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Artrite reumatoide

Artrite reumatoide. Inibitori del “tumour necrosis factor” (TNF). Tumour necrosis factor (TNF) is a member of the TNF superfamily , which includes a number of structurally and functionally related trimeric molecules including: lymphotoxin alpha ( LTa ), previously known as TNFb ,

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Artrite reumatoide

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  1. Artrite reumatoide

  2. Inibitori del “tumour necrosis factor” (TNF) • Tumour necrosis factor (TNF) is a member of the TNF superfamily, which includes a number of structurally and functionally related trimeric molecules including: • lymphotoxin alpha (LTa), previously known as TNFb, • the pro-apoptotic molecule Fas, • the B cell regulatory molecule CD40 • and receptor activator of nuclear factor kappa-b

  3. The TNF polypeptide is synthesized as a 26 kDa membrane-associated form (mTNF) which is proteolytically cleaved by a TNF-alpha converting enzyme to produce a 17 kDa soluble homotrimer (sTNF). Both mTNF and sTNF are biologically active. All TNF inhibitors are recombinant proteins and are too large to be filtered at the glomerulus. The half-life of intravenously administered human IgG is between 30 and 40 days, but is rather more variable for specific antibodies.

  4. The TNF ligand superfamily has diverse functions in the immune system, one of which is the induction of apoptotic cell death in target cells. This function is performed by a family subgroup coined the Death Inducing Ligands, comprising the archetypal member TNF, FasL, and TRAIL. For instance, TNF proved to have potent tumoricidal activity in vitro and in mouse models in initial studies, a finding that sparked interest in the development of TNF for cancer therapy.

  5. TNF: Tumor necrosis factor Fas: Fibroblast-associated cell-surface FasL: Fibroblast-associated cell-surface ligand TRAIL: TNF-related apoptosis-inducing ligand TNFR1: TNF receptor 1 TNFR2: TNF receptor 2 TRAIL-R1: TRAIL receptor 1 TRAIL-R2: TRAIL receptor 2 DD: Death domain LT𝛼: Lymphotoxin alpha scFv: Single chain fragment of variable regions NF𝜅B: Nuclear factor kappa B FADD: Fas-associated death domain TRADD: TNFR-associated via death domain cIAP: Cellular inhibitor of apoptosis protein TRAF2: TNF-receptor associated factor 2 cFLIP: Cellular FADD-like IL-1b-converting enzyme inhibitory protein FAP: Fibroblast activation protein DcR3: Decoy receptor 3 DISC: Death inducing signaling complex EGFR: Epidermal growth factor receptor HER2: Human epidermal growth factor receptor 2 IL13R𝛼2: Interleukin 13 receptor alpha 2 Bcl-2: B-cell lymphoma/leukemia 2 gene Bcl-xL: B-cell leukemia xL.

  6. Figure 1: TNFL/TNFR signaling characteristics. (a) TNF-ligands are typically produced as type II transmembrane proteins, but the extracellular domain of most of these ligands can also be proteolytically cleaved by proteases, such as ADAM-17 (also known as TACE) , into a soluble form. Typically, the soluble ligand retains binding activity but has lost some or all receptor-activating activity. This activity can be restored by secondary cross-linking. (b) Signaling requirements of 4-1BB-signaling by s4-1BBL. (c) The cross-linking requirement of sTNF ligands makes their inclusion into an antibody fragment approach attractive. In brief, such a TNFL-fusion protein comprises a scFv antibody fragment genetically fused to the TNFL.This scFv:TNFL fusion protein is essentially inactive en route. However, upon target binding of the scFv antibody fragment domain the soluble ligand is converted into a signaling competent membrane-like ligand. (d). Illustration of target cell-restricted activation by scFv:4-1BBL.

  7. FAS signal FasL (also known as CD95L) is a type II transmembrane protein expressed on immune effector cell such as T-cells. The main receptor for the ligand of FasL is the type I transmembrane receptor Fas (CD95).

  8. CD40 Figure 6: CD40L/CD40-based agonists for cancer therapy. Soluble CD40L is only capable of sub-optimal CD40 signaling. However, enforced trimerization of CD40L or agonistic antiCD40 antibodies can trigger effective CD40-signaling, but with severe side-effects due to ubiquitous CD40-activation.

  9. Although the use of TNF inhibitors has revolutionized the treatment of aggressive RA, these agents are expensive and around 30% of patients fail to respond adequately.

  10. Farmacocinetica dei TFN inibitori Despite infliximab having a half-life of 9–12 days, it is administered every 8 weeks, compared with adalimumab, which is administered every other week, but has a longer half-life of around 15 days. This is also the likely explanation for the observation that 50 mg of the fusion protein etanercept given once weekly has been shown to be as effective as 25 mg given twice weekly in RA.

  11. Tumour necrosis factor alpha (TNF-a) is a key molecule of the inflammatory response and data derived from studies in experimental animal models and humans suggest that TNF-a may be implicated in the pathogenesis of various autoimmune and non-infectious inflammatory conditions. Encouraged by the positive results obtained from the use of TNF-a antagonists in terms of efficacy and safety and due to the increasingly accumulating evidence regarding the implication of TNF-a in the pathogenesis of numerous disorders, anti-TNF-a agents have been considered for the management of diseases other than the ones they were initially approved for.

  12. Golimumab is a human monoclonal antibody to tumor necrosis factor-α (TNF-α), indicated for the treatment of rheumatoid arthritis (RA).

  13. CDAI, Clinical Disease Activity Index; CRP, C reactive protein; DAS28, Disease Activity Score employing 28 joints; HAQ-DI, Health Assessment Questionnaire-Disability Index; JSN, joint space narrowing; MTX, methotrexate; SDAI, Simplified Disease Activity Index; vdH-S, van der Heijde-Sharp.

  14. The review concentrates on nine drugs: tocilizumab, rituximab, ofatumumab, belimumab, epratuzumab, abatacept, golimumab, certolizumab, and sifalimumab, which are used as therapies for rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, systemic sclerosis, or vasculitis.

  15. RITUXIMAB Adverse effects and safety One of the AEs associated with rituximab is an infusion reaction, characterized by fever, chills, rash, swelling (of hands, feet, and face), bronchospasm, and hypotension. In most cases, the reaction is immediate (30 minutes to 2 hours), usually during the first infusion, but is less severe with subsequent infusions. Pretreatment with acetaminophen and an anti-histamine is recommended to prevent this infusion reaction

  16. GOLIMUMAB Adverse effects and safety The main AEs are infections (mostly of the URT) and nausea. Additional AEs include hypertension, abnormal liver function (patients with latent TB were required to take prophylactic treatment, resulting in greater liver abnormalities), paresthesia, dizziness, constipation, local skin reaction, and some cases of malignancy (basal and squamous cell carcinomas, and prostate, lung, and breast cancers) were reported.

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