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McNally, DO, FACP, FACG University Colorado Denver School of Medicine Center for Human Simulation Aurora, Colorado 80045Z>Siegel CA1&2, Marden SM2, Persing SM2, Larson RJ2, Sands BE3. ?           $ $((,, 00Risk of Lymphoma Associated with Combination of Anti-Tumor Necrosis Factor and Immunomodulator Therapy for the Treatment of Crohn s Disease: A Meta-Analysis Clin Gastroenterol and Hepatol. 2009;7:874-881.  IntroductionCrohn s disease is a chronic inflammatory disorder afflicting roughly 600,000 Americans. The disorder strikes men and women in equal proportions, usually between the ages of 15-35 yrs. The disease is chronic without cure and medical treatment is directed at blocking excessive intestinal inflammation. Even with effective medical therapy, surgery is required in 50-60% of patients with this disorder. Anti-TNF drugs have been an major medical advance in the treatment of moderate to severe Crohn s disease, but concerns over increased risk for malignancy and infection with anti-TNF drugs have tempered clinical use.pPp4# IntroductionAnti-TNF drugs have been associated with small, but significant increased risk for infections, especially TB and opportunistic infections. Anti-TNF drugs have been association with an increased incidence for malignancy, specifically Non Hodgkin's Lymphoma (NHL) and Non Melanoma Skin Cancer (NMSC). Estimation of the true risk for malignancy with Anti-TNF drugs is confounded by study design, limited longitudinal follow up, and the co-administration of other treatments known to independently increase this risk [Azathioprine (AZA), 6-mercaptopurine (6MP), methotrexate (MTX)]..JZGJAim`The authors sought to determine the most reliable estimate of Anti-TNF related rates of NHL in patients with Crohn s disease from an extensive literature search: MEDLINE, EMBASE, Cochrane Collaboration and Web of Science. Comparisons were made with expected cancer rates derived from the National Cancer Institute (NCI), Surveillance Epidemiology and End Results (SEER) data base. http://seer.cancer.gov/csr/1975_2006/index.html &Z1.F9/Study Design: Meta-AnalysisRequirements for Inclusion in Meta-Analysis Study Design Randomized Clinical Trial (RCT) Prospective or Retrospective Cohort Case Series of Consecutive pts All Articles or Abstracts must be published Anti-TNF Treatment Infliximab (IFX) Adalimumab (ADA) Certolizumab (CTZ) Only Crohn s disease patients Outcomes reported & median follow up > 48 wk, c" A5" K, cA  5CStudy Design: Meta-AnalysisResults: Meta-AnalysisICharacteristics of Included Studies Total of 26 studies involving 8,905 pts Study Type RCT n = 9 Cohort n = 3 Case Series n = 14 Patient Mean age 36.9 yr Mean duration of disease 9.3 yr Treatment IFX n = 22 studies ADA n = 3 studies CTZ n = 1 study 77% of pts concomitantly treated with immunomodulator drug. |$40D~$40D  } Study 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   m+Results: Rates of NHL Observed vs. Expected,,Observed NHL 13 lymphomas in 21,178 pt-yrs Rate 6.1 NHL per 10,000 pt yrs Expected NHL Comparator SEER 1.9 per 10,000 pt-yrs http://seer.cancer.gov/. (Accessed on 6 November 2007) x ?5! ?5  !Results: Rates of NHL for SEER, Immunomodulator, and Anti-TNF Treated PatientsPP=+Results: Age/Gender Specific NHL Rate & SIR,,NCharacteristics of Crohn s Pts with NHLHStudy Results: Rates SEER, Immunomodulator, & Anti-TNF Treated PatientsII1Rate of NHL by Subgroup Analysis of Study Design@Sensitivity Analysis Excluding Studies With > 15% Drop-Out Rate  Study Summary2 Use of Anti-TNF drugs for the treatment of Crohn's disease is associated with an increased risk for NHL. Absolute risk for NHL among these patients is: 6.1 per 10,000 pt-yrs (NHL Meta-Analysis) or 3x greater than the expected 1.9 per 10,000 pt-yrs (NHL SEER rate) P-P*P&PP8  f&  Study Summary The majority of pts with NHL were receiving BOTH Anti-TNF and Immunomodulator Rx. 10 of 13 (77%) reported NHL patients were on both Anti-TNF & Immunomodulator Rx. 2 of 13 (15%) reported NHL patients were on Anti-TNF, but Immunomodulator Rx use was not reported. 1 of 13 (8%) reported NHL patients were on ONLY Anti-TNF.8TPPSn:TLh Study SummaryV Overall risk for NHL for Crohn s patients given both Anti-TNF and an Immunomodulator Rx seems to be greater for men and patients older than 55 yrs. At least 4 patients were discovered to have NHL after the 1st infusion of Anti-TNF. This might suggest that the effect of even one dose may be significant to increase lymphoma risk or alternatively that a significant number of NHL pts in this report were just pre-clinical.:   B?Reviewer CommentsSiegel, et al, do not answer the following questions? What is the risk for NHL among newly diagnosed  nave Crohn s patients receiving only Anti-TNF drugs? 77% of the patients with NHL in this study received both Anti-TNF & Immunomodulator Rx. Only one of the 13 (7%) reported cases of NHL was receiving ONLY Anti-TNF.N7j" " 7jJI`Reviewer Comments/The investigators included one Case Series study with obvious outlier data. When the data from the Ljung study are excluded from the Case Series data, the SIR to SEER NHL rate is calculated to be 2.7 which is comparable to the rates derived for both the RCT and Cohort groups, 2.6 and 2.3 respectively.0" P0Reviewer CommentsThe first Anti-TNF drug approved for the treatment of Crohn s Disease (IFX) is chimeric. It is more commonly associated with neutralizing antibody formation than ADA or CTZ. This lead to the common practice of Anti-TNF immunomodulator co-therapy. Now we are left to retrospectively review the influence of past practices/conventions of combination therapy as they relate to risk for NHL and opportunistic infections. As shown in this study combination Anti-TNF and Immunomodulators are associated with an increased risk for HNL  albeit small 6.1 per 10,000 pt-yr vs. 1.9 per 10,000 pt-yr (SEER). The risk for NHL for  naive Crohn s pts receiving mono Anti-TNF ( ADA or CTZ) needs to be examined..Z" Zn$Reviewer CommentsRecent reports of the Sonic trial suggest that IFX and Immunomodulator combination therapy is better at maintaining remission than mono therapy. 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S  6p{_ OPn  ~ >*   6_ O n ~ @* H  0޽h#6 ? 3380___PPT10. 8(    0 M P  ~ >*   0 {\   ~ @*   6@L OPn  ~ >*   6L O n ~ @* H  0޽h#6 ? 3380___PPT10. `  2(  ~  s *B ~ ~  s *p@p  ~   c J@A$ da_Vinci_Sketch_13"rZ  C 2AHeader_NONEpH  0޽h ? 33___PPT10u.8dW+D=' = @B +` pT(  px p c $q\N ~  p  <LԔ S"   ~  p 00H  ~1Dartmouth-Hitchcock IBD Center, Lebanon, New Hampshire, 2Dartmouth Institute for Health Policy and Practice, Hanover, NH, 3MGH Crohn s and Colitis Center and Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Mass.f|( _ 8 A   H p 0޽h ? Oa(___PPT10u.e+D=' C= @B +? ` JBx(  xx x c $ L  ~  x  0 Lo pp ~  x 0LC"?` Lichtenstein GR, et al. Management of Crohn s Disease in Adults. AM J Gastroenterol. 2009 Feb;104(2):465-83.  n 2lH x 0޽h ? Oa(___PPT10u. w;+D=' C= @B +I ` TL(  x  c $@K  ~    0gHo  ~   0BHC"?` Lichtenstein GR, et al. Management of Crohn s Disease in Adults. AM J Gastroenterol. 2009 Feb;104(2):465-83. *n 2lH  0޽h ? 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FPK!5傄drs/downrev.xmlDN@&䚸10Eie FJBv.mq~H[މ \-:ؑ0&V֦[|@#QYCz򰘟05:nC" T!4羨HچLi 1Kmkůd5&>TcE[ H};,ݏiB\^tunCH7$MwyjA 7PK-!Zf[Content_Types].xmlPK-!1_a /_rels/.relsPK-!/۬*drs/shapexml.xmlPK-!5傄drs/downrev.xmlPK  5Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881"6l _26BH  0޽h ? Oa(___PPT10u.@P1+D=' = @B +6  ` A 9 p (  ~  s *`  ~    <pԔ S" ` ~ U  lPoaoao?Text Box 35#"&@PK!Zf[Content_Types].xmlMO &2WR=cJ`F0iK`#̼vLw 9uSq:w`G ^i ½KI)c/ $oVjTMRc|}042ҥCƔM̏P~*ka/8^DkHbL8e i"K\XN\6rco4y@_;oPK!1_a _rels/.relsj0 ѽqCNo^K [ILcX&m߾0XFo;>0xM e`|X}đ I`߽N4aG2$RKIZ)4(M9`ctB{m:f@`3n|O,ܗr޾jxR0T ,0@}WBLǬ5vPK!/۬drs/shapexml.xmlUMo6 x-V;* 'ˆ炒( E $}CʎSA4#̛7_vyeMίdISJMɡmFTy·?rdAnC u A](/@<6n^s~3G }V%mGN/П5*HǴjr>J n8&1ҳPSP3T P "FP SB|Bܹ8ܵs0z&$0d>AKż觏G]=%3x{9zLU$ >$h*Y?bz &?R,̓{!`5aV//TfBJZuD$dڬ2e\!įȣwYWߖ:|=jzkс oKѭN7u@-p},U}軡H!fHSRX :kTcUHQΥFq. FPK!5傄drs/downrev.xmlDN@&䚸10Eie FJBv.mq~H[މ \-:ؑ0&V֦[|@#QYCz򰘟05:nC" T!4羨HچLi 1Kmkůd5&>TcE[ H};,ݏiB\^tunCH7$MwyjA 7PK-!Zf[Content_Types].xmlPK-!1_a /_rels/.relsPK-!/۬*drs/shapexml.xmlPK-!5傄drs/downrev.xmlPK  5Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881"6l _26BH  0޽h ? Oa(___PPT10u.@P1+D=' = @B +6  ` A 9  (  ~  s *P  ~    <Ԕ S"  ~ U  l0oaoao?Text Box 35#"&@PK!Zf[Content_Types].xmlMO &2WR=cJ`F0iK`#̼vLw 9uSq:w`G ^i ½KI)c/ $oVjTMRc|}042ҥCƔM̏P~*ka/8^DkHbL8e i"K\XN\6rco4y@_;oPK!1_a _rels/.relsj0 ѽqCNo^K [ILcX&m߾0XFo;>0xM e`|X}đ I`߽N4aG2$RKIZ)4(M9`ctB{m:f@`3n|O,ܗr޾jxR0T ,0@}WBLǬ5vPK!/۬drs/shapexml.xmlUMo6 x-V;* 'ˆ炒( E $}CʎSA4#̛7_vyeMίdISJMɡmFTy·?rdAnC u A](/@<6n^s~3G }V%mGN/П5*HǴjr>J n8&1ҳPSP3T P "FP SB|Bܹ8ܵs0z&$0d>AKż觏G]=%3x{9zLU$ >$h*Y?bz &?R,̓{!`5aV//TfBJZuD$dڬ2e\!įȣwYWߖ:|=jzkс oKѭN7u@-p},U}軡H!fHSRX :kTcUHQΥFq. FPK!5傄drs/downrev.xmlDN@&䚸10Eie FJBv.mq~H[މ \-:ؑ0&V֦[|@#QYCz򰘟05:nC" T!4羨HچLi 1Kmkůd5&>TcE[ H};,ݏiB\^tunCH7$MwyjA 7PK-!Zf[Content_Types].xmlPK-!1_a /_rels/.relsPK-!/۬*drs/shapexml.xmlPK-!5傄drs/downrev.xmlPK00  5Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881"6l _26BH  0޽h ? Oa(___PPT10u.@P1+D='  = @B +  ` '   (  ~  s *O  ~    0C`>   ~ $8@08XU  lI`oaoao?Text Box 35#"&@PK!Zf[Content_Types].xmlMO &2WR=cJ`F0iK`#̼vLw 9uSq:w`G ^i ½KI)c/ $oVjTMRc|}042ҥCƔM̏P~*ka/8^DkHbL8e i"K\XN\6rco4y@_;oPK!1_a _rels/.relsj0 ѽqCNo^K [ILcX&m߾0XFo;>0xM e`|X}đ I`߽N4aG2$RKIZ)4(M9`ctB{m:f@`3n|O,ܗr޾jxR0T ,0@}WBLǬ5vPK!/۬drs/shapexml.xmlUMo6 x-V;* 'ˆ炒( E $}CʎSA4#̛7_vyeMίdISJMɡmFTy·?rdAnC u A](/@<6n^s~3G }V%mGN/П5*HǴjr>J n8&1ҳPSP3T P "FP SB|Bܹ8ܵs0z&$0d>AKż觏G]=%3x{9zLU$ >$h*Y?bz &?R,̓{!`5aV//TfBJZuD$dڬ2e\!įȣwYWߖ:|=jzkс oKѭN7u@-p},U}軡H!fHSRX :kTcUHQΥFq. FPK!5傄drs/downrev.xmlDN@&䚸10Eie FJBv.mq~H[މ \-:ؑ0&V֦[|@#QYCz򰘟05:nC" T!4羨HچLi 1Kmkůd5&>TcE[ H};,ݏiB\^tunCH7$MwyjA 7PK-!Zf[Content_Types].xmlPK-!1_a /_rels/.relsPK-!/۬*drs/shapexml.xmlPK-!5傄drs/downrev.xmlPK  5Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881"6l _26BH  0޽h ? Oa(___PPT10u.ߺ+D=' `R`= @B +& ` %%+HZ%(  ~  s *@`1  ~    6a> 0 ~ $8@08XU  laoaoao?Text Box 35#"&@PK!Zf[Content_Types].xmlMO &2WR=cJ`F0iK`#̼vLw 9uSq:w`G ^i ½KI)c/ $oVjTMRc|}042ҥCƔM̏P~*ka/8^DkHbL8e i"K\XN\6rco4y@_;oPK!1_a _rels/.relsj0 ѽqCNo^K [ILcX&m߾0XFo;>0xM e`|X}đ I`߽N4aG2$RKIZ)4(M9`ctB{m:f@`3n|O,ܗr޾jxR0T ,0@}WBLǬ5vPK!/۬drs/shapexml.xmlUMo6 x-V;* 'ˆ炒( E $}CʎSA4#̛7_vyeMίdISJMɡmFTy·?rdAnC u A](/@<6n^s~3G }V%mGN/П5*HǴjr>J n8&1ҳPSP3T P "FP SB|Bܹ8ܵs0z&$0d>AKż觏G]=%3x{9zLU$ >$h*Y?bz &?R,̓{!`5aV//TfBJZuD$dڬ2e\!įȣwYWߖ:|=jzkс oKѭN7u@-p},U}軡H!fHSRX :kTcUHQΥFq. FPK!5傄drs/downrev.xmlDN@&䚸10Eie FJBv.mq~H[މ \-:ؑ0&V֦[|@#QYCz򰘟05:nC" T!4羨HچLi 1Kmkůd5&>TcE[ H};,ݏiB\^tunCH7$MwyjA 7PK-!Zf[Content_Types].xmlPK-!1_a /_rels/.relsPK-!/۬*drs/shapexml.xmlPK-!5傄drs/downrev.xmlPK  5Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881"6l _26B p H #"&S2)22p ~ A <pa ?"`   S9.4 @` ? <pa ?"`l   T18.8 @` = <a ?"`E l  T2125 @` ; < a ?"`M E  Q4 @` 9 <a ?"` M  Z Case Series*   @`  <a?  O2.7 @`  <b?   O2.3 @`   <b?O   O2.6 @`   <@b?pO  W SIR to SEER   @`   <P!b?l  O5.2 @`   <,b?E l  P1923 @`  <6b?M E M1 @`  <pAb? M W Case Series** @`  <pLb?l   O4.6 @`  < Wb?E l  R15,192 @`  <ab?M E  M7 @`  <lb? M  RCohort @`  <0wb?l O   O5.2 @`  <b?EO l  P3860 @`  <b?MO E  M2 @`  <@b?O M  ORCT @`  <b?l pO  bNHL per 10,000 pt-yrs @`  <b?Epl O  RPt-Yrs @`  <b?MpEO  ONHL @`  <b?pMO  RDesign @``B  0o ?ppZB   s *1 ?O O ZB ! s *1 ?  ZB " s *1 ?  `B # 0o ?`B $ 0o ?pZB % s *1 ?MpMZB & s *1 ?EpEZB ' s *1 ?l pl ZB ( s *1 ?p`B ) 0o ?pZB : s *1 ?   G 0b0P} Z* Calculations includes Ljung T, et al, data. ** Calculations excludes Ljung, et al, data[ 2[H  0޽h ? Oa(___PPT10u.ߺ+D=' 8= @B +  ` '   (  ~  s *Yc1  ~    0Pac> ` P ~ $8@08XU  loaoao?Text Box 35#"&@PK!Zf[Content_Types].xmlMO &2WR=cJ`F0iK`#̼vLw 9uSq:w`G ^i ½KI)c/ $oVjTMRc|}042ҥCƔM̏P~*ka/8^DkHbL8e i"K\XN\6rco4y@_;oPK!1_a _rels/.relsj0 ѽqCNo^K [ILcX&m߾0XFo;>0xM e`|X}đ I`߽N4aG2$RKIZ)4(M9`ctB{m:f@`3n|O,ܗr޾jxR0T ,0@}WBLǬ5vPK!/۬drs/shapexml.xmlUMo6 x-V;* 'ˆ炒( E $}CʎSA4#̛7_vyeMίdISJMɡmFTy·?rdAnC u A](/@<6n^s~3G }V%mGN/П5*HǴjr>J n8&1ҳPSP3T P "FP SB|Bܹ8ܵs0z&$0d>AKż觏G]=%3x{9zLU$ >$h*Y?bz &?R,̓{!`5aV//TfBJZuD$dڬ2e\!įȣwYWߖ:|=jzkс oKѭN7u@-p},U}軡H!fHSRX :kTcUHQΥFq. FPK!5傄drs/downrev.xmlDN@&䚸10Eie FJBv.mq~H[މ \-:ؑ0&V֦[|@#QYCz򰘟05:nC" T!4羨HچLi 1Kmkůd5&>TcE[ H};,ݏiB\^tunCH7$MwyjA 7PK-!Zf[Content_Types].xmlPK-!1_a /_rels/.relsPK-!/۬*drs/shapexml.xmlPK-!5傄drs/downrev.xmlPK  5Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881"6l _26BH  0޽h ? Oa(___PPT10u.ߺ+D=' cn= @B +  ` '   (  ~  s *`Ed  ~    0Md>   ~ $8@08XU  leoaoao?Text Box 35#"&@PK!Zf[Content_Types].xmlMO &2WR=cJ`F0iK`#̼vLw 9uSq:w`G ^i ½KI)c/ $oVjTMRc|}042ҥCƔM̏P~*ka/8^DkHbL8e i"K\XN\6rco4y@_;oPK!1_a _rels/.relsj0 ѽqCNo^K [ILcX&m߾0XFo;>0xM e`|X}đ I`߽N4aG2$RKIZ)4(M9`ctB{m:f@`3n|O,ܗr޾jxR0T ,0@}WBLǬ5vPK!/۬drs/shapexml.xmlUMo6 x-V;* 'ˆ炒( E $}CʎSA4#̛7_vyeMίdISJMɡmFTy·?rdAnC u A](/@<6n^s~3G }V%mGN/П5*HǴjr>J n8&1ҳPSP3T P "FP SB|Bܹ8ܵs0z&$0d>AKż觏G]=%3x{9zLU$ >$h*Y?bz &?R,̓{!`5aV//TfBJZuD$dڬ2e\!įȣwYWߖ:|=jzkс oKѭN7u@-p},U}軡H!fHSRX :kTcUHQΥFq. FPK!5傄drs/downrev.xmlDN@&䚸10Eie FJBv.mq~H[މ \-:ؑ0&V֦[|@#QYCz򰘟05:nC" T!4羨HچLi 1Kmkůd5&>TcE[ H};,ݏiB\^tunCH7$MwyjA 7PK-!Zf[Content_Types].xmlPK-!1_a /_rels/.relsPK-!/۬*drs/shapexml.xmlPK-!5傄drs/downrev.xmlPK  5Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881"6l _26BH  0޽h ? Oa(___PPT10u.ߺ+D=' e0= @B +$@ t4(  td t c $    ~ t s *L 0  ~  H t 0޽h#6 ? 3380___PPT10. @8@@ |P(  |d | c $    ~ | s *@L 0  ~ : H | 0޽h#6 ? 3380___PPT10. 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