Antitnf-Α Strategy: Present Status of This Therapeutic Paradigm J
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Educational Forum AntiTNF-α strategy: Present status of this therapeutic paradigm J. Singh, A. Suruchi Department of ABSTRACT Pharmacology, PGIMS, Tumor necrosis factor-alpha (TNF-α), a proinflammatory cytokine is involved in the pathophysiology Rohtak - 124001, India. of a number of disorders including Crohn’s disease, rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. AntiTNF-α strategies target this pathogenic element to provide clinical benefit. Received: 10.2.2003 The various strategies are in preliminary stage of experimentation and much remains to be elucidated Revised: 17.9.2003 before these are applied clinically. Though antiTNF-α therapy is currently approved only for Accepted: 20.9.2003 rheumatoid arthritis and Crohn’s disease, the future of this therapeutic paradigm holds much promise. The number of official indications for strategies against this biologic agent are likely to increase to include congestive heart failure, psoriasis, asthma, septic shock, stroke and malignancy. This will Correspondence to: make it a truly broad spectrum therapeutic weapon currently available to us. J.Singh E-mail: α [email protected] KEY WORDS: AntiTNF- therapy, etanercept, infliximab, tumor necrosis factor. Introduction Clinical strategies for antiTNF-α therapy Tumor necrosis factor-alpha (TNF-α) is a multi-functional AntiTNF strategies are aimed at blocking activity of TNF-α cytokine with important role in immune response, inflamma- either through antiTNF-α antibody or administration of solu- tion and response to injury.1 TNF family is primarily involved ble TNF receptor to mop up circulating TNF-α. In addition to in regulation of cell proliferation and apoptosis.1 TNF-α has these, some proteins, TNF secretion/production inhibitors and also been shown to have an important role in cell death through expression inhibitors are also available11-24 (Table 1). a variety of mechanisms including second messenger path- ways, arachidonate metabolism, protein kinase, oxygen free AntiTNF-α therapy for rheumatoid arthritis radicals, nitric oxide, transcription of a variety of cytotoxic genes, regulation of nuclear regulatory factors, ADP- TNF-α increases in rheumatoid joints and has a potential ribosylation and potentially DNA fragmentation.1 TNF regu- role in the establishment of rheumatoid synovitis and joint lates expression of a variety of peptide regulatory factors in- destruction.5 The use of TNF-α antagonists has taught us that cluding IL-1, IL-6, platelet derived growth factor, transform- selective targetting of a pathogenic element can provide sub- ing growth factors-ß as well as a group of eicosanoids and stantial benefit, setting a new therapeutic standard for RA.5 hormones including platelet activating factors and adrenaline.1 AntiTNF-α therapy induces a rapid improvement in multiple It is now well recognized that TNF-α participates in the patho- clinical assessment of disease activity including morning stiff- physiology of various diseases/conditions including diabetes, ness, pain score, Ritchre articular index and swollen joint count. multiple sclerosis, autoimmune diseases, cachexia, parasitic The clinical benefits are associated with an improvement in infections, AIDS,2 asthma,3 stroke,4 rheumatoid arthritis (RA),5 some serological parameters and histological features of the Crohn’s disease,6 neurodegenerative disorders and malig- synovium.25 Several controlled clinical trials have clearly dem- nancy.7 However, the role of TNF-α in the pathogenesis of ma- onstrated short and middle term efficacy and safety profile of lignancies remains controversial. Indeed, recent studies have antiTNF-α therapy26 and they will soon become available world- demonstrated a causative role for TNF-α in a group of dis- wide. Infliximab and etanercept have been approved in US and eases including septic shock,8 pre-eclampsia, 9 hemolytic Europe for treating RA.27 A multicentric double blind placebo uremic syndrome, allograft rejection, regional enteritis, and controlled phase III clinical trial on 428 patients with active congestive heart failure.10 This review describes the role of RA has shown that infliximab (3 mg/kg, every 4-8 weeks or 15 TNF-α antagonists as a potential therapeutic weapon in vari- mg/week) + methotrexate for 3 weeks was more efficacious ous clinical conditions. than methotrexate alone in patients with active RA not previ- 10 Indian J Pharmacol | February 2004 | Vol 36 | Issue 1 | 10-14 Antitnf-α strategy Table 1 els might offer a diagnostic tool to determine patients at high risk.34 Based on the available data, it can be inferred that Currently available antiTNF strategies antiTNF-α therapy may be beneficial in reducing the compli- 1. AntiTNF-alpha antibodies- CBOOO6,11 BAY x 1351, 11 afelimomab, 11 cations of diabetes, though no reports are available so far infliximab,12 adalimumab. 13 demonstrating them as potential therapeutic candidate. 11 11 14 14 2. Soluble TNF Receptor-TNFR 1, TNFR2, etanercept, onercept. 2 AntiTNF-α therapy in congestive heart failure 3. TNF inhibitory proteins -MnSOD,PA12, endogenous TNF, viral pro- tein (CrmA), T cell leukemia derived factor (htRx), protein encoded α by A20 clone and TIP-B1. TNF- and other cytokines have been shown to be elevated 4. TNF signal transduction blocker15-anethole, anethole dithiolethione. in patients with end stage heart failure, heart failure due to 5. Inhibitor of TNF production-ß-adrenergic agonists,16 isoproterenol,16 myocarditis and ischemic and idiopathic dilated cardiomyopa- phosphodiesterase inhibitor-pentoxyfylline.16 thy (CMP).10 TNF-α exerts negative inotropic effect, recapitu- 6. Inhibitor of TNF expression-thalidomide and analogues,17 lates cellular and biochemical abnormalities that character- grepafloxacin,18 mycophenolic acid,19 amiodarone,16 ouabain,16 ise the failing human heart, uncouples ß-adrenergic receptors estrogens,16 ACE inhibitors, 17 pyrrolidone-dithiocarbamates,17 from adenylate cyclase, activates metalloproteinases and pro- vesnarinone,17 olopatadine,20 trichodimerol, milrinone, 16 oligodeoxy vokes a hypertrophic growth response in cardiac myocytes.10 nucleotides. TNF-α expression/production inhibitors have been shown to 7. Inhibitors of TNF mediated actions-alcohol,20 toremifene,7 possess therapeutic utility in the management of patients with ropivacaine,21 heparin.22 CHF. For an antiTNF-α drug to be useful in heart failure, it 8. Inhibitors of TNF gene transcription-antioxidants- N-acetyl cysteine,23 should not only be highly effective in reducing TNF-α levels 23 24 rotenone, resveratrol. but should also have other positive actions and should be orally active and cheap. As yet, no drug fits this description. Davey and Ashrafian17 demonstrated the therapeutic benefits of tha- lidomide and its derivatives in management of advanced heart ously responding to methotrexate. 28 However, some questions failure. Recently, recombinant soluble TNF-α protein (S TNFR2) remain unresolved concerning their place in the general thera- have been shown to be safe and capable of reducing raised peutic strategy against RA, due to uncertainties of their use in levels of TNF-α-concomitantly lessening the severity of heart the long run. If clinical efficacy is sustained and the safety failure in patients with NYHA class III CHF.35 Intravenous infu- profile remains benign over long term, TNF-α antagonists may sion of etanercept increased exercise tolerance, ejection frac- replace methotrexate as a gold standard and become the agent tion and reported life score.35 Despite beneficial effects with of choice for combination therapy in RA. Further studies are antiTNF-α therapy, both hypertrophy and fibrosis persist sug- needed to clarify their ultimate position in the therapeutic al- gesting early but not late therapy, using anticytokine ap- gorithm. Ankylosing spondylitis has also been successfully proaches might benefit patients with CHF. treated with infliximab.29,30 Similarly antiTNF strategies are be- ing targeted at chronic inflammatory arthritides,12 such as AntiTNF-α therapy in stroke psoriatic arthritis, sarcoidosis arthritis, idiopathic juvenile arthritis and spondyloarthropathy. A rapid over production of TNF-α in the cerebral post- ischemic inflammatory response leads to the stimulation of AntiTNF-α therapy in Crohn’s disease adhesive molecules expression with subsequent accumulation of leukocytes in the ischemic zone. The proinflammatory ac- TNF is considered to be a crucial mediator of Crohn’s dis- tivity of TNF-α results mainly in extending the area of brain ease (CD). Inflammatory cells of gastrointestinal lesions pro- infarct.4 TNF-α appears also to contribute to neuronal necro- duce TNF and its concentration is increased in serum, tissue sis by its involvement in the process of apoptosis as well as in and stool. Present et al31 demonstrated that single i.v. infusion the death of neurons.4 Recent evidence suggests that TNF-α of infliximab (10 mg/kg) decreased the CD activity index score also promotes neurodegeneration through inhibition of a vital with improvement in colonoscopic evaluation. Infliximab has survival signal, 1GF-I. 36 The use of neuronal growth factors in been found to be very effective in the treatment of fistula in the treatment of neurodegenerative diseases such as cerebral patients with CD.31 Similar results have been reported in a ischemia and the AIDS dementia complex, may prove much controlled trial with etanercept.32 more effective if the elevated expression of TNF-α in these disorders is neutralized.36