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McNally, DO, FACP, FACG University Colorado Denver School of Medicine Center for Human Simulation Aurora, Colorado 80045Z_Burmester GR1, Mease P2, Dijkmas BAC3, Gordon K, Lovell D4, Panaccione R5, Perez J6, Pangan AL6`          $ $ ((, , 004 4Adalimumab Safety and Mortality Rates from Global Clinical Trials of Six Immune-Mediated Inflammatory Diseases. Ann Rheum Dis. Ann Rheum Dis. 2009;68:1863-9.o/ Introduction Tumor necrosis factor (TNF) plays an important role in the pathogenesis of a variety of inflammatory disorders: Rheumatoid Arthritis (RA) Juvenile Idiopathic Arthritis (JIR) Psoriatic Arthritis (PsA) Ankylosing Spondylitis (AS) Crohn s Disease (CD) Psoriasis (Ps) Anti-TNF Rx have been developed and used effectively in all of these inflammatory disorders.FrPP]Pr] Introduction= Anti-TNF drugs approved for RA, PsA, AS, Ps Adalimumab (Humira*) ADA Etanercept (Enbrel*) ETC Infliximab (Remicaide*) IFX Anti-TNF drugs approved for CD Adalimumab (Humira*) ADA Certolizomab (Cimzia*) CTZ Infliximab (Remicaide*) IFX Anti-TNF drugs approved for JIA Adalimumab (Humira*) ADA Etanercept (Enbrel*) ETC-ZOZZQZ Z2Z-OQ   2 IntroductionBased on the review of clinical trials, Anti-TNF drugs have been associated with an increased risk for serious infections, especially tuberculosis (TB), and malignancy. Many of the previous reviews for Anti-TNF drugs have been a composite analysis of multiple Anti-TNF drugs either confined to one type of inflammatory disorder or inclusive of many different types. Studies of this type have been hampered by retrospective analysis, short longitudinal follow up, variability of the Anti-TNF drugs themselves, and the co-administration of other treatments known to independently increase this risk for infection and malignancy, i.e., Azathioprine (AZA), 6-mercaptopurine (6MP), methotrexate (MTX).PAimpThe authors sought to specifically assess the safety of a single Anti-TNF, adalimumab (Humira), in the treatment of six immune mediated disorders over time and to compare adalimumab malignancy and mortality rates with data on the general population. Six Inflammatory Disorders included: Rheumatoid Arthritis (RA) Psoriatic Arthritis (PsA) Ankylosing Spondylitis (AS) Crohn s Disease (CD) Psoriasis (Ps) Juvenile Idiopathic Arthritis (JIA).!ZZ!Io Study Design% Retrospective analysis of 19,041 patients exposed to adalimumab in 36 global clinical trials (RA, PsA, AS, CD, Ps, JIA). Last patient inclusion date April 15, 2007. Adverse Events reported per 100 patient-years format Serious adverse events (SAEs) reported after the first dose through 70 days after the last dose. Standardized incidence rates (SIRs) were calculated for malignancies using national and state specific databases. Standardized mortality rates (SMRs) were calculated for each disease using data from the World Health Organization.:IH Study DesignqInclusion Criteria: (+) for active index disease RA PsA AS CD Ps JIA Met study enrollment criteriarr )Exclusion Criteria: Clinically active TB Active listeriosis Acute or chronic hepatitis B History of hepatitis C Persistent or serious infections requiring hospitalization Antibiotics 30D prior or IV and 14D prior PO Sx for demyelinating disorder Significant health issues Malignancy HIV $*Z) Study Design Serious Adverse (AEs) Events AEs occurring after 1st dose up to 70 days (5 half-lives) SAEs defined as Life threatening illness Fatal Inpatient hospitalization Significant disability Birth anomaly/miscarriage Rates reported in number of events per 100 pt-yrsB Zf    Study Design Malignancy and Mortality Data NCI, SEER database http://seer.cancer.gov/ Standardized Incidence Rates (SIRs) Ratio of Observed Events to Expected Events in a populationl,$<  f$<o2IStudy AnalysisRStandardized Incidence Ratio (SIR) Ratio of Observed Events to Expected Events in a population Example: If 5 malignancies observed in a study trial If 20 malignancies expected in a general population Then SIR = 0.25 Meaning When SIR < 1.0, # observed events less than expected When SIR > 1.0, # observed events greater than expectedx#Gq m#Gp   m2Results: Baseline Characteristics by Disease State33=Results: Serious AEs, event/100 pt-yrs (As of April 15, 2007)>>'Results: Time to 1st Serious Infection .( Results: Expected Events"Expected number of cancers for SIR calculations based on two sources: 5 yr age specific cancer incidence rates obtained from the National Cancer Institute (NCI) Surveillance Epidemiology and End Results (SEER) database (1993-2001) for all cancers other than non-melanoma skin cancer (NMSC). 10-yr age specific incidence rate for NMSC from NCI survey of 8 locations in US (1977-1978).&G;G;Malignancy (all types)The SIR for malignancies in clinical trials for all diseases combined was 0.83 (95% CI, 0.72-0.96). SIR < 1, means observed malignancy rate less than expected for entire ADA treated group. Malignancy (Lymphoma)l! Lymphoma for RA pts only, SIR 2.98 (95% CI, 1.89-4). Lupus-Like SyndromeGLupus-like syndrome was infrequent among all patients treated with ADA. >Opportunistic Infections (OI s),OI s were only seen in RA and CD: oral candidiasis most common. RA had 17 OI s: 6 histoplasmosis, 3 cytomegalovirus, 1 each for coccidiomycosis, toxoplasmosis, listeriosis, nocardiosis, aspergilloma, Pneumocystis jioveri, esophageal candidiasis and candida sepsis. CD had 2 OI sZ Tuberculosis (TB)eImportant: TB presented with extra-pulmonary involvement in 33 of 53 (62%) cases reported in RA pts. efd 2Serious Infections (SI s)SI rates vary by disease state, but most common among RA and CD patients. Pneumonia was the most common SI for RA. Abscess was the most common SI for CD.Study Conclusions Based on 10 years of clinical trial experience across six diseases, ADA has a stable safety profile and  acceptable risk benefit ratio. !Risk for Malignancy (all): SIR = 0.83 !Risk for Lymphoma in RA: SIR = 2.98 !Risk for TB: Note 62% extra-pulmonary in RA !Risk for OI s: RA #1 Lung & CD #1 Abscess Risk for Demyelinating disease: infrequent Risk for Lupus Syndrome: infrequentReviewer CommentsBurmester, et al, do not answer the following questions? What is the safety and risk profile for the non-RA indications for ADA? Comment: 65% of all pts in this ADA safety trial had RA, the other 5 inflammatory disorders comprised only 1/3 of the remainder of pts. Number of subjects examined in each of the 5 other disease states are too small to offer conclusive safety data for each. What is the true long term safety and risk profile for ADA? Comment: Only 8% of all ADA pts received drug for > 5 yrs. The lead time for neoplastic risk may require a decade or more to estimate true risk. Furthermore risk stratification by disease state is needed, i.e., lymphoma risk is 2x RA than the general population.:H" " <" " :Iff  ff<ff  ff$$ff((ffReviewer CommentsBBurmester, et al, do not answer the following questions? It is common in clinical practice to use both an Anti-TNF + Immunomodulator in many of the 6 inflammatory disorders. In the study by Burmester, et al, mono-ADA therapy was more common in PS (99%), AS (80%), CD (60%) and JIR (50%) than in RA (40%) and reported among other Anti-TNF Rx. 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S  6pb OPn   >*   6b O n  @* H  0޽h#6 ? 3380___PPT10. 8(    0n P   >*   0Pn    @*   6@o OPn   >*   6o O n  @* H  0޽h#6 ? 3380___PPT10.  0l 2(  l ~ l s *p+eB  ~ l s *`!@p    l c J@A$ da_Vinci_Sketch_13"rZ l C 2AHeader_NONEpH l 0޽h ? 33___PPT10u.8dW+D=' = @B + p7(  px p c $֐N   p  < ؐԔ S"     p 0Pݐ  a1Charite-University Medicine Berlin, Free University and Humbolt University Berlin, Germany; 2Sweedish Medical Center, Seattle, Washington, USA; 3VU medical Centre and Jan van Breemen Institute, Amsterdam, Netherlands; 4Evanston Northwestern Healthcare, Skokie, Illinois, USA; 5University of Calgary, Calgary, Alberta, Canada; 6Immunology Development, Abbott Laboratories, Parsippany, New Jersey, USA.|( _ \ 3   I 9  1$$( (J,,H p 0޽h ? Oa(___PPT10u.e+D=' C= @B +  xr(  xx x c $`T    x  0Uo p   . x 00nC"? P XMurdaca G, et al. Anti-TNF inhibitors: a new approach for inflammatory immune mediated diseases. Int J Immunopathol Pharmacol. 2009;22:557-65. Schiff MH, et al. Safety of adalimumab (HUMIRA) in global clinical trials and US post marketing surveillance of pts with RA. Ann Rheum Dis. 2006;65:889-894.- 2-H x 0޽h ? Oa(___PPT10u. w;+D=' o= @B +  R(  x  c $H <@?1 5  M0.3 @` =H <&? 1 5  N49.7 @` ?  KJIA @`  H <H?   JAS @`  H <R?   KPsA @`  H <\?  JRA @` H <f? R  @``B NH 0o ?ZB OH s *1 ?ZB PH s *1 ?ZB QH s *1 ?ZB RH s *1 ?00ZB SH s *1 ?33ZB TH s *1 ?R R ZB UH s *1 ?1 1 ZB VH s *1 ?5 5 ZB WH s *1 ?8 8 `B XH 0o ?;;`B YH 0o ?;ZB ZH s *1 ?;ZB [H s *1 ?  ;ZB \H s *1 ?  ;ZB ]H s *1 ?  ;ZB ^H s *1 ?;ZB _H s *1 ?;`B `H 0o ?; yH 0`@ `1472 of 19,041 (8%) patients received ADA > 5 YRS 12,345/19,041 (65%) of all pts treated had RA(a 2*6/ |H Z`xaxao ?`  3Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.4Z4H H 0޽h ? Oa(___PPT10u.@P1+D=' = @B +O  NNn N(   ~  s *0 1   K ~   #"B6 ~    <@?   N0.13 @`   < Ý?   K0 @`   <Ν?   K0 @`   <ٝ?@  N0.08 @`   <? @  K0 @`   <  ?"`   N0.05 @`   <  ?"`   ZDemyelinating Ds @`   <?   N0.04 @`   <p?   K0 @`   <0?   K0 @` }  < %?@  K0 @` {  <0? @  K0 @` y  <@; ?"`   N0.07 @` w  <@F ?"`   T Lupus-like   @` t  <Q?  K0 @` r  <[?  K0 @` p  <f?  K0 @` n  <pq?@  N0.16 @` l  <{? @  K0 @` j  <?  N0.23 @` h  < ?"`  MCHF @`    < ?   K0 @`    < ?   N0.12 @`   <?   K0 @`   <м?@  N0.08 @`   <0? @  K0 @`   <Ҟ ?"`   N0.17 @`   <ݞ ?"`   NNMSC @`   < ?   N0.08 @`   <?   K0 @`   <?   K0 @`   <?@  N0.08 @`   <? @  M0.2 @`   < ?"`   N0.12 @`   <( ?"`   RLymphoma   @`   <3?   N0.46 @`   < >?   N0.49 @`   <@I?    K0 @`   <T?@   N0.08 @`   <P^? @  M0.3 @`   <Pi ?"`   N0.76 @`    <s?   T Malignancy   @` !  <?o  N0.08 @` "  <p?o  K0 @` #  <? o  K0 @` $  < ?@ o   K0 @` %  <p?o@   K0 @` &  <Ь?o  N0.09 @` '  < ?o  aOpportunistic Infection @` (  <PP?o N0.13 @` )  <P?o N2.76 @` *  <P? o K0 @` +  <P+P?@  o K0 @` ,  <-P?@ o N0.30 @` -  <AP?o N0.29 @` .  <`CP?o LTB @` /  <VP?} N5.18 @` 0  <YP?} N1.32 @` 1  <`lP? } N2.76 @` 2  <nP?@ }  N1.11 @` 3  <P?}@  N2.81 @` 4  <pP?} N4.65 @` 5  <P?} \Serious Infections @` 6  <pP?} N2373 @` 7  <P?} N2424 @` 8  < P? } M398 @` 9  <pP?@  } N1255 @` :  <P?@ } M997 @` ;  < P?} O18284 @` <  <P?} V Exposure PYs   @` =  < P? N2228 @` >  <P? N1819 @` ?  <Q?  M171 @` @  <0Q?@   N1641 @` A  <Q?@  M837 @` B  <Q? O12345 @` C  <00Q? KN @` D  <2Q?~ JCD @` E  <DQ?~ JPs @` F  <NQ? ~ KJIA @` G  <XQ?@ ~  JAS @` H  <bQ?~@  KPsA @` I  <lQ?~ JRA @` J  <vQ?~ R  @``B K  0o ?~~ZB L  s *1 ?ZB M  s *1 ?ZB N  s *1 ?}}ZB O  s *1 ?ZB P  s *1 ?ooZB Q  s *1 ?  ZB R  s *1 ?  ZB S  s *1 ?  ZB T  s *1 ?  `B U  0o ?`B V  0o ?~ZB W  s *1 ?~ZB X  s *1 ?~ZB Y  s *1 ?@ ~@ ZB Z  s *1 ? ~ ZB [  s *1 ?~ZB \  s *1 ?~`B ]  0o ?~ZB x  s *1 ?  ZB   s *1 ?    0Q0 mPYs patient years; Malignancy (exclude NHL/NMSC), NMSC nonmelanoma skin cancer; CHF, congestive heart failuren 2n/  ZpQxaxao ?`  3Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.4Z4H  0޽h ? Oa(___PPT10u.@P1+D=' = @B +  0r (   ~  s *Q0 P    p 0 NA ? S"    q 0Q@ ' SN pts = 6807 3574 2258 1544 1316 699 207 64T 2T/ r ZQxaxao ?`  3Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.4Z4H  0޽h ? Oa(___PPT10u.@P1+D=' Q`= @B +  PP(  P~ P s *@O    P  <o S" PP  / P ZpQxaxao ?`  3Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.4Z4H P 0޽h ? 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KJIA @` ?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwx  V,N,>W +(   ~  s * S    x  c $S`   q)  ^ V  #"*888888  S  <S ?"`p& N0.08 @` Q  <pS ?"`Pp& K0 @` O  <pT ?"` pP& K0 @` M  < T ?"` p & N0.08 @` K  < T ?"` p & N0.20 @` I  < T ?"`pp & N0.12 @` G  <3T ?"`pp& c# Lymphoma (#/100 pt-yrs) @` ;  <>T ?"` 8  K2 @` 9  <IT ?"`P 8  K0 @` 7  <LT ?"` P8  K0 @` 5  <P_T ?"` 8  K1 @` 3  <aT ?"`  8  K2 @` 1  <uT ?"`p 8  L23 @` /  <`wT ?"` p8  U N, lymphoma   @`   <T ?"`&^ LNS @`   <`T ?"`P&^ LNS @`   <T ?"` &P^ LNS @`   <T ?"` & ^ LNS @`   <`T ?"` & ^ LNS @`   <T ?"`p& ^ N2.98 @`   <T ?"`&p^ MSIR @`   <pT ?"`P8 p N2424 @`   <T ?"`P   N1819 @`   <@T?P   JPs @`   <`T ?"`8 p N2373 @`   <T ?"` 8 Pp M398 @`   < U ?"` 8 p N1255 @`   <pU ?"` 8  p M997 @`   <!U ?"`p8 p O18284 @`   < $U ?"`8 pp V Exposure PYs   @`   <7U ?"`   N2228 @`   < :U ?"` P  M171 @`   <pMU ?"`  N1641 @`   <OU ?"`   M837 @`   < cU ?"`p  O12345 @`   <eU ?"` p  U N, patients   @`   <xU?   JCD @`   <U? P  KJIA @`   <U?  JAS @`   <U?   KPsA @`   <U?p  JRA @` !  <U? p  R  @``B "  0o ?  ZB #  s *1 ?  ZB $  s *1 ?  ZB %  s *1 ?pp`B &  0o ?^^`B '  0o ? ^ZB (  s *1 ?p p^ZB )  s *1 ? ^ZB *  s *1 ?  ^ZB +  s *1 ? ^ZB ,  s *1 ?P P^`B -  0o ? ^ZB .  s *1 ? ^ZB 0  s *1 ?8 8 ZB H  s *1 ?&&/ W ZUxaxao ?`  3Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.4Z4H  0޽h ? Oa(___PPT10u.@P1+D=' = @B +'  &&6$ %(  $ ~ $ s *U    x $ c $ U`@  :#  $  #"&88P88  $  <U ?"` c  K6 @` $  < V ?"` c  K1 @` $  <V ?"` c  K0 @` $  <0V ?"` c  K0 @` $  <+V ?"` c  K0 @` $  <-V ?"` c  L35 @` $  <0AV ?"` c  e# Lupus-Like Syndrome cases @` $  <CV ?"`c  N0.04 @` $  <0WV ?"`c  K0 @` $  <YV ?"` c  K0 @` $  <lV ?"` c  K0 @` $  <@oV ?"` c  K0 @` $  <V ?"`c  N0.07 @` $  <V ?"`c  o%Obs Lupus-Like Syndrome # / 100 pt-yr&& @` Y$  <V ?"`   N2373 @` W$  <V ?"`   N2424 @` U$  <V ?"`   M398 @` S$  <V ?"`  N1255 @` Q$  <@V ?"`  M997 @` O$  <V ?"`  O18284 @` M$  <V ?"`   V Exposure PYs   @` $  <V ?"`H   N1819 @` $  <V?H  JPs @` $  <@V ?"`H   N2228 @` $  <0W ?"` H   M171 @` $  < W ?"` H  N1641 @`  $  <pW ?"` H  M837 @` !$  <0#W ?"`H  O12345 @` "$  <-W ?"`H   KN @` #$  < 8W?H  JCD @` $$  <BW? H  KJIA @` %$  <LW?  H  JAS @` &$  <VW?  H  KPsA @` '$  <`W? H  JRA @` ($  <jW?H  R  @``B )$  0o ?ZB *$  s *1 ?H H ZB +$  s *1 ?  `B -$  0o ?`B .$  0o ?ZB /$  s *1 ?ZB 0$  s *1 ?  ZB 1$  s *1 ?  ZB 2$  s *1 ?  ZB 3$  s *1 ?`B 4$  0o ?ZB 5$  s *1 ?ZB N$  s *1 ?  ZB $  s *1 ?c c / $ ZWxaxao ?`  3Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.4Z4H $ 0޽h ? Oa(___PPT10u.@P1+D='  = @B +'  &&6D4 %(  4 ~ 4 s *pW    x 4 c $W`@  6#  C4  #"&88888*   4  <W ?"`b  N0.08 @` 4  <W ?"`b  K0 @` 4  <W ?"` b  K0 @`  4  <@W ?"` b  K0 @`  4  <W ?"` b  K0 @`  4  <W ?"`b  N0.09 @`  4  <@X ?"`b  t*Obs OI s # /100 pt-yr @`  4  <PX ?"`* b  K2 @` 4  <X ?"`* b  K0 @` 4  <pX ?"` * b  K0 @` 4  <0X ?"` * b  K0 @` 4  < 3X ?"` * b  K0 @` 4  <pFX ?"`* b  L17 @` 4  <HX ?"`* b  \# of OI s   @` 4  <p\X ?"` *  N2373 @` 4  <^X ?"` *  N2424 @` 4  < rX ?"` *  M398 @` 4  <tX ?"` *  N1255 @` 4  <ЇX ?"` *  M997 @` 4  <0X ?"` *  O18284 @` 4  <X ?"` *  V Exposure PYs   @` 4  <0X ?"`   N1819 @` 4  <X?  JPs @` 4  <X ?"`   N2228 @` 4  <PX ?"`   M171 @` 4  <X ?"`  N1641 @`  4  <X ?"`  M837 @` !4  <`X ?"`  O12345 @` "4  <X ?"`   KN @` #4  <0X?  JCD @` $4  <Y?   KJIA @` %4  <Y?   JAS @` &4  <Y?   KPsA @` '4  <&Y?  JRA @` (4  <0Y?  R  @``B )4  0o ?ZB *4  s *1 ?  ZB +4  s *1 ?  `B ,4  0o ?`B -4  0o ?ZB .4  s *1 ?ZB /4  s *1 ?  ZB 04  s *1 ?  ZB 14  s *1 ?  ZB 24  s *1 ?`B 34  0o ?ZB 44  s *1 ?ZB 54  s *1 ?* * ZB 64  s *1 ?b b / D4 ZIYxaxao ?`  3Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.4Z4H 4 0޽h ? Oa(___PPT10u.@P1+D=' 8= @B +&  &%69< %(  < ~ < s * @Z    x < c $AZP  #  8<  #"&88888  <  <FZ ?"`b  N0.13 @` <  <QZ ?"`b  K0 @` <  <\Z ?"` b  K0 @`  <  <^Z ?"` b  K0 @`  <  <@rZ ?"` b  N0.30 @`  <  <tZ ?"`b  N0.29 @`  <  <Z ?"`b  `Obs # TB # / 100 pt-yr @`  <  <Z ?"`* b  K4 @` <  <Z ?"`* b  K0 @` <  < Z ?"` * b  K0 @` <  <pZ ?"` * b  K0 @` <  <еZ ?"` * b  K0 @` <  < Z ?"`* b  L53 @` <  <Z ?"`* b  T # cases TB   @` <  < Z ?"` *  N2373 @` <  <Z ?"` *  N2424 @` <  <Z ?"` *  M398 @` <  <0Z ?"` *  N1255 @` <  < [ ?"` *  M997 @` <  < [ ?"` *  O18284 @` <  <0 [ ?"` *  V Exposure PYs   @` <  <"[ ?"`   N1819 @` <  <5[?  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