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Well conducted randomized clinical trial is considered gold standard in drug safety and efficacy evaluation. Drug development can be challenging in rare diseases, or in ethically sensitive populations (pregnant women, children, patient with cognitive defect), because of low number of subjects. The low rate of observed events at a sample scale in this population can lead to a biased evaluation of drugs compared to the general population. The aim of this work was to address alternative methods for drug evaluation in particular populations, especially pharmaco-epidemiology on populational database of the SNDS (Système National des Données de Santé). We first evaluate the safety of anti-TNFα in French pregnant women with a diagnosis of Inflammatory Bowel Disease (IBD), and in their children during their first year of life, using the SNDS database. Anti-TNFα use was associated with an increased risk of overall maternal complications during pregnancy, whatever the duration of treatment. There was no increased risk in children up to 1 year of age. In this same cohort, we then studies the security of recommended vaccines during the first year of life in children exposed in utero to antiTNF, and born to mothers with IBD. No adverse event related to tuberculosis or measles was observed. Those results demonstrate the value of alternative methods as useful tools for drug evaluation, and can strengthen the quality of clinical recommendations, in populations where clinical trial cannot be considered., La référence de l’évaluation clinique de l’efficacité et la sécurité du médicament est l’essai thérapeutique randomisé rigoureux sur le plan méthodologique. Le développement du médicament peut être compliqué dans les maladies rares, ou dans les populations éthiquement difficiles à inclure dans les essais cliniques (femme enceinte, enfants, pathologies avec atteinte cognitive), faute d’effectif suffisant. Le manque de puissance ou d’événements observables à l’échelle de l’échantillon entraine un défaut d’évaluation du médicament comparé à la population générale. L’objectif de cette thèse est d’aborder les autres méthodes possibles d’évaluation du médicament dans ces populations particulières, et particulièrement la pharmaco-épidémiologie sur la base populationnelle du Système National des Données de Santé (SNDS). Nous avons d’abord évalué la sécurité des anti-TNFα chez les femmes françaises enceintes atteintes de Maladies Inflammatoires Chroniques Intestinales (MICI), et chez leurs enfants durant la première année de vie à partir des données du SNDS. Les anti-TNFα étaient associés à un risque accru de complications maternelles durant la grossesse, indépendamment de la durée de traitement. Il n’y avait pas de risque infectieux accru chez l’enfant jusqu’à 1 an. Dans cette même cohorte, nous avons ensuite étudié la sécurité des vaccins recommandés durant la première année de vie chez les enfants exposés in utero aux anti-TNFα. Aucun événement indésirable lié au vaccin contre la tuberculose ou la rougeole n’a été détecté chez ces enfants. Ces résultats permettent de démontrer l’intérêt de ces méthodes alternatives comme outil de l’évaluation du médicament, et peuvent participer à l’amélioration des recommandations cliniques de meilleure qualité, dans les populations où l’essai clinique randomisé n’est pas envisageable.

Repeated intra-articular hemorrhages lead to hemophilic arthropathy in severe hemophilia. Inflammation and pro-inflammatory cytokines (e.g., tumor necrosis factor alpha (TNF&alpha, )) might be involved in this pathogenesis. We hypothesized that anti-TNF&alpha, may provide adjuvant protection for hemophilic arthropathy management. We measured TNF&alpha, in synovial lavage from hemophilia mice subjected to hemarthrosis induction and synovial fluid from patients with hemophilic arthropathy (n = 5). In hemophilia mice, recurrent hemarthroses were induced, anti-TNF&alpha, was initiated either from day (D)7 after one hemarthrosis episode or D21 after three hemarthroses episodes (n &ge, 7/treatment group). In patients with hemophilic arthropathy (16 patients with 17 affected joints), a single dose of anti-TNF&alpha, was administered intra-articularly. Efficacy, characterized by synovial membrane thickness and vascularity, was determined. Elevated TNF&alpha, in synovial lavage was found in the hemophilia mice and patients with hemophilic arthropathy. Hemophilia mice subjected to three hemarthroses developed severe synovitis (Synovitis score of 6.0 &plusmn, 1.6). Factor IX (FIX) replacement alone partially improved the pathological changes (Synovitis score of 4.2 &plusmn, 0.8). However, anti-TNF&alpha, treatment initiated at D7, not D21, significantly provided protection (Synovitis score of 1.8 &plusmn, 0.9 vs. 3.9 &plusmn, 0.3). In patients with hemophilic arthropathy, intra-articular anti-TNF&alpha, significantly decreased synovial thickness and vascularity during the observed period from D7 to D30. Collectively, this preliminary study seems to indicate that TNF&alpha, may be associated with the pathogenicity of hemophilic arthropathy and anti-TNF&alpha, could provide adjuvant protection against hemophilic arthropathy. Further studies are required to confirm the preliminary results shown in this study.

Background and Aims Patients with inflammatory bowel diseases may have higher incidences of non-melanoma skin cancers and non-Hodgkin lymphoma, potentially linked to underlying disease and treatments. This analysis assessed incidence rates of these malignancies in Japanese patients with ulcerative colitis or Crohn’s disease, and their association with thiopurine and/or anti-tumor necrosis factor-α treatment, using data from a nationwide administrative database in Japan. Methods Patients diagnosed with inflammatory bowel disease without malignancy were identified from the Medical Data Vision database. Incident cases of non-melanoma skin cancers and non-Hodgkin lymphoma diagnosed after prescription of thiopurine and/or anti-tumor necrosis factor-α were identified between April 2008 and January 2018. Age- and sex-adjusted incidence rate ratios were calculated relative to the total treated patient population. Results A total of 75 673 eligible patients were identified at the index date. Thiopurine prescription with or without anti-tumor necrosis factor-α agents increased incidence rate ratios for non-melanoma skin cancers relative to the overall population (3.39 and 4.03, respectively). There were no notable differences in non-Hodgkin lymphoma incidence relative to the total population in any treatment subgroup, regardless of prescription of thiopurine and/or anti-tumor necrosis factor-α (all incidence rate ratios, ~1). Conclusions There is no evidence for an increased incidence of non-Hodgkin lymphoma attributable to thiopurine or anti-tumor necrosis factor-α treatment in Japanese patients with inflammatory bowel disease. The impact of racial differences on non-Hodgkin lymphoma incidences should be considered. Thiopurine therapy may be a risk factor for non-melanoma skin cancers in Japanese patients.

Therapeutic antibodies display complex pharmacokinetic properties. When the antigenic mass increases, they are eliminated faster, and thus an active disease is responsible for a fast clearance. Moreover, patients can produce antibodies to the drug, leading to a strongly accelerated clearance. In this work, we studied the variability of the pharmacokinetics and of the concentration-effect relationship of anti-TNFα antibodies in inflammatory bowel diseases (IBD). The intra-individual variability of infliximab was described using compartmental modelling, and the relationship between disease activity and clearance was demonstrated at the individual level. A model was built to detect clearance increases putatively linked to immunogenicity, independently from evidencing any anti-drug antibodies in blood samples, thus avoiding the analytical issues that hampers the detection of immunization. The time-varying pharmacokinetics was comfronted to the clinical response, showing that clearance was predicitive of the respsonse in induction and de-escalation settings. Therefore, it was hypothetized that monitoring the clearance could help the follow-up of the disease, as an early marker of disease activity and evolution. Last, it was shown that cumulated exposure to infliximab was linked to the risk of developping opportunistic infections. Based on this data, recommandations regarding the modalities of regimen adaptations could be built, that are currently lacking. All the work presented here contribute to enhance our knowledge of the pharmacology of anti-TNFα antibodies, but also of other therapeutic antibodies, and to improve their use in clinical settings., Les anticorps thérapeutiques ont une pharmacocinétique complexe. Lorsque la masse antigénique augmente, les anticorps thérapeutiques sont éliminés plus vite ; ainsi une maladie active détermine une clairance élevée. De plus, les patients peuvent s’immuniser contre le médicament, produisant des anticorps responsables d’une élimination très accélérée. Dans ce travail, nous avons étudié la variabilité de la pharmacocinétique et de la relation concentration-effet des anti-TNFα dans les maladies inflam-matoires chroniques de l’intestin (MICI). Nous avons décrit par modélisation compartimentale la variabilité pharmacocinétique intra-individuelle de l’infliximab et étudié ses sources, démontrant l’étroite relation entre activité de la maladie et clairance. Nous avons également proposé un modèle capable de détecter les variations de clairance évocatrices d’immunisation indépendamment de la mise en évidence des anticorps anti-médicaments, permettant de s’affranchir du manque de sensibilité analytique de la recherche d’immunisation.Les variations de pharmacocinétique au cours du temps ont été confrontées à la réponse clinique, et nous avons montré que la clairance était prédictive de la réponse en induction et au cours de la désescalade thérapeutique. Nous avons donc proposé que le monitoring des traitements puisse inclure un suivi de l’évolution de la clairance comme marqueur précoce de l’activité de la maladie. Enfin, nous avons montré que l’exposition cumulée était relié au risque d’infection opportuniste dans les MICI. Cela pose les bases de recommandations concernant les modalités d’adaptations poso-logiques qui font actuellement défaut. L’ensemble des travaux présentés ici contribuent à améliorer notre connaissance de la pharmacologie des anti-TNFα et des anticorps thérapeutiques en général et ainsi à optimiser leur utilisation chez les patients.

Therapeutic antibodies display complex pharmacokinetic properties. When the antigenic mass increases, they are eliminated faster, and thus an active disease is responsible for a fast clearance. Moreover, patients can produce antibodies to the drug, leading to a strongly accelerated clearance. In this work, we studied the variability of the pharmacokinetics and of the concentration-effect relationship of anti-TNFα antibodies in inflammatory bowel diseases (IBD). The intra-individual variability of infliximab was described using compartmental modelling, and the relationship between disease activity and clearance was demonstrated at the individual level. A model was built to detect clearance increases putatively linked to immunogenicity, independently from evidencing any anti-drug antibodies in blood samples, thus avoiding the analytical issues that hampers the detection of immunization. The time-varying pharmacokinetics was comfronted to the clinical response, showing that clearance was predicitive of the respsonse in induction and de-escalation settings. Therefore, it was hypothetized that monitoring the clearance could help the follow-up of the disease, as an early marker of disease activity and evolution. Last, it was shown that cumulated exposure to infliximab was linked to the risk of developping opportunistic infections. Based on this data, recommandations regarding the modalities of regimen adaptations could be built, that are currently lacking. All the work presented here contribute to enhance our knowledge of the pharmacology of anti-TNFα antibodies, but also of other therapeutic antibodies, and to improve their use in clinical settings.; Les anticorps thérapeutiques ont une pharmacocinétique complexe. Lorsque la masse antigénique augmente, les anticorps thérapeutiques sont éliminés plus vite ; ainsi une maladie active détermine une clairance élevée. De plus, les patients peuvent s’immuniser contre le médicament, produisant des anticorps responsables d’une élimination très accélérée. Dans ce travail, nous avons étudié la variabilité de la pharmacocinétique et de la relation concentration-effet des anti-TNFα dans les maladies inflam-matoires chroniques de l’intestin (MICI). Nous avons décrit par modélisation compartimentale la variabilité pharmacocinétique intra-individuelle de l’infliximab et étudié ses sources, démontrant l’étroite relation entre activité de la maladie et clairance. Nous avons également proposé un modèle capable de détecter les variations de clairance évocatrices d’immunisation indépendamment de la mise en évidence des anticorps anti-médicaments, permettant de s’affranchir du manque de sensibilité analytique de la recherche d’immunisation.Les variations de pharmacocinétique au cours du temps ont été confrontées à la réponse clinique, et nous avons montré que la clairance était prédictive de la réponse en induction et au cours de la désescalade thérapeutique. Nous avons donc proposé que le monitoring des traitements puisse inclure un suivi de l’évolution de la clairance comme marqueur précoce de l’activité de la maladie. Enfin, nous avons montré que l’exposition cumulée était relié au risque d’infection opportuniste dans les MICI. Cela pose les bases de recommandations concernant les modalités d’adaptations poso-logiques qui font actuellement défaut. L’ensemble des travaux présentés ici contribuent à améliorer notre connaissance de la pharmacologie des anti-TNFα et des anticorps thérapeutiques en général et ainsi à optimiser leur utilisation chez les patients.

A higher risk of atherosclerosis and related cardiovascular disease has been observed in patients with rheumatoid arthritis. Anti-TNFα monoclonal antibodies are used for the treatment of resistant rheumatoid arthritis resulting in inhibition of TNFα binding to cellular receptors that activate disease-associated pro-inflammatory pathways. The effect of TNFα inhibition on the lipoprotein pattern may provide information on the risk of atherosclerosis in these patients. In the present study the lipoprotein profiles of patients with rheumatoid arthritis have been examined before and after treatment with anti-TNFα. 85 patients (76 women, 89%) with established RA (disease duration ≥5 years), mean age 57 ± 12 (68% with RF positive), no known cardiovascular disease, thyroid disorder and thyroid disorder’s treatment with DMARDs and not receiving biological agents as treatment, were divided into 2 groups, those who had DAS28 3.2 (43 patients) who were additionally reserved anti-TNFα biological factor for ≥12 months and those who had DAS28≤3.2 (42 patients) who continued DMARD treatment and were monitored at the same time as a control group. Samples were taken at two times with a difference of ≥12 months. Separation of the lipoprotein subtypes was done by 4% polyacrylamide native gel electrophoresis. Two LDL (LDLA and LDL B) and six HDL (HDL1, HDL2a, HDL2b, HDL3a, HDL3b and HDL3c) subtypes were characterized. In patients receiving DMARDs, a decrease in the LDL-B subtype by 11.9% (p = 0.014) and an increase in HDL-3c by 2.38% (p = 0.049) were observed. In PA patients receiving anti-TNFα, a reduction in the LDL-B subtype was observed by 2.33% (p = 0.005), LDL-A by 2.33% (p = 0.0001), HDL3a by 11.63% = 0.072) and HDL3c by 4.65% (p = 0.035). In RA patients receiving anti-TNFα, a reduction in the LDL-B fractions was observed by 2.33% (p = 0.005), LDL-A by 2.33% (p = 0.0001), HDL3a by 11.63% = 0.072) and HDL3c by 4.65% (p = 0.035)., Aristotle Biomedical Journal, Vol 1, No 1 (2019)

Macular edema (ME) represents the most common cause for visual loss among uveitis patients. The management of uveitic macular edema (UME) may be challenging, due to its often recalcitrant nature. Corticosteroids remain the mainstay of treatment, through their capability of effectively controlling inflammation and the associated ME. Topical steroids may be effective in milder cases of UME, particularly in edema associated with anterior uveitis. Posterior sub-Tenon and orbital floor steroids, as well as intravitreal steroids often induce rapid regression of UME, although this may be followed by recurrence of the pathology. Intra-vitreal corticosteroid implants provide sustained release of steroids facilitating regression of ME with less frequent injections. Topical nonsteroidal anti-inflammatory drugs may provide a safe alternative or adjuvant therapy to topical steroids in mild UME, predominantly in cases with underlying anterior uveitis. Immunomodulators including methotrexate, mycophenolate mofetil, tacrolimus, azathioprine, and cyclosporine, as well as biologic agents, notably the anti-tumor necrosis factor-α monoclonal antibodies adalimumab and infliximab, may accomplish the control of inflammation and associated ME in refractory cases, or enable the tapering of steroids. Newer biotherapies have demonstrated promising outcomes and may be considered in persisting cases of UME.

Axial spondyloarthritis (Ax SpA) refers to chronic inflammatory rheumatic diseases that mainly affect the axial skeleton, leading to erosions and new bone formation in the sacroiliac joints and/or the spine. Ax SpA includes the radiographic form of the disease, ie, ankylosing spondylitis (AS), and the nonradiographic Ax SpA (non-Rx Ax SpA) forms. Anti-tumor necrosis factor alpha (TNFα) agents are used in the treatment of Ax SpA in patients who do not respond to or are intolerant to nonsteroidal anti-inflammatory drugs. In these patients, anti-TNFα agents show promising results by targeting the inflammatory process and providing symptomatic relief. Golimumab is a fully human anti-TNFα agent that is currently approved for the treatment of both AS and non-Rx Ax SpA in Europe. This review focuses on the results of clinical trials with golimumab for the treatment of AS (GO-RAISE studies) and non-Rx Ax SpA (GO-AHEAD study) and on the effects of this agent on imaging findings (radiographic progression, magnetic resonance imaging inflammation) as well as on biological parameters. Overall, golimumab is a valid therapeutic option in patients with AS and non-Rx Ax SpA in Europe.

Introduction: Ankylosing Spondylitis (AS) is a chronic inflammatory rheumatic disease characterized by pain, functional deformities, negatively affecting quality of life. A previous study showed that Tai Chi had a positive effect on disease activity and flexibility of patients with AS. The aim of this study was to investigate the effect of Tai Chi exercises on disease activity, functionality, spinal mobility, quality of life and inflammatory markers in patients with AS. Methods: This randomised controlled trial allocated 36 patients with AS to either a Tai Chi or a home exercise group using the block randomization. Both groups received a 1-h exercise program twice a week for 10 weeks and encouraged to practice at home. Outcome measures included: The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functionality Index (BASFI), Bath Ankylosing Spondylitis Metrology Index (BASMI), Ankylosing Spondylitis Quality of Life (ASQoL) scales and Erythrocyte Sedimentation Rate (ESR) and C-reactive protein (CRP). Results: After training, there was a statistically significant difference within groups for the Tai Chi and the home exercise groups for all parameters (p:0.00). When the delta values were compared between the groups, BASDAI (p:0.00), cervical rotation (p:0.02), and ASQoL (p:0.00) were found to be significantly in favor of the Tai Chi group. No side-effects were noted during or after the exercise programs. Conclusion: Tai Chi should be considered for inclusion in rehabilitation programs as a safe alternative type of exercise to reduce disease activity, improve spinal mobility and quality of life in patients with AS. Trial registration: https://clinicaltrials.gov/ct2/show/NCT03807180. Clinical trial number: NCT03807180. © 2020 Elsevier GmbH

Systemic and local chronic inflammation might enhance the risk of pancreatic ductal adenocarcinoma (PDAC), and PDAC-associated inflammatory infiltrate in the tumor microenvironment concurs in enhancing tumor growth and metastasis. Inflammation is closely correlated with immunity, the same immune cell populations contributing to both inflammation and immune response. In the PDAC microenvironment, the inflammatory cell infiltrate is unbalanced towards an immunosuppressive phenotype, with a prevalence of myeloid derived suppressor cells (MDSC), M2 polarized macrophages, and Treg, over M1 macrophages, dendritic cells, and effector CD4+ and CD8+ T lymphocytes. The dynamic and continuously evolving cross-talk between inflammatory and cancer cells might be direct and contact-dependent, but it is mainly mediated by soluble and exosomes-carried cytokines. Among these, tumor necrosis factor alpha (TNFα) plays a relevant role in enhancing cancer risk, cancer growth, and cancer-associated cachexia. In this review, we describe the inflammatory cell types, the cytokines, and the mechanisms underlying PDAC risk, growth, and progression, with particular attention on TNFα, also in the light of the potential risks or benefits associated with anti-TNFα treatments.

Cogan's syndrome (CS) is a rare autoimmune disease, characterized by ocular and vestibulo-auditory involvement. Treatment of CS could be challenging, and the only evidence-based data comes from case reports or series.There have recently been several reports of new treatment strategy involving the use of biological disease-modifying anti-rheumatic drugs such as TNFα inhibitors, anti-CD20 or anti-IL6 receptor antibodies, in cases resistant to first- or second-line drugs.Corticosteroids are the cornerstone of CS therapy at disease onset and during acute phases of the disease. Conventional immunosuppressive therapy, such as methotrexate, could be used in relapsing patients or as a glucocorticoid sparing agent, but efficacy is often modest. The anti-TNFα monoclonal antibody Infliximab appears to be the most frequently used, leading to an improvement in hearing loss in 89% of the cases and allow corticosteroid tapering in 86% of the patients. The appropriate timing of Infliximab treatment has yet to be thoroughly investigated, but it seems to be more effective when started at an early stage of the disease. Efficacy of others anti-TNFα agents is controversial. Rituximab and Tocilizumab are a safe option, but results on hearing loss have still to be confirmed on larger patients' cohorts.

The first infliximab biosimilar for the treatment of inflammatory bowel disease (IBD) was introduced in 2013, and today eight anti-TNF alpha biosimilars (three for infliximab and five for adalimumab) have been approved and licensed by the European Medicines Agency. Biosimilars present great potential in terms of cost saving and possible consequential reinvestment in the health care system. The increasing knowledge about the process of biosimilar development and use in IBD and the publication of many prospective clinical studies and real-life clinical experiences have progressively changed the point of view of IBD physicians. In the present position paper, the Italian Group for the Study of Inflammatory Bowel Disease present and discuss their updated statements and positions on this topic, with emphasis on the concepts of biosimilarity and extrapolation across indications, safety and immunogenicity, interchangeability and switching, automatic substitution, and, finally, patient education about biosimilars.

Introduction: During treatment with biologic agents for psoriasis (Pso) in a number of patients a failure may occur and discontinuation with transitioning to another drug or an optimization strategy, consisting in a dose-adjustment or a co-medication with a traditional systemic agent, represent two possible alternatives. Objective: The SAFARI study objective was a retrospective observation of adalimumab efficacy and safety profile after switching from other anti-TNFα agents related to clinician behavior after the failure of the first-line agent. Results: The retrospective multicenter observation demonstrated that after a first-line anti-TNFα failure adalimumab efficacy was consistent at week-12 and 24 with a further significant improvement at week-48 with a proportion of patients achieving PASI75/PASI90/PASI100 of 83.3, 71.6, and 56.9.%, respectively. Clinician strategies to extend drug-survival after first-line anti-TNFα failure, such as co-medication or dose-adjustment, were irrelevant to future drug effectiveness. Conclusions: Adalimumab profile was excellent in this 5-year retrospective observation, showing the clinical validity of interclass transitioning among anti-TNFα options.

Background Monoclonal antibodies inhibiting tumour necrosis factor-α (TNFα) signalling pathway (anti-TNFα) have been widely used in Crohn’s disease (CD). However, treatment response varies among patients with CD and the clinical outcome is dependent on single nucleotide polymorphisms (SNP) in TNFα receptor superfamily 1A and 1B (TNFRSF1A/1B). Methods We tested nine SNPs in TNFα, TNFRSF1A and TNFRSF1B by TaqMan genotyping from peripheral blood samples of 104 subjects. Additionally, we quantified the effects of these SNPs on their corresponding gene expression by RT-PCR and susceptibility to Mycobacterium avium subsp paratuberculosis (MAP) infection by IS900 nested PCR. Results Four SNPs (TNFα:rs1800629, TNFRSF1A:rs767455, TNFRSF1B:rs1061624 and TNFRSF1B:rs3397) were over-represented significantly (p

Objective To describe the outcome and tolerance in patients treated with anti-TNFα in severe and refractory major vessel disease in Behcet's disease (BD). Methods A multicenter study evaluating 18 refractory BD patients with major vessel involvement [pulmonary artery (n = 4), aorta (n = 4) or peripheral artery aneurysm (n = 1) and/or pulmonary artery (n = 7), inferior vena cava (n = 5), or intra-cardiac (n = 3) thrombosis or Budd Chiari Syndrome (n = 2)] treated with anti-TNFα agents. Results Vascular remission was achieved in 16 (89%) patients. The 9 months risk of relapse was significantly higher with conventional immunosuppressants used prior anti-TNFα agents as compared to anti-TNFα therapy [OR = 8.7 (1.42–62.6), p = 0.03]. The median daily dose of corticosteroids significantly decreased at 12 months. Side effects included infection (n = 4) and pulmonary edema (n = 1). Conclusion TNFα-antagonists are safe and might be associated with a decreased risk of relapse at 9 months compared to conventional immunosuppressants in BD patients with major vessels disease.

Injecting anti-tumor necrosis factor (TNF)α antibodies into patient joints at the site of inflammation, inter-articular (IA) delivery, has demonstrated modest success for treatment of Spondyloarthritis (SpA), Rheumatoid Arthritis (RA), and osteoarthritis. However, IA delivery is not the treatment route of choice due to rapid clearance from the site of administration. Elastin-like polypeptides (ELPs) are reported to undergo phase transition; forming reversible aggregates above their transition temperature, which when injected into IA space have a 25-fold longer half-life compared to the soluble form. Here, we fused an ELP repeat to the C-terminus of each heavy chain of an anti-TNFα monoclonal antibody (mAb) and provide detailed characterization of the fusion IgG molecule. Expression and purification yielded homogenous protein confirmed by gels, hydrophobic-interaction chromatography, Capilary Electrophoresis (CE), Mass Spectrometry (MS), and analytical ultracentrifugation. The ELPs altered hydrophobicity and pI of the parent mAb and new elastic properties were imparted to the molecule; forming large stable complexes with a hydrodynamic radius of 40 nm above 39°C that dissociated into soluble, active monomer below 37°C. The fusion mAb retained its affinity and ability to neutralize TNFα as determined by surface plasmon resonance and cell-based assay, respectively, with equal potency to unmodified anti-TNFα mAb. Differential-scanning calorimetry studies show stabilization of adjacent CH2 and CH3 domains in the fusion molecule and the aggregated molecule was found to be fully functional after 7 days at 37°C. For the first time, we reveal architecture of an ELP-fusion mAb and binding to antigen using single-particle-transmission-electron microscopy. Unstructured ELP was visualized at the C-terminus and binding to antigen was shown at the N-terminus. Collectively, these studies indicate that it is possible to impart elastic properties to a monoclonal antibody while retaining purity, stability, and ability to effectively bind and neutralize antigen.

La polyarthrite rhumatoïde est une maladie auto-immune qui représente le rhumatisme inflammatoire chronique le plus fréquent de l'adulte.L’arsenal thérapeutique s’est considérablement enrichi ces dix dernières années. La meilleure compréhension des mécanismes physiopathologiques a permis de développer des traitements ciblés qui contrôlent l'inflammation et préviennent la destruction ostéo-cartilagineuse qui en fait toute la gravité. L'avènement des médicaments anti-TNFα représente une avancée considérable dans la prise en charge des patients atteints de maladies inflammatoires chroniques. En effet, ces traitements induisent chez les patients atteints de polyarthrite rhumatoïde une amélioration significative des manifestations cliniques inflammatoires, des capacités fonctionnelles et de la qualité de vie. Les médicaments anti-TNFα sont de plus en plus dispensés en officine car la plupart existe sous forme de seringues ou de stylos pré-remplis permettant ainsi au patient de pratiquer lui-même l'injection. Ainsi, leur dispensation doit faire appel à toute l’expertise du pharmacien et nécessite une attention particulière ainsi qu'une vigilance soutenue de tous les professionnels de santé. La première partie décrit la maladie de la polyarthrite rhumatoïde ainsi que ses traitements, la seconde partie porte sur les biothérapies et plus précisément sur les molécules anti-TNFα. La dernière partie consiste, de part un questionnaire dédié aux pharmaciens officinaux, de réaliser une fiche conseil pour la dispensation des biothérapies en particulier celles indiquées dans la PR telles que les médicaments anti-TNFα.

International audience; Background and Aims: Infliximab and adalimumab are increasingly used to prevent postoperative recurrence in Crohn's disease patients. The impact of previous exposure to one or more anti-tumour necrosis factor [TNF] agents before surgery on the efficacy of anti-TNF therapy on postoperative recurrence is unknown. Methods: We performed a retrospective analysis of Crohn's disease patients who underwent surgical bowel resection with anastomosis and prophylactic treatment with anti-TNF therapy between January 2005 and June 2013. Results: A total of 57 consecutive Crohn's disease patients with bowel resection and anastomosis followed by prophylactic treatment with anti-TNF were included; 21 [37%] and 24 [42%] patients had a previous exposure to one and more than one anti-TNF agents, respectively; 39 patients [68%] had a surveillance colonoscopy. Cumulative rates of postoperative endoscopic recurrence at 2 years were 45.5% [26.6-69.6%] in patients exposed to two or more anti-TNFα as compared with 29.1% [11.5-48.1%] in patients exposed to one or to zero anti-TNFα before surgery [p = 0.07]. Cumulative rates of clinical recurrence at 1 year were 21.6% [9.6-44.4%] in patients exposed to two or more anti-TNFα as compared with 6.9% [1.8-25.1%] in patients exposed to zero or one anti-TNFα before surgery [p = 0.02]. Multivariable analysis identified smoking and previous exposure to two or more anti-TNFα as risk factors for Crohn's disease clinical or endoscopic postoperative recurrence (hazard ratio [HR] = 3.17; 95% confidence interval [CI]: 1.3-7.8, p = 0.01 and HR = 4.2; 95% CI: 1.8-10.2, p = 0.001, respectively). Conclusions: Previous exposure to two or more anti-TNF agents was associated with a higher risk of postoperative recurrence in Crohn's disease patients.

Literature regarding the effect of biologics on the course of mycosis fungoides (MF) is scarce. This multicentre study analysed retrospective data on 19 patients with MF, who were treated with biologics; 12 for inflammatory conditions coexisting with MF, and 7 for MF misdiagnosed as an inflammatory skin disease. Eight patients were treated with anti-tumour necrosis factor-α-monotherapy; 6 had early-stage MF, in 3 patients MF preceded and in 3 MF was diagnosed after initiation of biologics, with no stage-progression or with stable disease, respectively (median treatment time concurrent with MF 57 months). Two patients had advanced stage MF: IIB, treated for 15 months with no stage-progression, and IVA1, treated for 8 months, died of disease 10 months later. The other 11/19 patients received anti-interleukin-17A and/or anti-interleukin-12/23 or anti-interleukin-23 (with/without anti-tumour necrosis factor-α/anti-interleukin-4/13), with stage-progression in 8 patients after a median of 8 months' treatment. Although, in general, biologics should be avoided in patients with MF, these results indicate that anti-tumour necrosis factor-α-monotherapy might not aggravate the disease course in early-stage patients. Interleukin-17A, interleukin-12/23 and interleukin-23 pathway-blockers may prompt progression of MF.

Background & Aims Therapeutic antibodies against tumor necrosis factor α (anti-TNF) are effective in patients with Crohn's disease (CD). Mucosal healing is a surrogate marker of efficacy, but little is known about the effects of anti-TNF agents on structural damage in the intestine. Small-intestine contrast ultrasonography (SICUS) is a valuable tool for assessing CD lesions. A new sonographic quantitative index (the sonographic lesion index for CD [SLIC]) was developed to quantify changes in CD lesions detected by SICUS. We explored whether the SLIC can be used to monitor transmural bowel damage in CD patients during anti-TNF therapy. Methods We performed a prospective study of 29 patients with ileal or ileocolonic CD treated with anti-TNF agents; patients underwent SICUS before and after scheduled induction and maintenance therapy. To determine whether changes that can be detected by SICUS occur independently of anti-TNF therapy, 7 patients with ileal CD treated with mesalamine were enrolled as controls. A clinical response was defined as steroid-free remission, with CD activity index scores less than 150. Results We observed significant improvements in SLIC scores and subscores after induction and maintenance therapy with anti-TNFs, compared with before therapy. SLIC scores and subscores and index classes were improved significantly in patients with vs without clinical responses. Controls had no improvements in terms of CD activity index or SLIC scores, or index classes. Conclusions Sonographic assessment using the quantitative index SLIC can be used to monitor changes in transmural bowel damage during anti-TNF therapy for CD.

ResumenIntroducciónSe ha registrado en la última década un aumento en la incidencia de reactivación de tuberculosis latente asociada al uso de inhibidores del factor de necrosis tumoral alfa (TNF-α), en particular con el infliximab (Remicade®). Estos agentes biológicos cada vez se emplean con mayor frecuencia para el control inflamatorio de enfermedades inmunes.Caso clínicoSe presenta el caso de un varón de 30años de edad con diagnóstico de artritis idiopática juvenil (AIJ), quien al iniciar tratamiento con infliximab desarrolló tuberculosis extrapulmonar (intestinal) diagnosticada mediante biopsia de ganglios mesentéricos y epiplón, requiriendo tratamiento antituberculoso. Además presentó inflamación intraocular no asociada a AIJ, atribuida a reactivación de tuberculosis, en forma de vitreítis e inflamación granulomatosa en cámara anterior caracterizada por precipitados retroqueráticos grandes.ConclusiónEs indispensable realizar pruebas de escrutinio para tuberculosis latente antes de iniciar tratamiento con agentes biológicos anti-TNF-α, particularmente con infliximab. Las pruebas que miden la producción de interferón gamma (IFN-γ) in vitro en respuesta a los antígenos tuberculosos son una alternativa a la prueba cutánea clásica con tuberculina (PPD) en la detección de tuberculosis, particularmente en individuos vacunados con el bacilo de Calmette-Guérin (BCG).AbstractIntroductionOver the last decade, there has been an increased in the incidence of latent tuberculosis reactivation associated with the use of anti-tumor necrosis factor alpha (TNF-α), particularly infliximab (Remicade®). Actually, these biologic agents are used more frequently to control the inflammatory response of different systemic immune disorders.Clinical caseWe present herein the case of a 30year-old male with the diagnosis of juvenile idiopathic arthritis (JIA), who developed extrapulmonar (intestinal) tuberculosis diagnosed by mesenteric ganglion biopsy, who required anti-tuberculosis therapy after he was started on infliximab therapy for JIA. Moreover, he developed uveitis unrelated to JIA, but rather attributed to reactivation of tuberculosis in the form of vitritis and anterior chamber granulomatous inflammation characterized by large KPs formation.ConclusionIt is mandatory to perform screening tests for latent tuberculosis before starting treatment with anti-TNF-α, particularly with infliximab. Tests that measure gamma interferon (IFN-γ) in vitro in response to tuberculous antigens are an alternative to the classic tuberculin skin test (PPD) to detect active tuberculosis, particularly in individuals vaccinated with the Calmette-Guerin (BCG) bacillus.