Tina Ding MSc, MRCP, ConsultantRheumatologist,Chris Deighton

BMedSci, MD, FRCP, ConsultantRheumatologist, Royal Derby

Hospital, Derbyshire

Anti-TNF drugs are a major treat-ment advance in the management ofinflammatory disorders such asrheumatoid arthritis, and are typi-cally considered following unsuc-cessful treatment with conventionaldisease-modifying antirheumaticdrugs (DMARDs). Drs Chris Deightonand Tina Ding review the availableanti-TNF-alpha drugs, and considertheir future place in therapy.

Rheumatoid arthritis (RA), psoriatic arthritis (PsA) andankylosing spondylitis (AS) arechronic inflammatory disorders thatlead to significant decreases in qual-ity of life due to pain and functionalimpairment, and have a significantincrease in morbidity.13 They areassociated with considerable socie-tal and personal costs specificallyrelated to loss of work productivityand healthcare costs.4 RA usuallyaffects hands and feet, PsA can affectboth peripheral joints and the spine,whereas AS affects the spine predom-inately. The worldwide prevalence of these conditions is approximately2% in the adult population.

In recent years, significantadvances have been made in understanding the pathogenesis ofmany inflammatory disorders, inparticular the role of TNF-alpha.TNF-alpha is a small protein knownas cytokine, which has diverse

biological activity with immuno-modulatory and proinflammatoryeffects. It plays a major role in all ofus in our defence against infection,but when over-expressed it is alsoinvolved in the pathogenesis ofmany inflammatory disorders. Inthese diseases the levels of TNF-alpha are elevated systemicallyand at inflammation sites, and act as a driver for inflammation that damages cartilage and bone.

LIMITATIONS OF CONVENTIONAL THERAPIESConventional DMARDs such asmethotrexate (MTX) and sulfas-lazine are used with variable andunpredictable results, and tend tohave high discontinuation rates over time due to toxicity or limitedefficacy. MTX has emerged as themost effective among traditionalDMARDs, with a good tolerability

and safety profile.5 Despite the useof higher doses of MTX alone or incombination with other DMARDs,more than 50% of patients fail toachieve a long-lasting satisfactoryimprovement and have to change toother drug regimens. Moreover, inthe spinal disease of spondylitis, traditional DMARD therapies areineffective. A better understandingof the pathogenesis of inflammatoryarthritis has led to the developmentof therapy targeted against TNF-alpha. These new drugs have beenshown to be rapidly effective at controlling the symptoms of thesedisorders, and may halt the radio-graphic progression of joint destruc-tion much more successfully thanconventional DMARDs.69

Anti-TNF drugs have made ahuge difference to the manage-ment of many patients with severe

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Anti-TNF-alpha drugs movinginto the mainstream?

Anti-TNF-alpha drugs are increasingly viable for patients as cost-effectiveness looks set to improve

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active disease that has failed torespond to conventional treatments.It is estimated that around 6% of RApatients in the UK may be on thistherapy,10 although whether thedrugs should be more widely avail-able is a source of ongoing negotia-tion with NICE. Currently there arethree anti-TNF drugs available forclinical use: etanercept (Enbrel), aconstruct of two p75 TNF receptorslinked together by an IgG1 mole-cule; infliximab (Remicade), achimeric anti-TNF monoclonal anti-body; and adalimumab (Humira), ahuman anti-TNF monoclonal anti-body. Humanised drugs have thepotential for fewer side-effects.

INCREASING ANTI-TNF CHOICEOver the past few years, two new anti-TNF agents have been evaluated indouble-blind, multicentre randomisedcontrolled trials. Golimumab is afully human monoclonal antibodydirected against TNF, and resemblesadalimumab in having advantagesover infliximab in terms of elicitingless immunogenic response anddevelopment of neutralising anti-drug antibodies. Certolizumab pegolis a pegylated Fc-free anti-TNF-alphaagent, which increases bioavailability,and retains the potency of anti-TNFswithout the possible cytotoxicitymediated by Fc.

Two of the currently availabledrugs (adalimumab and etanercept)are subcutaneous injections, whichcan be self-administered. The formeris given fortnightly and the latter isgiven either once or twice weekly.Infliximab is given intravenouslyevery eight weeks after initial induc-tion. The newer anti-TNFs, cer-tolizumab and golimumab, can begiven by two-weekly and four-weeklysubcutaneous injections respectively.Much earlier in the developmentprocess are oral TNF inhibitors,which would offer an advantage over

the products currently available, allof which are parenteral. However,this research is still at an early stage.

There are no head to head trials of any of the anti-TNF drugsand the data so far suggest that thefive anti-TNF agents are very similarin terms of efficacy and toxicity.11

A Cochrane review has suggestedthat patients tend to stay on etan-ercept for longer than adalimumaband infliximab due to more pro-longed efficacy.12 The over-ridingpressure to choose one particularanti-TNF is more likely to be drivenby cost differentials and health economic considerations.

SAFETY CONSIDERATIONSIn general, anti-TNF drugs are generally well tolerated. Commonside-effects, including injection sitereactions, rashes and constitutionalsymptoms, are usually mild and self-limiting, and generally do not leadto drug discontinuation. Of greaterconcern are serious adverse eventsthat may relate to TNF-alpha antag-onists, particularly infections13 andthe risk of tumour development.14

The evidence for both infectionand cancer risk of anti-TNF drugsis contradictory,15 but suggests: A slight increased risk of overallserious infection, perhaps two-fold,and particularly in the early stagesof administration (first 36 months) Definite vigilance is required fortuberculosis and other granuloma-tous and intracellular infections,with the need for pre-screening ofpatients and monitoring of allpatients closely thereafter No overall increased risk of cancer, but concerns over non-melanomatous skin cancers, andpossible greater risks for patientswith previous tumours.

Although the advantages of thesedrugs far outweigh their disadvan-tages, we cannot be complacent in

monitoring closely patients on anti-TNF drugs. Regular updated analy-ses of observational registers shouldidentify any emerging problems toheighten our vigilance further.

COST-EFFECTIVENESSConsideration needs to be given tohow the NHS should approach theadministration of these drugs. A GPwith a list size of 2000 patients willhave approximately 20 patients withestablished RA, varying from therecently diagnosed to chronic andseverely disabled patients, and a fur-ther 20 with other types of chronicinflammatory arthritis. One or twoof these may be on biological ther-apy, so it is important that GPs havean awareness of the efficacy andpotential toxicity of these drugs. Onthe one hand, inflammatory arthri-tis is an important cause of morbid-ity, disability and mortality. Thismakes it expensive, inflicting hugecosts on both the individual andsociety. The National Audit Officehas estimated that RA alone coststhe NHS around 560 million peryear in healthcare costs, and that theadditional cost to the economy ofsick leave and work-related disabil-ity is 1.8 billion per year.16 Otherchronic inflammatory arthritis addsto this financial burden. On theother hand, anti-TNF drugs arecostly (810 000 per year).

It is important to manageinflammatory arthritis optimallyfrom the start of symptoms, and target biological therapies to thosepatients most likely to benefit.NICE RA management guidelinessupport early and intensive use ofcombinations of DMARDs, andhealth economic modelling suggeststhat this approach is cost-effectiveand may decrease the need to usebiological therapies.16,17 The major-ity of patients with mild and stableestablished disease may be managed

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on conventional DMARDs in thecommunity with intermittent special-ist input. Only a minority of patientshave severe active disease needing tobe managed exclusively in secondarycare, with early and intensive use ofDMARDs, then appropriate use ofbiologics for non-responders.

It is hoped that the high cost ofanti-TNF drugs will prove to be bal-anced by savings from the benefitsof treatment, such as improvedwork productivity, reduced need forsurgery, reduced comorbiditiessuch as cardiovascular disease, andimproved longevity and quality oflife. In the UK the use of anti-TNFdrugs are guided by NICE based on health economic analyses.1821

NICE have deemed anti-TNF agentsto be cost-effective in severe activeinflammatory arthritis not respond-ing to conventional approaches.Each drug approved requirespatients to be under close specialistsupervision, and assessed regularlyto ensure non-responders are takenoff the drug.

SERVICE PROVISIONWith increasing use of anti-TNFdrugs in rheumatology, there is aneed to modernise our routinepractice to ensure: Adequate nurse specialistresources for optimal use of conven-tional DMARDs and assessment ofappropriate patients for anti-TNFtherapy, with monitoring of the disease response, and for drug side-effects Adequate facilities (such as daycase units) for patient training andadministration of anti-TNF drugs Comprehensive national regis-ters of patients on anti-TNF drugsto help with resource planning andmonitoring for rarer side-effects.The British Society for Rheumatol-ogy has such a register consisting of4000 RA patients on each of the

three established anti-TNF drugs,for long-term follow-up of side-effects.22 There are plans to estab-lish a similar register for AS.

CONCLUSIONSWith more than 10 years experiencein a large number of patients, theTNF-blocking agents have emergedas a major advance in the treatmentof severe active inflammatory arth-ritis. Selecting the most appropriatepatients to go on to biological therapy is the source of ongoingnegotiation between NICE andstakeholders. This debate would behelped by the development of bio-markers that identify patients withpoor prognosis who are unlikely torespond to conventional DMARDs,and are likely to do well on anti-TNFtherapy. There is also evidence tosuggest that early introduction ofanti-TNF drugs may induce remis-sion so that the drug can then bewithdrawn, but identification ofpatients suitable for this strategy isuncertain. A key element of cost-effectiveness is the cost of the drug,and if cheaper but high qualitybiosimilar or generic drugs aredeveloped, this will also increase theavailability of these therapies. Therheumatology community needs towork with NICE on determining thebest and most cost-effective ways ofusing these highly effective drugs.

DECLARATION OF INTERESTSThe Department of Rheumatology,Royal Derby Hospital has receivedsponsorship for support of clinicalmeetings and unrestricted grantsfrom Wyeth, Abbott and ScheringPlough Pharmaceuticals to supportan ultrasound machine, an anti-TNFaudit clerk and research nurse. DrDeighton has received honoraria fortalks at symposia sponsored by Wyethand Abbott. Dr Ding has nothing todeclare.

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