Anti-Tumour Necrosis Factor-alpha Therapy in Crohn s Disease: Clinical and Health Economic Aspects

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1 Anti-Tumour Nerosis Ftor-α Therpy in Crohn s Disese Anti-Tumour Nerosis Ftor-lph Therpy in Crohn s Disese: Clinil n Helth Eonomi Aspets Fion MGuire, 5th yer Meiine ABSTRACT Ojetives: Crohn s isese is hroni, relpsing inflmmtory isese of the gstrointestinl trt. Tumour nerosis ftor-lph (TNF-α) is pro-inflmmtory protein tht is elieve to ply mjor role in the pthogenesis of Crohn s isese (CD). Inflixim, himeri nti-tnf-α prolonl ntioy, whih inhiits the iotivity of TNF-α, is reent n exiting strtegy in the tretment of CD. The purpose of this stuy ws twofol. Firstly, the eonomi impt of inflixim therpy ws exmine. Seonly, hroni tive Crohn s isese ptients were nlyse for their response to inflixim therpy. Ptients n Methos: The meil reors of 25 ptients from the Deprtment of Gstroenterology, AMNCH (Dulin) were nlyse. Helth-re utiliztion t were ollete for eh ptient over the two yers pre- n post-inflixim therpy. The meil reors of ll hroni tive ptients were nlyse to investigte the role of inflixim s steroi-spring gent. The CDAI (Crohn s Disese Ativity Inex) ws employe s referene for evluting isese tivity. Results: Following initition of therpy with inflixim, the totl numer of hospitl missions erese y 46.9%. The men urtion of hospitl stys remine unhnge. The men ily osges of prenisolone erese over the 12 months post-inflixim therpy, ompre with the 12 months prior to therpy. Similrly, the men ily osge of uesonie erese in the 12-month perio following initition of inflixim therpy. Conlusion: The finings from this stuy of 25 ptients with hroni tive CD re omprle to those previously hieve in the ontrolle setting of linil trils. In ition, this stuy emonstrte tht inflixim my reue the overll osts of mngement of Crohn s isese y limiting ssoite helth re utiliztion. Results lso supporte the theory tht inflixim ts s steroi-spring gent. Further investigtion into the impt of inflixim on helthre usge n the presription of ortiosterois oul e n exiting n hllenging fiel for reserh in the future. INTRODUCTION Crohn s isese is hroni, relpsing, inflmmtory isese of the gstro-intestinl trt. Mnifesttions of the isese my e severe, n le to long-term therpy with vriety of meitions n/or surgery. There re two min lssifitions of the isese, inluing the relpsing-remitting hroni tive vriety, n the penetrting or fistulising vriety. Tumour nerosis ftor-lph (TNF-α) is pro-inflmmtory protein elieve to ply mjor role in the pthogenesis of Crohn s isese (CD). Signifintly higher levels of TNFα hve een foun in the intestinl muos of ptients with CD ompre with ontrols. The evelopment of n nti-tnf-α ntioy, whih inhiits the iotivity of TNF-α, is reent n exiting strtegy in the tretment of CD. 1 Inflixim, murine-humn himeri nti-tnf-α prolonl ntioy, is one suh phrmologil gent. In linil trils, pproximtely two-thirs of ptients with hroni tive CD respone to this therpy, n one-thir of ptients remine in full linil remission in the short-term. However, it my not e possile to urtely ientify potentil responers n non-responers. Although CD is severe, eilitting onition, the life expetny is the sme s for the generl popultion. 2 Thus, mny ptients with CD will require tretment for most of their ult lives. A stuy performe y Cohen n ollegues eluite tht surgery ounts for the mjority of hospitlistions in Crohn s isese, lmost 40% of the totl ost, n 75% overll hrges n reimursements. 3 Due to the initil high ost of tretment, etermining whih su-groups of ptients will respon to speifi ytokine therpy hs importnt implitions for ptient mngement n remins the hllenge of the future. It hs een lime tht inflixim (Remie, Centoor, In., Mlvern, PA, USA) hs role s steroi-spring gent in luminl Crohn s isese. 4 However, onfirmtion in linil settings hs proven iffiult. A reent stuy evlute the impt of inflixim on steroi usge using s "steroi equivlene test," ut file to yiel sttistilly signifint results. 5 49

2 TSMJ Volume 3: Originl Reserh MATERIALS AND METHODS Ptients The Deprtment of Gstroenterology, AMNCH, hs trete 46 ptients with inflixim over two n hlf-yer perio, 25 of whih were investigte for this stuy. This group of 46 ptients represents the lrgest single experiene with this tretment in Europe outsie linil trils. In 1998, prospetive oumenttion of linil response, helth eonomi n qulity of life t, n loo for serum ytokine nlysis ws initite. Ptient reors were nlyse for etermintion of the helth eonomi impt of tretment, n for investigtion of the role of inflixim s "steroi-spring" gent. These ptients inlue oth mles n femles, n those experiening oth hroni tive n fistulising forms of CD. Disese Ativity The CDAI (Crohn s Disese Ativity Inex) is stnr mesure of the tivity of isese n this prove useful tool in this stuy. A sore of higher thn 150 inites tive isese. Response to inflixim ws efine s reution in the CDAI either y 70 points or more, or to sore of less thn 150. The Eonomi Impt of Inflixim The etermintion of eonomi t involve intensive perusl of eh ptient s meil reors. All helthre usge ws reore for eh ptient for two yers pre- n post-inflixim therpy, n this perio of time ws ivie into eight six-month intervls. For eh ptient, etile eonomi nlysis ws performe, reoring: ) hospitl missions, ) length of sty, ) visits to the A & E eprtment, ) the numer of gstrointestinl (GI) surgeries performe, e) the numer of ourses of IV sterois ministere to eh ptient, f) the numer of osions where TPN ws require, n if so, the urtion of TPN in ys, g) the numer of OGDs, or olonosopies performe, s well s other proeures tht involve enosopy suh s ERCP, h) the numer of GI x-rys, ultrsouns n CTs et. performe, i) the numer of other (non-gi) proeures performe inluing other surgil proeures, j) the numer of non-gi x-rys, ultrsouns n CTs et. performe, k) the numer of GI lini visits n l) the numer of non-gi lini visits. This ws ollte with existing prospetive t. The methoology lso involve visiting or ontting numer of other hospitls to ollet informtion. Inflixim s Role s Steroi-Spring Agent In this stuy, the meil reors of ll hroni tive ptients were nlyse, noting the osges n urtion of tretments with stnr systemi orl sterois (e.g. prenisolone) n the more lolly ting, gstrointestinl trt-speifi sterois (e.g. uesonie). The yers leing up to n following initition of tretment with inflixim were nlyse, n n verge ily osge of oth prenisolone n uesonie ws lulte for eh 6-month perio. Finlly, the weeks in whih prenisolone ws not ministere were lulte, gin in eh 6-month perio pren post-inflixim therpy. RESULTS A totl of 25 ptients were nlyse for ge, gener, CDAI, su-type of CD, length of follow-up, smoking sttus, n response to inflixim (Tle 1). There ws 73.1% response to inflixim. Anlysis of Eonomi Dt Anlysis of the eonomi t yiele interesting results. Tle 2 summrises the min omponents of helth-re usge s note from eh ptient s meil reors. The totl usge of helth-re filities ws lulte for the perio efore n fter first infusion of inflixim, n the results were ompre, with perentge inrese or erese eing note. Certin prmeters, however, unerwent little hnge. For exmple, lthough the numer of missions to hospitl erese Tle 1. Ptient Chrteristis Chrteristi Age, Gener 34 ± 2.04 yers 73% femle CDAI, ± Preominnt CD su-type Follow-up, 69% hroni tive Smokers/ex-smokers 31%/12% Response to inflixim 20.2 ± 1.64 months 73% response CDAI, Crohn s Disese Ativity Inex 50

3 Anti-Tumour Nerosis Ftor-α Therpy in Crohn s Disese Tle 2. Eonomi Dt Type of Helthre Use Pre-Inflixim Post-Inflixim % Inrese or Derese Hospitl missions (totl n) % erese Amissions uring whih 43.5% 19.2% 24% erese IV sterois were employe(%) Ptients requiring t lest 63.5% 27.3% 36% erese one enosopy (%) Ptients requiring t lest 63.5% 40.9% 23% erese one riologil proeure (%) GI lini visits (totl n) % inrese mrkely, the men length of sty remine reltively unhnge, eresing y 3.6%. Also unremrkle ws the perentge hnge in the numer of missions involving GI surgery, smll inrese of 4.6% ws note. Finlly, the totl numer of ministrtions of TPN (totl prenterl nutrition) erese y 4.3%. Men Dose (units) Figure 1. Men ily osge of prenisolone: ) 12 months efore tretment with inflixim, ) 6 months efore tretment, ) the week of tretment, ) 6 months fter tretment n e) 12 months fter tretment. e Results for the Steroi Dt The results se on the nlysis of the steroi t for eh ptient re shown in Figures 1, 2 n 3. This stuy foun tht the men ily osge of prenisolone erese uring the 12 months post-inflixim therpy, when ompre with the 12 months prior to therpy. Similrly, the men ily osge of uesonie erese in the 12-month perio fter inflixim therpy (Figs. 1 n 3). Of note, s epite in Figure 2, the weeks free of prenisolone inrese in numer fter inflixim therpy. DISCUSSION The results of nti-tnf-α therpy in linil trils for ptients with CD emonstrte n exiting rekthrough in the meil mngement of inflmmtory owel isese. In ition, this stuy foun high response to inflixim, with 73.1% of ptients stuie eing lsse s responers. This is higher thn the 66.6% of responers note in linil Weeks Free of Pre Men Dose (unit s) 2 1 e Figure 2. Totl numer of weeks free of orl ortiosteroi prenisolone: ) 12 months efore tretment with inflixim, ) 6 months efore tretment, ) 6 months fter tretment, ) 12 months fter tretment Figure 3. Men ily osge of lolly-ting orl ortiosteroi uesonie: ) 12 months efore tretment with inflixim, ) 6 months efore tretment, ) week of tretment, ) 6 months fter tretment, n e) 12 months fter tretment. 51

4 TSMJ Volume 3: Originl Reserh trils. Possile resons for this ifferene oul e tht the su-group nlyse in this report my not hve inlue some of the ptients with more resistnt or omplite isese. The mjority of the ptients h very tive isese, s shown y the men CDAI, ± SE Inee, the mximum vlue for CDAI in the sugroup of ptients ws It is interesting to note tht 42.3% of ptients were either urrent smokers or h history of smoking, s smoking hs previously een implite in the pthogenesis of Crohn s isese. Meil eonomis sine the 1990s hs onentrte on the elivery of qulity meil re to ll ptients while trying to minimise osts. 6 The Hy n Hy nlysis of 1992 lulte tht hospitlistion n surgery ounte for most of the nnul meil osts ssoite with CD. 7 One might therefore onlue tht ny tretment tht reues the numer of surgil hospitlistions shoul erese oth the ost of Crohn s isese missions n the overll osts. Inflixim is n expensive meition, (over 1200 IR per infusion of the meition) thus, its impt on helth-re usge hs mjor implitions. Thus, the finings of this stuy re exiting, in tht, fter inflixim therpy, the numer of missions to hospitl erese mrkely, y 46.9%. It is interesting to note tht the numer of proeures suh s riologil investigtions n enosopies lso erese; perhps eh ptient s symptomti improvement fter infusion of inflixim reue the nee for performing investigtions. Of note, surgil proeures inrese in frequeny post-inflixim, s i GI lini visits. Inee, surgery is the finl option in mny ptients who fil to respon to inflixim. It woul e stimulting to further nlyse the eonomi t, perhps suiviing it into ptients who respone to tretment n those who i not. Sterois re ommonly employe in the tretment of ute flre-ups of hroni tive isese. Although they re effetive, they re ssoite with prolems, suh s the evelopment of steroi-epenent or steroiresistnt isese, n the prevlene of unplesnt sie effets inluing: trunl oesity, esy ruising, gstro-intestinl upset, moon-shpe fies, strie n even psyhoti episoes. A prtiulrly sinister sie effet of sterois is the inrese risk of eveloping osteoporosis in lter life. Thus, ny tretment tht reues the presription of ortiosterois will enhne their effiy in future use n erese the iniene of severe sie-effets. As epite in Figures 1 n 3, the men ily osges of prenisolone n uesonie inrese immeitely prior to tretment with inflixim, initing the evelopment of tive isese. Susequent to therpy with inflixim, the men ily osge erese. This woul support the postulte tht inflixim hs "steroi-spring" role. Figure 2 lmost mirrors these results, s the men numer of weeks free of stnr orl sterois (prenisolone) inreses post-inflixim. CONCLUSION The finings from this stuy of 25 ptients with hroni tive CD re omprle to those previously hieve in the ontrolle setting of linil trils. Inflixim hs een shown to reue the overll use of helth re, espeilly the totl numer of missions to hospitl. This suggests tht inflixim therpy, lthough expensive, my tully reue the overll ost of Crohn s isese. In ition, susequent to tretment with inflixim, ortiosterois in generl were presrie less, thus supporting the theory tht inflixim ts s steroi-spring gent. Further investigtion into the impt of inflixim on helth-re usge n the presription of ortiosterois oul e n exiting n hllenging fiel for reserh in the future. ACKNOWLEDGEMENTS I woul like to thnk ll who prtiipte in this stuy, in prtiulr Dr. Mri O'Sullivn n Prof. C. O'Morin for ll their support n guine. I lso wish to knowlege the Helth Reserh Bor (HRB) for funing this stuy. 52

5 Anti-Tumour Nerosis Ftor-α Therpy in Crohn s Disese REFERENCES 1. Blm ME, Stein RB, Lihtenstein GR. Integrting nti-tumor nerosis ftor therpy in inflmmtory owel isese: urrent n future perspetives. Amer J Gstroenterol 2001; 96(7): Tooson JD, Vrilek GW. Inflmmtory iseses of the olon. Nrrowing wie fiel of symptoms n possile uses. Postgr Me 1995 Nov;98(5):46-8, 54, 57-8 pssim. 3. Cohen RD, Lrson LR, Roth JM, et l. The ost of hospitliztion in Crohn s isese. Am J Gstroenterol 2000; 95(2): Cohen RD, Ppli P, Hnuer SB. Inflixim s steroi spring gent in luminl Crohn s isese. University of Chigo, Chigo, IL. 5. Oxfor IBD Stuy (unpulishe t). 6. Hy AR, Hy JW. Inflmmtory owel isese: meil ost lgorithms. J Clin Gstroenterol 1992; 14(4): Hy AR, Hy JW. Inflmmtory owel isese: osts-of-illness. J Clin Gstroenterol 1992; 14(4):