An update on the safety of long-term vedolizumab use in inflammatory bowel disease.

INTRODUCTION: Vedolizumab (Entyvio) is a humanized monoclonal antibody that disrupts the interaction between α4ß7 integrin on circulating T-lymphocytes and MAdCAM-1 on the vascular endothelium to prevent their egress to sites of gut inflammation. It has proven therapeutic efficacy for the treatment of moderate-to-severe Crohn's disease, ulcerative colitis, and pouchitis. AREAS COVERED: This narrative review assesses the safety profile of vedolizumab from the registration trial programs, open-label extension studies, observational real-world data, and pooled safety analyses. This includes an evaluation of the long-term overall safety in special populations typically underrepresented in clinical trials. EXPERT OPINION: Vedolizumab is an effective therapy for inflammatory bowel disease with a well-established safety profile. No unexpected long-term safety signals have been identified. Safety data in pregnancy, in pediatric and elderly populations, in patients undergoing surgery, and in patients with a prior history of cancer are reassuring. Due to its safety merits, we propose that vedolizumab is an excellent candidate for advanced combination treatment with an anti-cytokine approach using another biologic or novel small molecule inhibitor. This is important in patients with medically refractory IBD, in patients at high risk of developing disease-related complications, or in patients with concomitant uncontrolled immune-mediated inflammatory diseases.

Stemming the tide with ileocecal Crohn's disease: when is pharmacotherapy enough?

INTRODUCTION: Crohn's disease (CD) mostly affects the terminal ileum and ileocecal region and up to 80% of patients end up requiring surgery. Previously reserved for complicated or refractory forms, surgery is now considered as an alternative to medical treatment in localized ileocecal disease. AREAS COVERED: This review examines factors associated with response to medical treatment and those associated with the need for surgery in ileocecal CD to identify the patients' profile for whom pharmacotherapy might be enough. Factors associated with the recurrence and the postoperative complications are also reviewed to help the clinician identify patients for whom medical therapy might be preferred. EXPERT'S OPINION: LIR!C study long-term follow-up data show that 38% of infliximab-treated patients were still treated with infliximab at the end of their follow-up, while 14% had switched to another biologic or had received immunomodulator or corticosteroid and 48% had CD-related surgery. Only the combination with an immunomodulator was associated with a greater likelihood of continuing infliximab. Patients with ileocecal CD for whom pharmacotherapy might be sufficient are probably those with no risk factors for CD-related surgery.In addition, patients with high risk of recurrence or of post-operative complications may benefit more from medical treatment than from surgery.

Food avoidance and fasting in patients with inflammatory bowel disease: Experience from the Nancy IBD nutrition clinic.

BACKGROUND: Patients with inflammatory bowel disease (IBD) consider that their diet is important for controlling symptoms and frequently ask their physician for additional guidance on this matter. The objectives of the present study of patients with IBD were to characterize the prevalence of exclusion diets and fasting and to identify associated risk factors. METHODS: Using an anonymous questionnaire, we screened patients attending our IBD nutrition clinic between November 2021 and April 2022 for exclusion diets. The avoidance of a food category completely was defined as total exclusion and avoidance most of the time was defined as partial exclusion. We also asked patients whether they fasted totally, intermittently, or partially. RESULT: A total of 434 patients with IBD were included. On inclusion, 159 patients (36.6%) totally excluded at least one food category and 271 (62.4%) partially excluded at least one food. Intermittent, total, or partial fasting was reported by 30.8% of the patients. Disease activity (odds ratio (OR) [95% confidence interval] = 1.7 [1.1-2.7], p = 0.0130) and treatment with a small-molecule or an investigational drug (OR = 4.0 [1.5-10.6], p = 0.0059) were independently associated with an exclusion diet. A history of stenosis (OR = 2.0 [1.2-3.2], p = 0.0063) and active disease (OR = 1.9 [1.2-3.1], p = 0.0059) were associated with fasting. CONCLUSION: In this real-world study, approximately two-thirds of our patients with IBD reported the partial or total exclusion of at least one food category and one third reported fasting. A systematic nutritional evaluation might improve clinical management and quality of care for patients with IBD both Crohn's disease and ulcerative colitis.

Identification of circulating biomarkers of Crohn's disease and spondyloarthritis using Fourier transform infrared spectroscopy.

Crohn's disease (CD) and spondyloarthritis (SpA) are two inflammatory diseases sharing many common features (genetic polymorphism, armamentarium). Both diseases lack diagnostic markers of certainty. While the diagnosis of CD is made by a combination of clinical, and biological criteria, the diagnosis of SpA may take several years to be confirmed. Based on the hypothesis that CD and SpA alter the biochemical profile of plasma, the objective of this study was to evaluate the analytical capability of Fourier transform infrared spectroscopy (FTIR) in identifying spectral biomarkers. Plasma from 104 patients was analyzed. After data processing of the spectra by Extended Multiplicative Signal Correction and linear discriminant analysis, we demonstrated that it was possible to distinguish CD and SpA from controls with an accuracy of 97% and 85% respectively. Spectral differences were mainly associated with proteins and lipids. This study showed that FTIR analysis is efficient to identify plasma biosignatures specific to CD or SpA.

Ocular Manifestations in Patients with Inflammatory Bowel Disease in the Biologics Era.

Background: Extra-intestinal manifestations are frequent in inflammatory bowel disease (IBD). Ocular disorders are generally under diagnosed as they are challenging diagnosis. Aims: We assessed the prevalence of ophthalmological manifestations in patients with IBD, and investigated characteristics associated with ocular manifestations. Methods: We performed a retrospective study including patients followed for IBD and had an ophthalmologic visit from January 2013 to July 2020, among 1432 patients followed during this period. Two groups were considered: the first group included patients whose an ocular diagnosis was considered as "related to IBD", and the second group including patients whose an ocular diagnosis was considered "not related to IBD". Results: Among 1432 patients with IBD, eighty-seven (6.1%) patients had an ophthalmologic visit. Fifty-three patients (3.7%) were considered to have an ocular extra-intestinal manifestation or an iatrogenic effect of IBD treatment, and 34 diagnoses (2.4%) were considered not related to IBD. Inflammatory surface pathologies were the most frequent (33.2%), including 15 patients with dry eye (17.2%), 9 with blepharitis (10.3%), and 5 with chalazions (meibomian cyst) (5.7%). Uveitis was diagnosed in 13 patients (14.9%), episcleritis in 5 patients (5.7%), and scleritis in 2 patients (2.3%). Characteristics of patients with an ophthalmological diagnosis "related to IBD" versus "not related to IBD" were not statistically different. Conclusion: In our cohort, less than 5% of patients had ophthalmological extra-intestinal manifestation. The most frequent ocular diagnosis were dry eye and uveitis. No disease characteristics of IBD were found to be associated with ocular manifestations.

Impact of the Exposome on the Epigenome in Inflammatory Bowel Disease Patients and Animal Models.

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract that encompass two main phenotypes, namely Crohn's disease and ulcerative colitis. These conditions occur in genetically predisposed individuals in response to environmental factors. Epigenetics, acting by DNA methylation, post-translational histones modifications or by non-coding RNAs, could explain how the exposome (or all environmental influences over the life course, from conception to death) could influence the gene expression to contribute to intestinal inflammation. We performed a scoping search using Medline to identify all the elements of the exposome that may play a role in intestinal inflammation through epigenetic modifications, as well as the underlying mechanisms. The environmental factors epigenetically influencing the occurrence of intestinal inflammation are the maternal lifestyle (mainly diet, the occurrence of infection during pregnancy and smoking); breastfeeding; microbiota; diet (including a low-fiber diet, high-fat diet and deficiency in micronutrients); smoking habits, vitamin D and drugs (e.g., IBD treatments, antibiotics and probiotics). Influenced by both microbiota and diet, short-chain fatty acids are gut microbiota-derived metabolites resulting from the anaerobic fermentation of non-digestible dietary fibers, playing an epigenetically mediated role in the integrity of the epithelial barrier and in the defense against invading microorganisms. Although the impact of some environmental factors has been identified, the exposome-induced epimutations in IBD remain a largely underexplored field. How these environmental exposures induce epigenetic modifications (in terms of duration, frequency and the timing at which they occur) and how other environmental factors associated with IBD modulate epigenetics deserve to be further investigated.

Incidence of and Risk Factors for Colorectal Strictures in Ulcerative Colitis: A Multicenter Study.

BACKGROUND & AIMS: Ulcerative colitis (UC) is increasingly recognized as a progressive disease and patients with long-standing disease can develop colorectal stricture. Few data about its incidence in UC are available, while risk factors for colorectal strictures in UC remain to be determined. We assessed the incidence of and risk factors for developing colorectal strictures in a large UC population. METHODS: All adult patients followed at Nancy University hospital and at the centre hospitalier de Luxembourg for UC, between January 2004 and July 2019, were eligible for inclusion in this multicenter retrospective cohort study. RESULTS: A total of 439 patients with UC were included. Median follow-up duration was 9.6 years. Incidence of colorectal stricture was 3.6%. The cumulative probability of developing this complication was 1% at 5 years and 2.3% at 10 years. Median age at stricture diagnosis was 47.9 years (41.0; 63.0), and median time from UC diagnosis to onset of stricture was 11.5 years (5; 15.3). Montreal A3 classification (age > 40 years) (P = .008) and steroids use (HR = 4.1; 95% CI, 1.1-16.1) were independent risk factors for stricture, whereas mesalamine-treated patients carried a lower risk (HR = 0.3; 95% CI, 0.1-0.9). Dysplasia was found in 6 patients with strictures (42.9%) and among them 5 developed a colorectal cancer (33.3%). CONCLUSIONS: Patients with Montreal A3 classification and those exposed to steroids have a higher risk for strictures, while use of mesalamine lowers this risk. These factors should be assessed in daily clinical practice to prevent stricture occurrence in these patients.

IL-17 Inhibitors and Inflammatory Bowel Diseases: A Postmarketing Study in Vigibase.

Several gastrointestinal symptoms and chronic inflammatory bowel diseases (IBDs) have been reported after therapy with IL-17 inhibitors. To date, however, no study has shown a clear association between these drugs and IBD onset. We searched on Vigibase, the worldwide pharmacovigilance database, to investigate reporting prevalence, characteristics, and prognosis of all gastroenterological adverse events in patients treated with IL-17 inhibitors. In total, 1,129 gastrointestinal Individual Case Safety Reports (ICSRs) were identified, including 850 IBD (42.5% Crohn's disease, 31.9% ulcerative colitis, and 25.6% undifferentiated IBD) and 279 colitis (mainly undifferentiated colitis (79.2%), and microscopic colitis (10.4%)). ICSRs were associated with secukinumab (SEC, 83.6%) or ixekizumab (IXE, 16.3%), whereas only one colitis occurred with brodalumab (0.1%). Most IBD and colitis cases were detected within 6 months from therapy start in both the SEC (68.8% and 73.5%) and IXE groups (100% and 66.7%). Patients' outcomes were reported in 428 ICSRs (37.9%). Complete or ongoing recovery from symptoms was detected in about two-thirds of patients experiencing IBD (59.5%) or colitis (64.2%), whereas in the other cases, there was no recovery (33.9% and 29.5%) or there were sequelae (5.4% and 4.2%). Fatal events occurred in four patients (1.2%) in the IBD group (3 after SEC and on1e with IXE) and two SEC-treated subjects in the colitis group (2.1%). Treatment with IL-17 inhibitors is associated with a relevant number of exacerbations and new onset of IBD and colitis. Careful evaluation of gastrointestinal symptoms and the monitoring of intestinal inflammatory biomarkers should be recommended before prescribing these drugs.

Paradoxical gastrointestinal effects of interleukin-17 blockers.

Secukinumab, ixekizumab and brodalumab are monoclonal antibody therapies that inhibit interleukin (IL)-17 activity and are widely used for the treatment of psoriasis, psoriatic arthritis and ankylosing spondylitis. The promising efficacy results in dermatology and rheumatology prompted the evaluation of these drugs in Crohn's disease and ulcerative colitis, but the onset of paradoxical events (disease exacerbation after treatment with a theoretically curative drug) prevented their approval in patients with inflammatory bowel diseases (IBDs). To date, the pathophysiological mechanisms underlying these paradoxical effects are not well defined, and there are no clear guidelines for the management of patients with disease flare or new IBD onset after anti-IL-17 drug therapy. In this review, we summarise the literature on putative mechanisms, the clinical digestive effects after therapy with IL-17 inhibitors and provide guidance for the management of these paradoxical effects in clinical practice.

Constitutive activation of EGFR is associated with tumor progression and plays a prominent role in malignant phenotype of chondrosarcoma.

Chondrosarcoma is a highly agressive cancer with currently no effective therapies when unresectable or metastasized, thus the outcome remains poor. High-grade chordrosarcomas are resistant to conventional chemotherapy and radiotherapy and surgical resection remains the only treatment for the majority of chondrosarcomas. Constitutive activation of receptor tyrosine kinases has been shown to be important for malignant transformation and tumour proliferation. Here, we investigated the activation status of EGFR in chondrosarcoma tumor biopsies and cell lines. We found that EGFR is activated in grade II and grade III chondrosarcoma tumors but not in grade I tumors, suggesting a role in tumor progression. Interestingly, we showed that EGFR is activated through an autocrine loop and that inhibition of the EGFR by the TKI, tyrphostin AG1478 or EGFR neutralizing antibodies strongly reduced activation of oncogenic ERK1/2 and mTOR/AKT downstream pathways. Importantly, inhibition of EGFR profoundly reduces cell proliferation and migration, inhibits the expression of MMP13 and MMP3 and enhances cell death. Taken together, these data support the blocking of EGFR as new potential treatment for high-grade chondrosarcoma tumors.

Non-canonical Wnt induces chondrocyte de-differentiation through Frizzled 6 and DVL-2/B-raf/CaMKIIα/syndecan 4 axis.

Dysregulation of Wnt signaling has been implicated in developmental defects and in the pathogenesis of many diseases such as osteoarthritis; however, the underlying mechanisms are poorly understood. Here, we report that non-canonical Wnt signaling induced loss of chondrocyte phenotype through activation of Fz-6/DVL-2/SYND4/CaMKIIα/B-raf/ERK1/2 cascade. We show that in response to Wnt-3a, Frizzled 6 (Fz-6) triggers the docking of CaMKIIα to syndecan 4 (SYND4) and that of B-raf to DVL-2, leading to the phosphorylation of B-raf by CaMKIIα and activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling, which leads to chondrocyte de-differentiation. We demonstrate that CaMKIIα associates and phosphorylates B-raf in vitro and in vivo. Our study reveals the mechanism by which non-canonical Wnt activates ERK1/2 signaling that induces loss of chondrocyte phenotype, and demonstrates a direct functional relationship between CaMKIIα and B-raf during chondrocyte de-differentiation. The identification of Fz-6, SYND4, and B-raf as novel physiological regulators of chondrocyte phenotype may provide new potential anti-osteoarthritic targets.

Experimental colitis delays and reduces the severity of collagen-induced arthritis in mice.

Amongst extraintestinal manifestations (EIM) occurring in IBD patients, rheumatologic manifestations are the most frequent. Understanding the relationships between arthritis and colitis is a prerequisite to improving the management of these patients. Microbiota of patients with IBD or rheumatologic diseases, like spondyloarthritis (SpA) is modified compared to healthy individual. Thus, we have evaluated the impact of colitis in the development of arthritis in mice and we have analyzed microbiota changes. Collagen-induced arthritis (CIA) was induced at day 0 in DBA1 mice exposed or not to Dextran Sodium Sulfate (DSS) to induce colitis between day 14 and day 21. Animals were monitored regularly for arthritis and colitis severity (clinical score, hindpaw edema). Fecal microbiota was studied by 16S rRNA deep sequencing at critical time points (D14, D14, D21 & D41). At day 41, histological scoring of the intestines and ankles were performed at the end of experiment. Induction of colitis slightly delayed arthritis onset (2 ± 1 days of delay) and reduced its severity (5.75 ± 1.62 in arthritis only group vs 4.00 ± 1.48 in arthritis + colitis group (p = 0.02 at day 28) macroscopically and histologically. In contrast, colitis severity was not influenced by arthritis development. Induction of colitis promoted a modification of microbiota composition and a decrease of α-diversity. Fecal microbiota composition was different between "colitis" and "arthritis+colitis" groups during colitis development. Interestingly a milder decrease of bacterial diversity in the "arthritis+colitis" group was observed. Concomitant experimental colitis protects mice against collagen-induced arthritis and this is associated with changes in gut microbiome composition.

Management of patients with inflammatory bowel disease and spondyloarthritis.

INTRODUCTION: More than half of the patients with inflammatory bowel disease (IBD) experience at least one extra-intestinal manifestation (EIM). The most common EIM in patients with IBD is spondyloarthritis (SpA). Microscopic intestinal inflammation is documented in almost 50% of the patients with SpA. Areas covered: We give an overview of the classification, the epidemiology and the diagnosis of IBD and SpA. The treatment goals, the pharmacologic management options and the available treatment guidelines in IBD patients with SpA are discussed. Expert commentary: The coexistence of IBD and SpA generates challenges and opportunities for both the gastroenterologist and the rheumatologist. The potential of drugs with a gut-specific mode of action in the treatment of IBD-related arthritis warrants further exploration.

Association between rheumatoid arthritis and systemic mastocytosis: a case report and literature review.

Classically, mast cells (MC) are considered as important actors of the innate immune response playing a pivotal role in IgE-mediated allergic and antiparasite responses. In the last two decades, many experimental evidences demonstrated that these hematopoietic-derived cells present in both connective and mucosal tissues are also key modulators of the adaptive immune response and could contribute to autoimmune disease notably in rheumatoid arthritis (RA). Recently, Bader-Meunier et al. reported a series of 31 patients suffering from inflammatory joint diseases associated with mastocytosis, suggesting that mastocytosis was associated with a higher prevalence in spondyloarthritis. We discuss here the possible link between chronic inflammatory arthritis and mastocytosis through the report of a clinical case describing a patient developing RA after a long history of mastocytosis. Of great interest, antihistamine treatment alone was sufficient to treat RA in this patient.

PLGA-Based Nanoparticles: a Safe and Suitable Delivery Platform for Osteoarticular Pathologies.

PURPOSE: Despite the promising applications of PLGA based particles, studies examining the fate and consequences of these particles after intra-articular administration in the joint are scanty. This study was carried out to evaluate the neutrality of the unloaded delivery system on different articular cell types. To facilitate tracking, we have thus developed a fluorescent core of particles, combined to a hyaluronate shell for cell recognition. METHODS: Fluorescence pictures were taken at time intervals to assess the internalization and the corresponding inflammatory response was monitored by RT-qPCR and biochemical measurements. After NPs pre-treatment, mesenchymal stem cells (MSCs) were cultured into chondrogenic, adipogenic or osteogenic differentiation media, to investigate if NPs exposure interferes with differentiation ability. Finally, intra-articular injections were performed in healthy rat knees and joint's structure analysed by histological studies. RESULTS: Particles were detected in cytoplasm 8 h after exposure. Internalization led to a slight and reversible increase of inflammatory markers, but lower than in inflammatory conditions. We have confirmed particles exposure minimal neutrality on MSCs pluripotency. Histological exams of joint after intra-articular injections do not demonstrate any side effects of NPs. CONCLUSIONS: Our findings suggest that such a delivery platform is well tolerated locally and could be used to deliver active molecules to the joint.

The peroxisome proliferator-activated receptor γ agonist pioglitazone preserves bone microarchitecture in experimental arthritis by reducing the interleukin-17-dependent osteoclastogenic pathway.

OBJECTIVE: To investigate the effect of pioglitazone on inflammation-induced bone loss and changes in bone microarchitecture in rats with adjuvant-induced arthritis (AIA), focusing on the contribution of interleukin-17 (IL-17) and the balance of RANKL and osteoprotegerin (OPG). METHODS: Male Lewis rats sensitized with Freund's complete adjuvant were treated orally for 21 days with 30 mg/kg/day of pioglitazone or vehicle. Arthritis severity was evaluated by clinical and histologic examination. Bone mineral density (BMD) was assessed by dual x-ray absorptiometry. The therapeutic effect of pioglitazone on changes of the bone architecture was determined by micro-computed tomography (micro-CT). Levels of RANKL, OPG, and IL-17 were determined by serum immunoassay and by synovial tissue immunohistochemistry. Messenger RNA for IL-17 and retinoic acid receptor-related orphan nuclear receptor γt (RORγt) was evaluated by quantitative reverse transcription-polymerase chain reaction and IL-17 promoter activity by gene-reporter assay. RESULTS: Micro-CT analysis revealed that pioglitazone treatment reduced arthritis severity and bone erosion scores and increased BMD in comparison to vehicle treatment. Cortical bone thickness was preserved, although the major beneficial effect of pioglitazone was on indices of the trabeculae, especially trabecular separation. Pioglitazone reduced the ratio of RANKL to OPG, in both the serum and the inflamed synovium. Circulating levels of IL-17 were significantly reduced by pioglitazone treatment, as were the percentages of IL-17-positive cells, mainly polymorphonuclear cells, in the inflamed synovium. Induction of IL-17 was strictly dependent on the binding of RORγt to IL-17 promoter, and lentiviral overexpression of peroxisome proliferator-activated receptor γ (PPARγ) reduced the expression of RORγt. CONCLUSION: Pioglitazone decreased the level of inflammatory bone destruction and protected the bone microarchitecture in rats with AIA by controlling the circulating and local expression of IL-17, with a subsequent decrease in the RANKL-to-OPG ratio. Along with the inhibition of RORγt expression after PPARγ overexpression, these findings provide evidence of the major contribution of reduced IL-17/RANKL-dependent osteoclastogenesis.

Chondrocalcin is internalized by chondrocytes and triggers cartilage destruction via an interleukin-1ß-dependent pathway.

Chondrocalcin is among the most highly synthesized polypeptides in cartilage. This protein is released from its parent molecule, type II pro-collagen, after secretion by chondrocytes. A participation of extracellular, isolated chondrocalcin in mineralization was proposed more than 25 years ago, but never demonstrated. Here, exogenous chondrocalcin was found to trigger MMP13 secretion and cartilage destruction ex vivo in human cartilage explants and did so by modulating the expression of interleukin-1ß in primary chondrocyte cultures in vitro. Chondrocalcin was found internalized by chondrocytes. Uptake was found mediated by a single 18-mer peptide of chondrocalcin, which does not exhibit homology to any known cell-penetrating peptide. The isolated peptide, when artificially linked as a tetramer, inhibited gene expression regulation by chondrocalcin, suggesting a functional link between uptake and gene expression regulation. At the same time, the tetrameric peptide potentiated chondrocalcin uptake by chondrocytes, suggesting a cooperative mechanism of entry. The corresponding peptide from type I pro-collagen supported identical cell-penetration, suggesting that this property may be conserved among C-propeptides of fibrillar pro-collagens. Structural modeling localized this peptide to the tips of procollagen C-propeptide trimers. Our findings shed light on unexpected function and mechanism of action of these highly expressed proteins from vertebrates.

The cucurbitacins E, D and I: investigation of their cytotoxicity toward human chondrosarcoma SW 1353 cell line and their biotransformation in man liver.

Cucurbitacins are a class of natural compounds known for their numerous potential pharmacological effects. The purpose of this work was to compare the cytotoxicity of three cucurbitacins I, D, E on the chondrosarcoma SW 1353 cancer cell line and to investigate their biotransformation in man. Cucurbitacins I and D showed a very strong cytotoxicity, which was higher than that of cytochalasin D, used as a drug reference. Almost 100% of the cells were apoptotic as observed by DNA fragmentation (TUNEL assay) after 12 h with cucurbitacins I and D (1 µM) and cucurbitacin E (10 µM). In terms of IC(50) values, cucurbitacins I and E presented a higher toxicity compared to that of cucurbitacin D (MTT assay). Cucurbitacin E was readily hydrolyzed by human hepatic microsomes, leading to cucurbitacin I (K(m) 22 µM, V(max) 571 nmol/mg proteins/min). On the other hand, the three cucurbitacins were hydroxylated at a very low extent, but they were sulfated and glucuronidated. In terms of V(max)/K(m), the cucurbitacin E was the best substrate of UDP-glucuronosyltransferases. This study shows that cucurbitacins I, D and E present a potent cytotoxic activity toward the chondrosarcoma SW 1353 cell line and are metabolized as sulfate and glucuronide conjugates.

Alternative for anti-TNF antibodies for arthritis treatment.

Tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, plays a key role in the pathogenesis of many inflammatory diseases, including arthritis. Neutralization of this cytokine by anti-TNF-α antibodies has shown its efficacy in rheumatoid arthritis (RA) and is now widely used. Nevertheless, some patients currently treated with anti-TNF-α remain refractory or become nonresponder to these treatments. In this context, there is a need for new or complementary therapeutic strategies. In this study, we investigated in vitro and in vivo anti-inflammatory potentialities of an anti-TNF-α triplex-forming oligonucleotide (TFO), as judged from effects on two rat arthritis models. The inhibitory activity of this TFO on articular cells (synoviocytes and chondrocytes) was verified and compared to that of small interfering RNA (siRNA) in vitro. The use of the anti-TNF-α TFO as a preventive and local treatment in both acute and chronic arthritis models significantly reduced disease development. Furthermore, the TFO efficiently blocked synovitis and cartilage and bone destruction in the joints. The results presented here provide the first evidence that gene targeting by anti-TNF-α TFO modulates arthritis in vivo, thus providing proof-of-concept that it could be used as therapeutic tool for TNF-α-dependent inflammatory disorders.