Monitoring  IBD  Pa.ents:  Drug  Levels,  An.body  Tests  and  Fecal  

Calprotec.n  CDDW  2014  

Drs  J.  Jones  and  B.  Bressler  February  2014  

Disclosures  

•  Dr  Jones  – Consul.ng,  educa.onal  support  and  speaker  bureau  for  Takeda,  Janssen  Inc.,  Abbvie,  SHIRE  

•  Dr  Bressler  – Consul.ng,  educa.onal  support  and  speaker  bureau  for  Takeda,  Janssen  Inc.,  Abbvie,  SHIRE,  Ferring,  Aptalis,  Warner  ChilcoN  

2014  CDDW/CASL  Winter  Mee3ng  

ü Medical Expert (as Medical Experts, physicians integrate all of the CanMEDS Roles, applying medical knowledge, clinical skills, and professional attitudes in their provision of patient-centered care. Medical Expert is the central physician Role in the CanMEDS framework.)

Communicator (as Communicators, physicians effectively facilitate the doctor-patient relationship and the dynamic exchanges that occur before, during, and after the medical encounter.)

ü Collaborator (as Collaborators, physicians effectively work within a healthcare team to achieve optimal patient care.)

ü Manager (as Managers, physicians are integral participants in healthcare organizations, organizing sustainable practices, making decisions about allocating resources, and contributing to the effectiveness of the healthcare system.)

Health Advocate (as Health Advocates, physicians responsibly use their expertise and influence to advance the health and well-being of individual patients, communities, and populations.)

ü Scholar (as Scholars, physicians demonstrate a lifelong commitment to reflective learning, as well as the creation, dissemination, application and translation of medical knowledge.)

ü

Professional (as Professionals, physicians are committed to the health and well-being of individuals and society through ethical practice, profession-led regulation, and high personal standards of behaviour.)

CanMEDS Roles Covered:

Objec.ves  •  To  understand  in  what  clinical  circumstances  drug  levels  /  an.-­‐drug  an.body  levels  should  be  ordered  

•  To  understand  in  what  clinical  circumstances  fecal  calprotec.n  (FC)  should  be  ordered.  

•  To  gain  knowledge  of  the  evidence  for  the  use  of  drug  levels  /  an.-­‐drug  an.body  tes.ng  and  fecal  calprotec.n  in  IBD  

•  To  understand  how  to  interpret  and  respond  to  the  results  of  drug  levels/  an.  drug  an.bodies  and  fecal  calprotec.n  in  IBD  

Case  1  

– Ms.  Jones  is  a  32  year  old  female  with  well  characterized  ileocolonic  Crohn’s  disease  who  you  are  seeing  in  your  office  with  a  disease  flare.  

– The  pa.ent  was  diagnosed  5  years  ago.  Although  ini.ally  steroid  dependent  she  entered  a  steroid  free  clinical  remission  3  years  ago  on  AZA  2  mg/kg  body  weight.  No  EIMIBD.    

– She  has  been  experiencing  diarrheal  symptoms  with  10  to  12  BM  per  day  in  associa.on  with  lower  abdominal  cramping  as  well  as  10  lb  weight  loss  over  the  past  6  months  

Case  1:  Ques.on  

1.  What  tests  should  be  ordered  now?  

Fecal  Calprotec.n  Correlates  More  Closely  With  SES-­‐CD  Than  CRP,  Blood  Leukocytes,  and  the  CDAI  

Scatterplot demonstrating the correlation of the Simple Endoscopic Score of Crohn’s Disease (SES-CD) with fecal calprotectin (Spearman’s rank correlation coefficient r=0.75, P<0.001).

Schoepfer AM, et al. Am J Gastroenterol. 2010;105:162-169.

MAJOR RESULTS

Fecal  Calprotec.n  Correlates  More  Closely  With  SES-­‐CD  Than  CRP,  Blood  Leukocytes,  and  the  CDAI  

Schoepfer AM, et al. Am J Gastroenterol. 2010;105:162-169.

MAJOR RESULTS

Case  1  .  .  .  

–  laboratory  inves.ga.ons  reveal  the  following  abnormali.es:  Hb  96  (MCV  68);  PLT  800;  Alb  20;  hsCRP  100;  ferri.n  5;  fecal  Cp  500.  Stool  neg  for  enteric  pathogens.  

–  Ileocolonoscopy  (by  yourself)  demonstrates  ac.ve  inflamma.on  characterized  by  the  presence  of  large  ulcera.ons  (>  1cm)  and  patchy  erythema  throughout  the  ileum  and  en.re  colon  (rela.ve  rectal  sparing).  

Colonoscopy  

TI   Colon  

A  Combina.on  of  Fecal  Calprotec.n  and  hsCRP    to  Predict  Mucosal  Healing*  A  subanalysis  of  the  STORI  trial  

 

78%

39%

82% 74%

53% 72%

Sensitivity

Specificity

hsCRP <5 mg/L Calpro ≤250 µg/g hsCRP <5 mg/L and Calpro ≤250 µg/g

Lémann M, et al. UEGW 2010, Barcelona, Spain, October 23-27:OP370.

* Defined as CDEIS ≤3

Schoepfer AM. Inflamm Bowel Dis 2009;15:1851-8

Correla.on  of  Faecal  Calprotec.n  With  Endoscopic  Ac.vity  in  UC  

Controlled  clinical  data  not  as  convincing  

Feagan  B  et  al  NEJM  2013  

Case  1  .  .  .  

•  You  discuss  remaining  treatment  op.ons  with  the  pa.ent  and  she  decides  to  start  infliximab.  

•  You  prescribe  prednisone  40  mg  po  OD  while  she  awaits  provincial  reimbursement.  AZA  is  con.nued.  

•  One  week  later  she  starts  infliximab  induc.on  dosing  at  weeks  0,  2  and  6.  

•  You  see  her  back  in  your  office  3  months  aker  ini.a.on  of  infliximab  

Case  1:  Follow-­‐up  Visit  

•  Ms.  Jones  tells  you  that  she  is  feeling  great!  •  She  is  having  1  to  2  formed  BM  per  day  &  stools  are  formed  &  non  bloody  

•  She  has  regained  5  lbs  •  Labs:  Hb  110  (aker  iron  supplementa.on);  PLT  200;  Alb  28;  hsCRP  15;  Fe  26  

•  Fecal  CP:  180  

Case  1:  Ques.ons  

1.  Are  you  sa.sfied  with  Ms.  Jones’s  clinical  and  biochemical  response  to  infliximab  therapy?  

2.  If  not  what  lab  values  are  of  concern  to  you  and  how  would  you  interpret  them  in  the  context  of  this  case?  

3.  Are  there  any  addi.onal  tests  that  you  would  like  to  order?  

Empiric  vs.  TDM  

Loss  of  response  (or  inadequate  response?)  

81 %

19%

0.7

Shorten interval

Increase dose

Stop IFX

If shortening the interval, 72% shorten to q6w

A survey of 336 Canadian gastroenterologists asked: What do you do when patient loses response?

Jones J. et al. Can J Gastroenterol 2011;25(10):565-9.

Patients who re-established clinical response after crossover due to medication change: Patients Randomized as Responders (ACCENT I Trial: All Patients)

Janssen, Data on file

86 84 79

0

20

40

60

80

100

Single Dose 5 mg/kg 10 mg/kg

Frac

tion

of P

atie

nts

(%)

Op3mizing  beEer  than  Switching  within  class  

 

Consider  Dose  Op3misa3on  with  Current  An3-­‐TNF  Prior  to  Switching:    

 

ADA Dose: 160/80 160/80 80/40 40 mg EOW All patients IFX-naïve IFX-experienced

Remission at 4 weeks Maintenance of remission in Week-4 responders (CHARM)

Adapted from: Hanauer SB, et al. Gastroenterology 2006;130(2):323-33, Colombel JF, et al. Gastroenterology 2007;132(1):52-65, Sandborn WJ, et al. Ann Intern Med 2007;146(12):829-38.

21

Simple  Algorithm  

ATI  nega3ve   ATI  posi3ve  

IFX  less  than  threshold  

Increase  Dose   Switch  Agents  (high  .tre  ATI)  

OR  Dose  Op.mize  (low  

.tre  ATI)  

IFX  greater  than  threshold  

Re-­‐evaluate  for  ac.ve  disease  

Switch  Agent  

Khanna  R  et  al  APT  2013  

Result: Detectable ATI Result: Subtherapeutic IFX

Afif W, et al. Am J Gastroenterol 2010;105(5):1133-9.

p <0.004

Frac

tion

of P

ts

With

Res

pons

e (%

)

n = 12 n = 17 Increase

IFX Change Anti-TNF

n = 29 n = 6 Increase

IFX Change Anti-TNF

p <0.016

Frac

tion

of P

ts

With

Res

pons

e (%

)

Prometheus ELISA assay

•  Single centre, retrospective study, n = 155 pts with TDM test •  177 tests assessed; subtherapeutic IFX defined as undetectable

trough or IFX<12 µg/ ml at 4 wks after infusion •  Patients with subtherapeutic IFX had a significantly increased response

when dose optimized as compared to switching within class

Monitoring  Infliximab  Values  and  An.bodies:  U.lity  

DESIGN  •  Randomized,  mul.center,  controlled,  12-­‐wk,  single-­‐blind  study  

OBJECTIVE  •   Assess  u.lity  of  monitoring  of  drug  and  related  Ab  to  op.mize  IFX  therapies  

•   CD  pts,  2°  failure  IFX  (N=69)  •   IFX  dose  intensifica.on  5  mg/kg  q  4  wks  (n=36)  or  tx  based  on  serum  [IFX]  or  IFX  Ab  values  (n=33)  

OUTCOMES  •   70%  pts  w/2°  failure:  +  [IFX]  and  undetectable  Ab  at  .me  of  failure    

•  20%  pts:  +  IFX  Ab,  sub-­‐therapeu.c  [IFX]  •   4%  pts:  undetectable  IFX  Ab,  sub-­‐therapeu.c  [IFX]  

•   6%  pts:  +  [IFX],  +  IFX  Ab  

OUTCOMES    

Steenholdt C, et al. Gut. 2013.

Treatment algorithm for patients with Crohn’s disease (CD) with secondary loss of response to infliximab (IFX). Ab=antibody; IV=intravenously; sc=subcutaneously; TNF=tumor necrosis factor

Monitoring  Infliximab  Values  and  An.bodies:  U.lity  

OUTCOMES          

 

Steenholdt C, et al. Gut. 2013.

•  270  IBD  pa.ents  on  IFX  maintenance  therapy.  All  pts  had  their  IFX  trough  levels  adjusted  to  3-­‐7  mg/ml.  

•  Pts  randomized  to  2  groups,  then  will  be  followed  for  1  year:    –  group  1:  IFX  trough  levels  maintained  at  3-­‐7  μg/ml    –  group  2:  dosing  and  op.miza.on  based  on  clinical  symptoms    

Individualized  IFX  Treatment  Using    Therapeu.c  Drug  Monitoring:  Baseline  Data  

Vande  Casteele  et  al.  ECCO  2012,  Abstract  OP11  

>  7  μg/ml  

3-­‐  7  μg/ml  (43  %)  

Undetectable  

<  3  μg/ml  

Serum  IFX  Trough  Levels  of  Pa3ents  in  Remission  (N  =  270)  

Dose  decreased  (26  %)   Dose  increased  

(22  %)  

Dose  increased  (9  %)  

(77  %  ATI-­‐posi3ve)  

TAXIT  

Drug  Level  and  Symptom  Based  Treatment  Produce  Similar  Outcomes  in  Pa.ents  with  IBD  

•  N  =  251  stable  IBD  pts  (178  CD,  85  UC)  on  IFX  therapy  had  their  TL  adjusted  to  3-­‐7  μg/ml  and  were  randomized  to  2  groups:    

•  Clinically**  or  TL  based:  IFX  TL  maintained  at  3-­‐7  μg/ml    •  CD/UC  dura3on  of  dis.  ~15/11  y  &  IFX  treatment  ~6/4  y,    con-­‐IS  ~5%  •  Treatment  guided  by  TL  resulted  in  less  rescue  therapy;  rates  of  clinical  &  biological  remission  were  similar  for  both  groups  

Vande  Casteele  et  al.  UEGW  2013,  Abstract  OP001  

TAXIT  

Primary  Endpoint:    Remission*  at  1  Year  

69 72

0 20 40 60 80

100

Clinically based

Level based

*Clinical  (HBI  ≤  4    or  pMayo  ≤  2)  and  biologic  (CRP  <  5  mg/l)  remission  **Clinically  based:  dosing  &  op3miza3on  based  on  symptoms  

Frac3o

n  of  Pa3

ents  (%

)  

P  =  NS  Characteris3cs   CB  

n  =  110  

LB  n  =  113  

P-­‐value  

IFX  TL    3-­‐7  µg/ml   56%   78%   <0.001  

ATI  +ve   2.7%   0%   0.1  

Required  rescue  therapy†   17.3%   5.5%   <0.01  

Secondary  Endpoints:  Aper  Maintenance  Phase  (1  Year)  

†Use  of  steroids  or  TNF-­‐op3miza3on/switch  

n  =  110   n  =  113  

Case  1  .  .  .  

•  You  order  a  trough  serum  infliximab  drug  and  an.body  level  and  it  reveals  infliximab  concentra.on  of  2  μg/ml  

•  The  ADA  level  is  undetectable  

Case  1:  Ques.on  

•  What  is  your  interpreta.on  of  these  results?  

•  How  would  you  respond  to  these  results?  

•  How  many  of  you  have  access  to  drug  level  and  ADA  tes.ng?  

•  How  many  have  access  to  FC  tes.ng?  

Case  1  .  .  .  

•  You  and  Ms.  Jones  decide  jointly  to  increase  the  infliximab  dose  to  10  mg  /  kg  body  weight  with  plans  to  repeat  a  colonoscopy  within  3  -­‐  6  months  if  the  FC  does  not  normalize  

•  Ms.  Jones  con.nues  to  do  well  clinically  and  aker  another  3  months  you  recheck  her  inflammatory  markers  –  hsCRP  5  –  FC  30  – All  other  laboratory  parameters  normal  

Normaliza.on  of  Fecal  Calprotec.n  Aker  Induc.on  Predicts  Clinical  Outcomes  in  Pa.ents  with  IBD  

Molander  et  al.  UEGW  2011,  poster  P0397  

•  N=72 (39 CD, 33 UC) pts treated with IFX (n=49) or ADA (n=23) induction and maintenance therapy. Clinical remission defined by partial Mayo or HBI

•  Cut-off concentration of 139 µg/g for FC had 71% sensitivity and 82% specificity to predict risk of active disease within 1 year

81  

31  

0  

25  

50  

75  

100  

Normal  calprotec3n  aper  induc3on    

Elevated  calprotec3n  aper  induc3on  

p<0.001

Percen

t  pa3

ents  (%

)  

11/35  30/37  

Pa3ents  in  Clinical  Remission  at  12  Months  

median  41  μg/g  (0-­‐97)  

median  424  μg/g  (114-­‐5859)  

Case  1  .  .  .    

•  You  con.nue  to  follow  her  every  6  months  •  One  year  later  you  see  her  in  clinic  and  she  has  developed  .nea  versicolor.  She  has  also  started  to  experience  alopecia.  

•  However,  clinically  she  con.nues  to  do  excep.onally  well    

•  Her  laboratory  parameters  remain  normal  save  for  mild  lymphopenia.    

Case  1:  Ques.ons  

1.  Do  you  have  any  concerns  about  Ms.  Jones’s  presenta.on  a  this  .me?  

2.  How  would  you  advise  Ms.  Jones  at  this  .me?  

3.  Are  there  any  other  inves.ga.ons  you  might  order  at  this  .me?  

Case  1  .  .  .  

•  You  have  concerns  about  cell  mediated  immunity  and  opt  to  repeat  the  serum  infliximab  drug  level  again  

•  The  trough  serum  infliximab  concentra.on  is  15  μg/ml  

Case  1  .  .  .  

•  You  decrease  the  pa.ent’s  infliximab  dose  to  7.5  mg/kg  of  body  weight  and  con.nue  to  follow  Ms.  Jones  q  12  months  

•  She  does  well  long  term  

Case  2  

•  Mr.  Smith  is  a  25  year-­‐old  male  who  you  have  been  following  for  ileal  CD  for  4  years.  

•  He  exhibited  steroid  refractory  disease  early  in  his  disease  course  and  has  been  on  maintenance  therapy  with  combo  azathioprine  175  mg  daily  (51  kg)  and  infliximab  5  mg/kg  q  8  week  intervals  for  2  years  

Case  2  .  .  .  

•  While  undergoing  an  orthopedic  procedure  8  months  ago  he  had  a  16  week  hiatus  between  infliximab  infusions  

•  You  are  seeing  him  in  clinic  in  follow-­‐up  and  he  presents  with  worsening  symptoms  of  RLQ  abdominal  pain,  increased  stool  frequency  (5-­‐6  loose  non-­‐bloody  stools  per  day)  and  post-­‐prandial  bloa.ng  

Case  2  .  .  .  

•  You  elect  to  reevaluate  the  pa.ent’s  disease  ac.vity,  extent  and  severity  – Lab:  Hb  110  (microcy.c);  Fe  12;  WBC  12;  PLT  400;  hsCRP  5;  Alb  22;  FC  350  

– CTE:  long  segment  inflammatory  CD  (25cm)  with  bowel  wall  thickening,  enhancement  and  comb  sign  

–  Ileocolonoscopy:  Inflammatory  stricture  at  the  ICV  with  ulcera.on,  edema  and  friability  

CT  Enterography  

Case  2:  Ques.ons  

•  What  would  you  do  next?  

a.  Stop  current  therapy  and  switch  to  another  an.-­‐TNF?  

b.  Empirically  increase  the  infliximab  dose?  c.  Increase  the  azathioprine?  d.  Check  the  pa.ent’s  infliximab  drug  and  an.body  

levels?  

Calprotec.n  as  a  possible  predictor  of    symptoma.c  relapse  

De  Surray  N.  ECCO  2012:  P274  

STORI:  calprotec3n  data  months  before  relapse  

0  

800  

–14  

600  

400  

200  

–12   –10   –8   –6   –4   –2   0  Time  before  relapse  (months)  

Calpro  (m

icrog/g)  

p=0.0004  

Relapsers  

Non-­‐relapsers  

STORI  enrolled  115  Crohn's  disease  pa3ents  who  were  treated  with  infliximab  plus  an  immunomodulator  for  at  least  1  year,  and  who  were  in  stable  remission  for  at  least  6  months.  Infliximab  was  discon3nued,  and  39%  of  pa3ents  relapsed  within  1  year.    

Case  2  .  .  .  

•  You  elect  to  recheck  the  infliximab  trough  and  ADA  levels  

Ø Serum  infliximab  trough  level:  1  μg/ml  

Ø ADA  level  was  detectable  at  10  Au/ml  

 

Case  2:  Ques.ons  

1.  How  do  you  interpret  these  results  in  light  of  this  case?  

2.  How  would  you  respond  to  these  lab  results?  

Summary  •  Measurement  of  infliximab  trough  levels  and  ADA  levels  is  clinically  useful  –  Primary  non-­‐responder  or  par.al  responder  – Maintenance  therapy  –  Infec.ous  and  immune  mediated  complica.ons  

•  Unclear  as  to  long  term  outcomes  from  TDM  based  interven.ons  

•  FC  is  a  useful  adjunct  in  the  management  of  IBD  – Within  individual  comparisons  to  baseline  concentra.ons  to  guage  response  to  therapy  and  predict  disease  relapse  

•  Its  accuracy  and  reliability  as  a  surrogate  if  intes.nal  inflamma.on  is  s.ll  under  study