug-induced lupus, and two (2%) as a hypersensitivity reaction. Among the nine patients with paradoxical manifestations, all had Crohn's disease in clinical remission, three patients presented a spondyloarthropathy, and three developed associated paradoxical psoriasis. No patient discontinued anti-TNF because of the articular manifestations. Methotrexate was effective on articular symptoms in two of the three treated patients with paradoxical manifestations. No clinical or biological factors, including IFX trough levels, were associated with the occurrence of paradoxical manifestations. CONCLUSION: Paradoxical articular manifestations in IBD patients treated by anti-TNF are common, affecting more than 10% of patients. These events are generally mild and do not need discontinuation of anti-TNF therapy.

Effect of inflammatory environment on equine bone marrow derived mesenchymal stem cells immunogenicity and immunomodulatory properties.

Mesenchymal stem cells (MSCs) are being investigated for the treatment of equine joint diseases because of their regenerative potential. Recently, the focus mainly has addressed to their immunomodulatory capacities. Inflammation plays a central role in joint pathologies, since the release of proinflammatory mediators to the synovial fluid (SF) leads to the activation of enzymatic degradation of the cartilage. MSCs can modulate the local immune environment through direct or paracrine interaction with immune cells, suppressing their proliferation and re-addressing their functions. Proinflammatory molecules can induce MSC immunoregulatory potential, but they could also increase the expression of immunogenic molecules. Studying the effect of inflammatory environment on MSC immunomodulation and immunogenicity profiles is mandatory to improve cellular therapies. The aim of this study was to analyse the response of equine bone marrow MSCs (eBM-MSCs) to three inflammatory conditions. Equine BM-MSCs from three animals were exposed to: (a) 20% allogeneic inflammatory SF (SF); (b) 50 ng/ml of TNFα and IFNγ (CK50) and (c) 20 ng/ml of TNFα and IFNγ (CK20). After 72 h of exposure, expression of immunogenic and immunomodulation-related molecules, including cell-to-cell contact and paracrine signalling molecules, were analysed by RT-qPCR and flow cytometry. The gene expression of adhesion molecules was upregulated whereas MSC migration-related genes were downregulated by all inflammatory conditions tested. CK culture conditions significantly upregulated the expression of COX-2, iNOS, IDO and IL-6. MHC-I gene expression was upregulated by all conditions, whereas MHC-II was upregulated only after CK priming. The expression of CD40 did not significantly change, whereas the ligand, CD40L, was downregulated in CK conditions. Flow cytometry showed an increase in the percentage of positive cells and mean fluorescence intensity (MFI) of the MHC-I and MHC-II molecules at CK50 conditions, supporting the gene expression results. These outcomes reinforce the change of the immunophenotype of the eBM-MSCs according to the surrounding conditions. Inflammatory synovial environment did not lead to significant changes, so the environment found by eBM-MSCs when they are intraarticular administered may not be enough to activate their immunomodulatory potential. CK priming at tested doses enhances the immunoregulatory profile of eBM-MSCs, which may promote a therapeutic benefit. Even if CK priming induced an upregulation of MHC expression, costimulatory molecule expression however was not upregulated, suggesting that immunogenicity might not be increased. This study provides a better understanding about the behaviour of eBM-MSCs inside the inflamed joint and constitutes a first step to improve MSC-based therapies for equine joint diseases.

Ultrasound and magnetic resonance imaging assessment of joint disease in symptomatic patients with cystic fibrosis arthropathy.

OBJECTIVES: Cystic fibrosis arthropathy (CFA) is a term commonly used for joint pain with and without swelling seen in some patients with CF. Early studies into CFA focused on the presence of rheumatoid factor and immunological changes on synovial biopsy, with parallels drawn between respiratory and joint activity. Identification of anti-cyclic citrullinated peptide antibodies (anti-CCP) as a marker of rheumatoid arthritis (RA), along with increased access to sensitive imaging techniques including ultrasound (US) and magnetic resonance imaging (MRI), offer great potential to investigate and more accurately understand the type(s) of inflammatory arthritis that may underlie CFA. The aim of this study was to phenotype an active CFA cohort using serology and imaging, as a basis for further work in this understudied area. METHODS: This was a prospective observational cohort study of symptomatic CFA patients presenting with joint pain. Participants underwent serological testing, clinical and US joint and entheseal assessment, as well as MRI of the most symptomatic joint/joint area. RESULTS: Ten symptomatic patients were studied with 9/10 having positive clinical findings. Inflammatory changes on US were seen in 8/10 cases. Five patients had positive findings on MRI (3 of whom had received IV gadolinium contrast). This included patients with significant erosive changes. One patient was anti-CCP positive suggestive of RA, and two were anti-nuclear antibody positive. CONCLUSION: Imaging, and to a lesser extent serology, identified inflammatory joint pathology in a proportion of cases, providing important data to explore in a large CFA cohort examining the clinical and imaging phenotype of this group.