Antitnf-Α Strategy: Present Status of This Therapeutic Paradigm J

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-

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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 protein (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 thalidomide 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 being 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 AntiTNF-α therapy in diabetes AntiTNF-α therapy in asthma and allergy There is complex relationship between TNF-α and diabetic complications. TNF-α related apoptosis inducing ligand (TRAIL) TNF-α is released in allergic responses, from mast cells is involved in ß cell damage leading to type I diabetes, causes and macrophages via IgE dependent mechanisms.3 TNF-α in- insulin resistance, interferes with insulin signaling and influ- creases airway hyperreactivity in asthmatic subjects. Polymor- ence the formation of atherosclerotic vascular lesions in dia- phism of TNF-α gene has been associated with asthma and betic patients.33 Increased TNF-α levels in patients with dia- elevated levels of TNF have been demonstrated in betes has been demonstrated and determination of TNF-α lev- bronchoalveolar fluid of asthmatic subjects.3 Hashimoto et al18

Indian J Pharmacol | February 2004 | Vol 36 | Issue 1 | 10-14 11 Singh J, et al. demonstrated beneficial effect of grepafloxacin (a new ecule have exhibited specific tumoricidal activity against a va- fluoroquinolone) in controlling chronic airway inflammatory riety of tumors alone, or in combination with other cancer treat- disease via expression of inhibitory TNF-α induced IL-8 mRNA. ments.42 The TRAIL effector pathway appears to be a vital com- Therefore, an inhibitory effect of antiTNF-α therapy on IL-8 ponent of immunosurveillance of tumor cells, stimulating more production may apply to the treatment of chronic airway in- hope that manipulating TRAIL activity is a natural path to im- flammatory disease. However, further investigations are proved cancer immunotherapy. Lin et al43 found that breast needed to clarify this point. Treatment directed specifically at cancer cell lines resistant to chemotherapy or to recombinant a reduction in TNF-α activity may be useful as a glucocorticoid TRAIL protein are susceptible to TRAIL gene therapy –suggest- sparing asthma therapy. AntiTNF-α therapy may also be effec- ing that combination of TRAIL gene therapy and chemotherapy tive in the treatment of certain allergic conditions including is effective in the treatment of metastatic diseases. TRAIL Jarisch-Herxheimer reaction.37 It is well established that re- therapy is now being tried in a wide variety of neoplasms. cruitment of neutrophils and eosinophils associated with allergic condition is mediated via TNF-α.1 AntiTNF therapy in dermatology

AntiTNF-α therapy in sepsis and shock AntiTNF-α arsenal is an exciting addition to dermatologic therapy. New molecules are expected to enrich the antiTNF-α TNF-α is a principal mediator in the pathophysiology of arsenal. A recently reported double blind trail by Chaudhari et septicemia and elevated levels of TNF-α have been reported in al44 showed a greater than 75% improvement in psoriasis, area patients with sepsis.8,11 Attempts to block TNF-α activity have and severity index score at week 10, in 9 out of 11 (82%) pa- been associated with improved survival in animal models of tients receiving infliximab 5 mg/kg at weeks 0, 2 and 6, indi- sepsis and shock.11 In human studies, 7.5 mg/kg, TNF-α cating efficacy and rapidity of onset of therapeutic effect simi- monoclonal antibody provided a significant reduction in mor- lar to cyclosporine. Etanercept has been shown to possess tality 30 days after infusion.38 Antibodies have been found ef- good efficacy in moderate to severe psoriasis.45 Encouraging fective in reducing early morbidity and mortality but no re- sporadic results suggest potential indications in –Behcets dis- duction in 28 days mortality. Drugs that modify TNF in vivo ease, bullous dermatitis, neutrophilic dermatitis, toxic epider- may be an useful component of future management of sepsis mal necrolysis, systemic vasculitis, pyoderma gangrenosum46 either as monotherapy or as part of combined strategy of and pustular dermatitis.47 A recent report by Warnnissorn et immunomodulators. Afelimomab has been tested in 7300 pa- al48 has shown involvement of TRAIL in atopic dermatitis. tients with septic shock and found to be efficacious and well tolerated.11 However, in sepsis, findings have not been so con- AntiTNF-α therapy in other conditions vincing. The use of antiTNF-α in the wrong patient or at the wrong time may do more harm than good. Although antiTNF- Beneficial role of antiTNF-α therapy has also been demon- α such as afelimomab may yet prove valuable in treatment of strated in various clinical conditions such as alcoholic hepati- carefully selected patients with severe sepsis, further work is tis,49 cerebral malaria,50 hemolytic uremic syndrome,16 needed to clarify the selection criteria of patients who will be preeclampsia,9 allograft rejection, 16 otitis media, 51 snakebite,52 benefited the most. erythema nodosum and other granulomatous diseases.53 Po- tential new indications include, adult Still’s disease, AntiTNF−α therapy in malignancy myelodysplastic syndromes,54 graft versus host disease54 uvei- tis,54 dermatomyositis and polymyositis. 55 TNF-α promotes cell growth, differentiation, tissue remodeling and tumorigenesis.16 On the other hand, Adverse effects recombinant TNF-α is reported to be selectively cytotoxic for some tumor cell lines and causes necrosis of certain murine Early experience with antiTNF-α therapy has identified 7 tumors. Although TNF promotes angiogenesis,7 antiangiogenic types of adverse effects that seem to be of particular concern effect on tumor microvasculature has also been reported.39 (a) infection including sepsis and tuberculosis (b) malignancies Therefore, the role of TNF-α in the pathogenesis of malignan- such as lymphoma (c) hematological disorders such as anemia cies remains controversial. However, direct relationship be- and pancytopenia (d) demyelinating disorders and neuropathy tween the level of TNF expression and tumor grades in ovarian (e) exacerbation of CHF (f) production of autoantibodies and cancer has been reported.40 Naylor et al 40 demonstrated the autoimmune responses (immunosuppression) (g) infusion re- therapeutic potential of antiTNF therapy in human epithelial lated problems (as hypersensitivity – pain, erythema, localized ovarian cancer. Monoclonal antibodies against TNF-α have rash and hemorrhage at injection site. Immunocompromised proved successful in ameliorating cachexia of cancer.16 Skin and geriatric patients are at increased risk of severe side ef- tumors such as basal cell carcinoma have been shown to be fects.29,30 Blockers of TNF have been associated with occurrence associated with TNF microsatellites.41 Although a few prelimi- of cutaneous vasculitis also.56 Therefore, antiTNF-α therapy can nary studies have demonstrated beneficial effect of antiTNF be labeled as a double edged sword. therapy in ovarian and colorectal cancers, much remains to be elucidated as far as exact place of anti-TNF therapy in cancer Conclusion treatment is concerned. The TRAIL offers great promise in cancer therapy. Soluble recombinant versions of the TRAIL mol- AntiTNF-α therapy is currently approved for the treatment

12 Indian J Pharmacol | February 2004 | Vol 36 | Issue 1 | 10-14 Antitnf-α strategy of rheumatoid arthritis and Crohn’s disease. It is clear that 21. Zhang XW, Thorlacius H. Inhibitory actions of ropivacaine on TNF-alpha-in- the number of official indications for antiTNF-α therapy will duced leukocyte adhesion and tissue accumulation in vivo. Eur J Pharmacol 2000;392:1-3. increase to include congestive heart failure, psoriasis, malig- 22. Salas A, Sans N, Soriano A, Reverter JC, Anderson DC,Pique JM, et al. Heparin nancy and asthma. However, the compound has already gained attenuates TNF-alpha-induced inflammatory response through a CD-11b de- a unique niche as a biologic therapy. Exciting pilot studies are pendent mechanism. Gut 2000;47:88-96. being done on TNF-α antibodies to find their utility in clinical 23. Chandel NS, Trzyna WC, McClintock DS, Schumacker PT. 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Journal of Postgraduate Medicine on occassion of its Golden Jubilee presents JPGM Gold Con: 50 years of Medical Writing An International Conference on Medical Writing and Publishing 23rd-26th September 2004, Mumbai, India

Highlights of the program

Program on Writing Program on Editing Program on E-publishing Scientific papers: structure & getting started Peer review process Impact of open access Importance of 250 words (Abstracts) Dealing with authors Good e-publication guidelines Illustrating a paper Ethical issues Electronic journal management Dealing with journals Journal indexing Open access and e-publishing initiatives Statistics Quality parameters Archiving: Self and institutional Looking out for references Society run journals Who pays for open access? Clinical practice and publishing Style and print Economic models for open access journals Research Integrity and Publication Ethics Financial and legal aspect Solutions for the developing world The future of scientific publishing Industr y and journals Failures, successes and future

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Philip Abraham Barbara Gastel Kiran Marthak R.Raveendran Rakesh Aggarwal Jaideep Gogtay Ana Marusic H. P. S. Sachdev Doug Altman Jean- Claude Guédon R. A. Mashelkar Peush Sahni Subbiah Arunachalam Stevan Harnad Faith McLellan K. Satyanarayana S. K. Bichile Bruce Hugman Hooman Momen Pippa Smart Amy Brand Tom Jefferson Sally Morris Peter Suber Leslie Chan R. J. Jha Arun Nanivadekar Pritpal S Tamber Ranjit Roy Choudhury S. P. Kalantri Samiran Nundy M. Venkateswarlu Alastair Dryburgh Rajendra Kale Ivan Oransky Julie Esanu Thomas Lang Roy M. Pitkin

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