Major challenges in Rheumatology: will we ever treat smarter, instead of just harder?

SPECIALTY GRAND CHALLENGE published: 26 June 2019 doi: 10.3389/ med.2019.00144 F on ie s in Medicine | www. on ie sin.o g 1June 2019 | Volume 6 | A icle 144 Edi ed by: Michel Goldman, F ee Uni e si y o B ussels, Belgium Re iewed by: Pa ick Du ez, Cliniques Uni e si ai es Sain -Luc, Belgium *Co espondence: João Eu ico Fonseca [email p o ec ed] Special y sec ion: This a icle was submi ed o Rheuma ology, a sec ion o he jou nal F on ie s in Medicine Recei ed: 10 May 2019 Accep ed: 10 June 2019 Published: 26 June 2019 Ci a ion: Romão VC and Fonseca JE (2019) Majo Challenges in Rheuma ology: Will We E e T ea Sma e , Ins ead o Jus Ha de ? F on . Med. 6:144. doi: 10.3389/ med.2019.00144 Majo Challenges in Rheuma ology: Will We E e T ea Sma e , Ins ead o Jus Ha de ? Vasco C. Romão1,2 and João Eu ico Fonseca 1,2 * 1Depa men o Rheuma ology, Cen o Hospi ala Uni e si á io Lisboa No e, Hospi al de San a Ma ia, Lisbon Academic Medical Cen e, Lisbon, Po ugal, 2Rheuma ology Resea ch Uni , Ins i u o de Medicina Molecula , Faculdade de Medicina, Uni e sidade de Lisboa, Lisbon, Po ugal Keywo ds: heuma ology, pe sonalized medicine, s a i ica ion, heuma oid a h i is, bioma ke s “[A eply o le e s ecommending emedies]: Dea Si (o Madam): I y e e y emedy sen o me. I am now on No. 67. You s is 2,653. I am looking o wa d o i s bene icial esul s.” Ma k Twain, quo ed in My Fa he Ma k Twain, by Cla a Clemens THE TREATMENT REVOLUTION IN RHEUMATOLOGY The ield o heuma ology has wi nessed as onishing p og ess in he unde s anding and managemen o heuma ic diseases since he second hal o he wen ie h cen u y. The disco e y and in oduc ion o glucoco icoids and con en ional syn he ic disease-modi ying an i heuma ic d ugs (csDMARDs) in o he he apeu ic a mamen a ium o heuma ologis s enabled, o he i s ime, o e ec i ely change he na u al cou se o disease and imp o e mos clinical ou comes (1). The new millennium pushed he e olu ion u he a an exponen ial le el wi h he ad en o sophis ica ed, biologically-enginee ed d ugs— he so-called biologicals o bDMARDs— ha a ge ed speci ic molecules in key pa hogenic pa hways and d ama ically modi ied he p ognosis o mos pa ien s wi h immune-media ed heuma ic diseases (2). This p og ess, which was d i en by emendous esea ch e o s o be e unde s and he complex mechanisms behind each disease, has been pa icula ly ema kable in in lamma o y join diseases such as heuma oid a h i is (RA) and spondyloa h i is (including ankylosing spondyli is and pso ia ic a h i is), and slowe in he a ea o connec i e issue diseases (e.g., sys emic lupus e y hema osus, Sjög en’s synd ome) and asculi is. Indeed, as o Ma ch 2019, 10 o iginal bDMARDs wi h 5 di e en mechanisms o ac ion a e app o ed in Eu ope o he ea men o RA, 9 o pso ia ic a h i is (4 mechanisms o ac ion), 6 o ankylosing spondyli is (2 mechanisms o ac ion), only 1 o sys emic lupus e y hema osus and small- essel asculi is and none o Sjög en’s synd ome (3). Ye , despi e hese signi ican ad ances, majo unme needs endu e. The case o RA is pa adigma ic o he cu en challenges aced by heuma ologis s and pa ien s alike in daily clinical p ac ice. While a i s , and especially when pa alleled o o he heuma ic diseases, RA seems o be he lucky ela i e o he heuma ology amily wi h a a ie y o inno a i e bDMARDs a ailable o ea ing and modi ying he disease and imp o ing pa ien s’ li es and ou comes, in p ac ice he eali y is mo e complex (4,5). “ME-TOO” DRUGS AND THE TRIAL AND ERROR APPROACH Fi s ly, a e he majo b eak h oughs shown a ound he u n o he millennium by he pionee bDMARDs app o ed o RA (in liximab and e ane cep ) in compa ison o he s anda d o ca e Romão and Fonseca Majo Challenges in Rheuma ology a ailable a he ime (csDMARDs), he ollowing decade obse ed a su ge o o he d ugs ha demons a ed a compa able e ec in simila popula ions o pa ien s (6). Wi h a ew excep ions (e.g., ocilizumab and sa ilumab exhibi ing supe io i y o e me ho exa e in mono he apy), new coming he apies usually con eyed a “me- oo” e ec ha hough impo an o inc ease ea men op ions in he e en o ine icacy o in ole ance, did no gene a e as emendous an impac as i s p edecesso s (7). Secondly, he wide di e si y o bDMARDs and modes o ac ion con as s wi h he p o ound lack o eliable, ep oducible clinical and biological ma ke s o in o m ea men selec ion. Indeed, in spi e o all he no able p og ess seen so a , we a e somewha su p isingly unable o ecognize be o ehand which indi idual pa ien s will bene i mo e om a gi en d ug, which will no espond a all and which a e a a highe isk o oxici y o in ole ance (8). Taking he speci ic example o RA, i should be acknowledged ha he e a e a ew well-es ablished p ognos ic indica o s ha a e associa ed a a g oup le el wi h ea men - esis an disease, including emale gende , olde age, long las ing disease, ailu e o p e ious biologics, smoking, and high baseline disabili y (8,9). Bu hese ea u es seem o be gene ically associa ed wi h wo se ea men ou comes as a whole, a he han cons i u ing speci ic p edic o s o esponse o a gi en d ug. A couple o excep ions exis , such as he ole o heuma oid ac o / an i-ci ullina ed p o ein an ibodies se oposi i i y in de e mining a be e esponse o i uximab (10) and aba acep (11) bu also he e his is a g oup e ec and some se onega i e pa ien s will s ill show imp o emen wi h hese ea men s, while o he se oposi i e pa ien s will no expe ience any bene i . O he a iables such as ele an como bidi ies (e.g., lymphoma o monoclonal gammopa hy) o in ec ious isk may u he concede sligh p e e ence o one bDMARD o e ano he and hus aid in he ea men decision p ocess (12,13), al hough again his is no d i en by a pa icula ly s ong ac o ha iden i ies he bes ea men o a gi en pa ien . This cu en landscape has ine i ably led o he so-called ial and e o app oach ha is he hallma k o p esen ea men s a egies in RA and o he in lamma o y join diseases and which has signi ican implica ions in e ms o cos , isk and, ul ima ely, ou come. LIMITATIONS OF PRESENT TREATMENT MODALITIES Undeniably, coupled wi h he majo bene i s b ough by hese he apies, a ew sho comings ha e eme ged. These a e powe ed by he a o emen ioned unp ecise ea men pa adigm, wi h implica ions bo h a he pa ien and socie al le el. The i s ac o is ela ed o he signi ican di ec cos s associa ed wi h hese d ugs, which has pu addi ional inancial p essu e in al eady s uggling heal hca e sys ems (14). Howe e , i has been shown ha he o e all cos associa ed wi h RA managemen has no inc eased signi ican ly o e he las decades, due o a majo d op in indi ec cos s and p oduc i i y losses ha compensa ed o he highe d ug- ela ed expendi u e (14,15). In ac , he main conce n is ha lacking obus pe sonalized ea men s a egies, pa ien s may be ea ed wi h cos ly bDMARDs o an ex ended pe iod o ime wi hou expe iencing any ele an bene i bu s ill be exposed o i s isks and po en ial ad e se e en s. I is ema kable ha in such a case, he isk-bene i a io is clea ly il ed in he w ong di ec ion, and ye , heal h au ho i ies, physicians and pa ien s, all seem o igno e o accep his ac as ine i able. Cu en ly, bDMARDs ha e a well-es ablished sa e y p o ile (16), ha needs o be balanced agains he co esponding bene i s p o ided by he ea men i sel . A numbe o se ious condi ions—such as ube culosis and o he se ious in ec ions o li e and medulla y oxici y, o name jus a ew (17)—a e associa ed wi h bDMARDs and a e accep ed only in e u n o subs an ial e icacy and imp o emen o sho - and long- e m ou comes. I his second pa o he equa ion is missing, as is he case o he conside able p opo ion o pa ien s ha ail o see any bene i a all, i may be e hically (and inancially, as explained abo e) unaccep able o p esc ibe and adminis e hese d ugs. Hence, he p oblem elies in he ac ha we a e unable o iden i y hese pa ien s be o ehand, emphasizing he limi a ions o his ea men model and he need o an indi idualized app oach. The scena io is agg a a ed when we also ake in o accoun he sho - e m, highly-in ensi e, emission- inducing egimens ha a e applied in se e al heuma ic diseases, usually wi h subs an ial oxici y, in an indisc imina e manne (18–20). These ea men modali ies ep esen he s anda d o ca e, bu pe sonalized ea men could e olu ionize he cu en pa adigm o an all-o -no hing app oach simply based on he exis ence o a ce ain diagnosis. Ano he aspec ha should be conside ed when analyzing he issue o undisce ning d ug selec ion is e ec i e ea men delay. T ea - o- a ge (T2T) app oaches ha e shown ha , in e ms o p ognosis, mo e impo an han he d ug adminis e ed is he he apeu ic a ge de ined and he quickness o a ain i (21,22). Subjec ing pa ien s o ea men s ha will no be e ec i e o long pe iods—a leas 3 o 6 mon hs as pe s anda d ecommenda ions (23)—will cos p ecious ime du ing which disease ac i i y is high and s uc u al damage eadily occu s. This leads o poo long- e m ou comes and is ye ano he eason o why a gene alized same-d ug- o -all s a egy is lawed. The disco e y o p ecise bioma ke s o esponse o in o m ea men selec ion could sa e up his los ime and, hus, syne gis ically ein o ce he T2T s a egy. In spi e o his, T2T ad oca es ha e, somewha su p isingly, dis ega ded he impo ance o pe sonalized medicine s. he main goal o aba ing disease ac i i y ega dless o he mechanism implied and d ug chosen (24). Howe e , as hey poin ou , his only e lec s he cu en s anding, whe e p ecise bioma ke s ha ha e a majo impac on ea men selec ion and can modi y and guide clinical p ac ice a e s ill missing (8,25). Impo an ly, one should no o ge o he addi ional ac o s con ibu ing o ea men limi a ions. Despi e majo imp o emen s in he a ea o ea ly diagnosis, i has ecen ly been epo ed ha in daily clinical p ac ice he eali y is s ill a om op imal (26–28). Mo eo e , he e has also been a con inuous global e o o he de elopmen and upda e o classi ica ion c i e ia o heuma ic diseases, bu hese a e aimed a pa ien ec ui men in esea ch s udies, in mos cases pe o m poo ly F on ie s in Medicine | www. on ie sin.o g 2June 2019 | Volume 6 | A icle 144 Romão and Fonseca Majo Challenges in Rheuma ology in a eal-wo ld se ing, and he e o e should no be applied o clinical diagnosis (29). Finally, wi h he inco po a ion in o ou ine ca e o highly sensi i e diagnos ic echniques such as ul asonog aphy o magne ic esonance imaging, he conce n o o e diagnosis and o e ea men o heuma ic diseases is al eady a eali y, ha should be add essed (30). These aspec s allow o be e unde s and he delica e landscape in which d ugs a e p esc ibed and unde sco e he need o imp o e ea men app oaches. NEW PLAYERS: THE ROLE OF BIOSIMILARS AND NOVEL TARGETED SYNTHETIC MOLECULES As we ha e exposed, cu en ly a ailable bDMARDs compose an he e ogeneous g oup o d ugs, wi h se e al modes o ac ion, dis inc dosages, schedules, and ou es o adminis a ion and some pa icula i ies in e ms o concomi an medica ion, moni o ing, o ad e se e en s. Howe e , he o e all e icacy and sa e y be ween bDMARDs is conside ed o be oughly simila and long- e m ou comes o pa ien s ea ed wi h hese d ugs a e no subs an ially di e en (2,7). Fo his ma e , we should highligh he impo ance o disease egis e s, bo h na ional and in e na ional, which ha e g ea ly con ibu ed o demons a e he bene i s and pi alls o ea men s in a eal-li e se ing (31). I is in his se ing ha in he las 5–10 yea s wo new ea men classes ha e appea ed o add o he complexi y o heuma ic pa ien s managemen : biosimila DMARDs (bsDMARDs o biosimila s) and a ge ed syn he ic DMARDs ( sDMARDs). Bo h ha e con ibu ed o widen he op ions a ailable o ea ing RA pa ien s, bu also b ough along addi ional challenges o he able. Biosimila s eme ged ollowing he pa en expi y o bDMARDs and p omised o inc ease pa ien access by signi ican ly dec easing ea men cos s while, simul aneously, showing compa able e icacy and sa e y (32,33). Following igo ous clinical ial p og ams demons a ing equi alence o he o iginal bDMARDs, he e a e cu en ly 16 bsDMARDs app o ed in Eu ope o he ea men o RA (4 in liximab, 3 e ane cep , 6 adalimumab, 3 i uximab), wi h o he s awai ing app o al (2 adalimumab), al eady wi hd awn (2 adalimumab) o no ha ing applied o RA indica ion (3 i uximab) (3). These imp essi e numbe s speak well o he po en ial impac o bsDMARDs in he ield. Indeed, i s main added alue elies in he educed cos -−20 o 40% below e e ence bDMARDs, depending on coun y—and, consequen ly, he la ge numbe o pa ien s ha can be ea ed wi h hese d ugs (33,34). While his pa ially esol es one o he issues men ioned abo e (cos ), he o he wo (sa e y and ime los ) emain unchanged. Ul ima ely, he inc ease in o e could e en ampli y he p oblem, wi h pa ien s swi ching o en be ween di e en bDMARDs and bsDMARDs in he pu sui o he igh d ug, wi h he associa ed implica ions in ea men delay and pha maco igilance issues. This u he ein o ces he need o pa ien s a i ica ion and a ional ea men selec ion. None heless, bsDMARDs ha e undoub edly opened a new e a in he ea men o heuma ic diseases. Ra es o i s bsDMARD a e ising in Eu ope (34), and a e he main pi o al ials, good quali y obse a ional da a ha e con i med he sa e y o swi ching pa ien s om he o iginal d ug o i s biosimila (35– 37). Concu en ly, o he challenges a ise, such as selec ion and swi ching be ween biosimila s o he same bDMARD, di e en immunogenici y pa e ns and, po en ially, lack o e idence o es ablished p ognosis ma ke s ha may di e om hose known o he o iginal d ug (35,36). This la e aspec may be ueled by a low willingness o bsDMARD d ug de elope s o be e explo e disease he e ogenei y, as his could po en ially be comme cially una ac i e and limi he p omo ion o hese d ugs. Addi ionally, he nocebo e ec — he nega i e e ec o a ea men ha is a ibu able o poo pa ien expec a ions—is a well-de ined phenomenon ha is pa icula ly oublesome when swi ching eal-wo ld pa ien s om o iginal bDMARDs o bsDMARDs, due o he impo ance played by subjec i e measu es (e.g., pain and global assessmen , ende join coun s) in he e alua ion o disease ac i i y and ea men esponse (38). A no el class o o al highly speci ic small molecules inhibi ing in acellula signaling pa hways, he sDMARDs, has also become a ailable (39). To aci inib, a Janus kinase inhibi o app o ed in he Uni ed S a es (2012) and Eu ope (2017), was ecen ly ollowed by ba ici inib (2018 and 2017, espec i ely) as he i s wo o al d ugs ha ha e an e icacy and sa e y p o ile compa able o bDMARDs (40). This is a majo ad ance, gi en he p e e ence o many pa ien s o o al s. pa en e al adminis a ion. O he po en ial ad an ages include apid clinical e icacy, e en in mono he apy, absence o immunogenici y and a sho e hal - li e, acili a ing he managemen o ad e se d ug eac ions (39, 40). Howe e , i s place in ea men algo i hms (be o e o a e cs/b/bsDMARDs) is s ill o be ully unde s ood. Mos impo an ly, while sDMARDs will de ini ely be bene icial o a la ge numbe o pa ien s, he lack o p edic i e bioma ke s p ecludes i s a ional applica ion a he indi idual pa ien le el and i s in oduc ion in he clinical a mamen a ium ollows he same ial and e o app oach. THE LAG OF PERSONALIZED MEDICINE IN RHEUMATOLOGY A numbe o easons can be pu o wa d as o why pe sonalized medicine is aking a long ime o ma e ialize in heuma ology. Fi s , he he e ogeneous and mul i ac o ial na u e o immune- media ed heuma ic diseases, wi h complex pa hogeneses, makes i unlikely ha a single ma ke o a gi en pa hway will disc imina e esponse o se e al di e en DMARDs wi h con as ing modes o ac ion (41). Second, a conside able amoun o e o is dedica ed o iden i ying bioma ke s in he blood, a om he key immunopa hologic e en s happening a he syno ial issue, which may p o e mo e in o ma i e (42). Thi d, one aspec ha is no so commonly ci ed ela es o he subjec i e na u e o a signi ican pa o he ools used o assess ea men esponse, emission s a us o disabili y. This applies bo h o he pa ien (e.g., isual analog scale) and he physician (e.g., join coun s) and is, by de ini ion, in luenced by many o he indi idual- ela ed ac o s, such as pe sonali y, p e ious expe ience wi h a gi en d ug, expec a ions, pa ien -doc o ela ionship, cul u al con ex , F on ie s in Medicine | www. on ie sin.o g 3June 2019 | Volume 6 | A icle 144 Romão and Fonseca Majo Challenges in Rheuma ology como bidi ies, e c. (43,44). Indeed, his sca ci y o ha d ou comes con as s o ha seen, o ins ance, in he a ea o oncology (e.g., dea h, umo - ee su i al), whe e pe sonalized ea men has long been a eali y. To wha ex en is he cu en si ua ion explained by his ac is unclea , bu subjec i e measu es a e likely o play an impo an ole in con ounding s udy esul s, po en ially leading o he loss o a weak, albei unique signal. CONCLUSIONS AND FUTURE PERSPECTIVES In summa y, he p esen momen in heuma ology is an exci ing one, a e wo as -paced decades ha ans o med he p ognosis o pa ien s wi h in lamma o y heuma ic diseases. This was mainly due o a deep expansion o a ailable, e ec i e he apies ha ha e come, none heless, coupled wi h majo challenges ha need o be ackled. We a gue ha his is he ime o do so, whe e esea ch e o s should be bes di ec ed a es ablishing obus bioma ke -based ea men models ha will allow indi idualized ca e. I success ul, he ou come o his app oach is likely o ansla e in o mo e subs an ial bene i s, compa ed o he meek pu sui o new d ugs—o en wi h he same o close mechanisms o ac ion— ha will p o ide a simila o e all e ec o cu en ly a ailable op ions. Syno ial issue should be a he cen e o hese in es iga ions, as a ge ing he disease p ocess a i s co e will a guably p o e mos aluable. This is de ini ely a sinuous pa h, no wi hou many expec able se backs, bu one wo h acking as i s comple ion may inally lead o a new longed- o e a o pe sonalized medicine in heuma ology. No ably, despi e all he cu ing-edge science behind hese inno a ions, clinical expe ise o heuma ologis s will be o s a egic impo ance in guiding he p ocess along he way. AUTHOR CONTRIBUTIONS VR and JF con ibu ed o manusc ip concep ion and design, li e a u e e iew, manusc ip p epa a ion, and c i ical e iew. Bo h au ho s ha e ead and app o ed he inal e sion o he manusc ip . FUNDING VR’s wo k was pa ially suppo ed by Fundação pa a a Ciência e Tecnologia (In e no Dou o ando Bu sa y e e ence SFRH/SINTD/95030/2013). REFERENCES 1. Agga wal D, Ab aham S. Rheuma oid a h i is ea men s: a his o ical pe spec i e. JSM A h i is. (2016) 1:1011. 2. Con i F, Cecca elli F, Massa o L, Cip iano E, F anco M Di, Alessand i C, e al. Biological he apies in heuma ic diseases. Clin Te . 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Pain Ca as ophizing, subjec i e ou comes, and in lamma o y assessmen s including ul asound: esul s om a longi udinal s udy o heuma oid a h i is pa ien s. A h i is Ca e Res. (2018) 70:703–12. doi: 10.1002/ac .23339 44. Dougados M, Na a H, S einbe g G, Rouane S, Falissa d B. Rela i e impo ance o doc o - epo ed ou comes s pa ien - epo ed ou comes in DMARD in ensi ica ion o heuma oid a h i is: he DUO s udy. Rheuma ol. (2013) 52:391–9. doi: 10.1093/ heuma ology/kes285 Con lic o In e es S a emen : The au ho s decla e ha he esea ch was conduc ed in he absence o any comme cial o inancial ela ionships ha could be cons ued as a po en ial con lic o in e es . Copy igh © 2019 Romão and Fonseca. This is an open-access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (CC BY). The use, dis ibu ion o ep oduc ion in o he o ums is pe mi ed, p o ided he o iginal au ho (s) and he copy igh owne (s) a e c edi ed and ha he o iginal publica ion in his jou nal is ci ed, in acco dance wi h accep ed academic p ac ice. No use, dis ibu ion o ep oduc ion is pe mi ed which does no comply wi h hese e ms. F on ie s in Medicine | www. on ie sin.o g 5June 2019 | Volume 6 | A icle 144