NOR-DRUM Study: TNF Inhibitor Therapeutic Drug Monitoring is Effective Save

New research presented this week at ACR Convergence, the American College of Rheumatology’s annual meeting, shows that proactive therapeutic drug monitoring, a newer treatment strategy where a patient’s drug serum levels are regularly assessed to adjust the dose and intervals, controlled disease more effectively than standard therapy with infliximab, a tumor necrosis factor (TNF) inhibitor (Abstract #1946). This data will be presented on Tuesday November 8th, at 2:45pm EST during a session entitled: Spondyloarthritis Including PsA – Treatment II: Biologic Therapies (1943–1946).

TNF inhibitors  approved by  the  FDA  include  infliximab,  adalimumab,  etanercept,  golimumab  and certolizumab  pegol.  In  healthy  individuals,  excess  TNF in  the  blood  is  blocked naturally,  but  in those  who  have rheumatic  conditions,  higher  levels  of  TNF in  the  blood lead to  more inflammation and  persistent  symptoms.  These medications  can  alter  a disease’s  effect  on  the body  by  controlling  inflammation in  the joints,  gastrointestinal  tract, and  skin.   

Therapeutic  drug  monitoring  has  been  proposed to improve  safety  and  efficacy  for  patients taking  these  drugs  regularly  as  maintenance  therapy.  Patients’  blood  samples  are tested according  to  a schedule  to  check  drug  serum  levels,  then  their  medication  dose  and  treatment intervals,  or  how  often  they  receive  infusions  or  injections,  are  adjusted  according  to  an algorithm.  Researchers  conducted  this  52-week,  randomized,  controlled,  open-label  multicenter trial  to  find  out  if  therapeutic  drug  monitoring  prevents  disease flares  compared  to  a  standard approach.   

“By  optimizing  drug  concentrations  and  facilitating  early  detection  of  anti-drug  antibodies, proactive therapeutic  drug monitoring  has  the potential  to  prevent  treatment  failure  and  has been  proposed  to improve long-term  efficacy  of  TNF inhibitors,”  says  Silje Watterdal  Syversen, MD,  PhD,  a rheumatologist  at  Diakonhjemmet  Hospital  in  Oslo,  Norway,  and  the  study’s  author. “Treatment  recommendations  differ  with  respect  to  the use  of  proactive  monitoring  during maintenance  therapy  with  TNF inhibitors  within  rheumatology  as  well  as  gastroenterology  and dermatology,  mainly  due  to  lack  of  data from  randomized  controlled  trials.”

The trial  randomized  patients  to  be treated  with  infliximab,  a  TNF  inhibitor,  with  either therapeutic  drug  monitoring  or  standard  therapy  schedule  for  a  minimum  of  30  weeks  between June  2017  and  December  2019. Participants  (458)  had  a  variety  of  immune-mediated inflammatory  diseases  including  rheumatic  diseases:  79 with  rheumatoid  arthritis,  138  with spondyloarthritis,  and  53 with  psoriatic  arthritis.  Patients  in  the  monitoring  group had  their infliximab dose  and  treatment  intervals  carefully  adjusted  to  keep  serum  drug levels  within the range  of  3-7  mg/L.  Infliximab  dosing  and intervals  for  patients  in  the  standard  therapy  group were  adjusted  based on  the  doctor’s  clinical  judgment.  The  primary  outcome for  the trial  was sustained  disease  control  without  disease  worsening based  on  specific  scores  or  an  agreement between  the  doctor  and patient  that  prompted a  major  change  in treatment.

During the  one  year  of  follow-up,  167  patients  in  the  monitoring  group  achieved  sustained disease control  without  disease  worsening  compared to 127  patients  in  the  standard  therapy group.  These results  remained  consistent  in  sensitivity  analyses.  When  investigators  compared disease activity  and patient-reported  outcomes  at  week  52,  they  found no  significant  differences between  the  two  groups.  The  mean  infliximab  dose  that  patients  in  both  groups  received  during the  trial  was  4.8  mg/kg. In  the  monitoring  group,  21  patients  (9.2%)  developed  clinically  relevant levels  of  anti-drug  antibodies  compared  to  27  patients  (15%)  in  the standard  group.  In  addition, 137  patients  in  the  monitoring  group and  142  patients  receiving  standard therapy  reported adverse  events  during  the trial.

“The results  of  these  trials  support  the implementation  of  proactive  therapeutic  drug  monitoring during  maintenance  therapy  with  infliximab.  Maintenance  therapy  with  infliximab usually  lasts  for several  years,  and  preventing  disease  worsening  and  its  potential  impact  on  quality  of  life  and long-term  outcome  can make  a  great  difference  to a  large  number  of  patients  with inflammatory joint  diseases,”  says  Dr.  Syversen.  “Using  proactive  monitoring  in  all  patients  on infliximab  will require  feasibility  with testing,  availability  of  testing  at  a  low  cost,  as  well  as  education  of  health care providers.  Due to the  immunogenicity  profile  of  infliximab,  these  data  can  not  necessarily be  extrapolated to  other  TNF inhibitors  or  biologics,  but  they  encourage  further  therapeutic  drug monitoring  research  within rheumatology.”