Three Studies Show the Benefit of Concomitant Therapy for Inflammatory Bowel Disease (Part 2)

Continued from yesterday…

The third study (HM Kansen et al. JPGN 2017; 65: 425-29) retrospectively (2009-2014) examined 162 children (with available data) with Crohn’s disease (CD) for the development of anti-infliximab antibody (ATI) while receiving either monotherapy or concomitant therapy. This was a collaborative study from the Kids with Crohn’s Colitis (KiCC) working group (Netherlands).  In the majority of their patients (222 of 229), IFX was initiated as step-up therapy. Key findings:

  • 15% developed ATIs
  • 6 of 62 (10%) developed ATIs while receiving ongoing concomitant immunosuppression
  • 11 of 81 (14%) developed ATIs after receiving early concomitant immunosuppression (median of 6.2 months of concomitant immunosuppression followed by IFX monotherapy) 10 of 11 who developed ATIs  within the first 12 months, compared to 1 of 26 (4%) after 12 months.
  • 8 of 19 (42%) developed ATIs on IFX monotherapy

In their discussion, the authors note concerns regarding the safety of thiopurines. However, they point out that “the benefit of combination therapy (reduction of ATI formation) relative to IFX monotherapy should outweigh the risk of serious infections and malignancies to achieve an optimal treatment strategy for paediatric CD.” The authors: “combination therapy for approximately 12 months from initiation of IFX, followed by IFX monotherapy, may be equally effective alternative to continuous combination therapy.”

Overall, the totality of the evidence favors combination therapy for most patients with CD.  Yet, there is wide variation in clinical practice. As I was thinking about this, I came across a recent commentary: “The Power of Regret” (J Groopman, P Hartzband. NEJM 2017; 377: 1507-9).  The authors note that “disappointment is an unavoidable aspect of making difficult choices…but disappointment is not associated with self-recrimination and thus differs notably from regret.”  They indicate that “process regret” occurs when patients do not consider information about all available choices before making a decision.  I wonder if many patients/families fear using concomitant therapy because they worry they will regret the decision if a complication occurs.  Perhaps, working with all available information, some reluctant patients/families will feel better about their decision if the process for their decision was thorough, considering the risks/benefits of the treatment but also the risks/benefits of not choosing the treatment. .

My take: Overall, for most pediatric patients with CD, to date, concomitant therapy has been the most effective treatment.  More prospective studies are needed to determine more conclusively the benefit and optimal duration/timing of combined therapy, particularly with the more frequent use of therapeutic drug monitoring. Also, as will be noted in future posts from annual meeting, thiopurine use is declining.

Related blog posts:

New Target Drug Levels in Inflammatory Bowel Disease

According to a recent review (Vaughn BP, Sandborn WJ, Cheifetz AS. Inflamm Bowel Dis 2015; 21: 1435-42), higher target levels of infliximab should be considered.

After reviewing the relevant studies which are summarized in Table 1, the authors state that in their experience infliximab (IFX) levels of 5 to 10 mcg/mL are desirable.  Using this standard, they note in a retrospective review that proactive testing identifies only 29% of patients in this range.

Similarly, the TAXIT study (Casteele NV et al. Gastroenterol 2015; 148: 1320-29) identified 44% of patients with a trough concentration of 3-7 mcg/mL at baseline screening.  In this study, after achieving an adequate trough concentration, they found that patients had ~70% clinical remission at 1 year.  TAXIT acronym = the Trough Concentration Adapted Infliximab Treatment trial.  The TAXIT study was a 1-year randomized control trial with 263 adults (178 with CD and 85 with UC).

Recommendations from this review:

  • When therapeutic drug monitoring is used to react to symptomatic patients (Figure 1), if they test negative for antibodies to infliximab (ATIs) and have a low IFX level, then increasing the dose is recommended.  In those with therapeutic IFX and negative ATIs, then consider change in drug class or surgery (rather than dose escalation).
  • When therapeutic drug monitoring is used to react to symptomatic patients, if they test positive for ATIs, if there is a low level ATI (<15 mcg/mL for the referenced assay), then increasing the dose is recommended, otherwise consider change in drug class or surgery (rather than dose escalation).
  • For proactive monitoring, if negative ATI, and IFX trough level is >10 mcg/mL consider extending interval.  If the IFX level is low, increase dose.  If IFX is therapeutic, continue same dose and consider re-check in 6-12 months.
  • For proactive monitoring (Figure 3), if positive ATI, the authors recommend increasing dose if faced with low level ATI and consider change in drug class or surgery (rather than dose escalation). [If someone is doing well, I would not agree with this recommendation.  I would not stop a therapy based on a single blood test.]

One more useful point:

The authors note that combination therapy improves IFX levels and lessens the likelihood of ATIs.  “Current evidence suggests that combination of an anti-TNF with an immunomodulator is the most efficacious treatment for new-onset IBD.”  They speculate that proactive monitoring may allow IFX monotherapy without the need for combination therapy or allow de-escalation of combination therapy.

Bottomline: Consider a higher infliximab target level (5-10 mcg/mL) and using proactive monitoring to achieve higher remission rates.

Related blog posts:

Cumberland Island

Cumberland Island

Briefly noted:

Casen C, et al. Aliment Pharmacol There 2015; 42: 71-83. (Thanks to Ben Gold for this reference). After studying the stool of 165 healthy controls, the authors used 54 DNA probes targeting >300 bacteria.  This genetic analysis-map dysbiosis test, subsequently analyzed 330 more patients; it confirmed dysbiosis in 73% of IBS patients, 70% of treatment-naive IBD patients and 80% of IBD patients in remission compared with 16% of healthy individuals.  Take-home point: Ultimately stool analysis could lead to more accurate evaluation and monitoring of individuals with suspected IBS or IBD.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.


Four IBD Articles –Four Teaching Points

  1. Inflamm Bowel Dis 2014; 20: 1891-1901
  2. Inflamm Bowel Dis 2014; 20: 1996-2003
  3. Inflamm Bowel Dis 2014; 20: 2013-21.
  4. Inflamm Bowel Dis 2014; 20: 2056-66.

The first article is listed as a ‘basic science’ article.  However, it has direct relevance to the clinical problem of anti-TNF-induced psoriasiform skin lesions.  The article notes that this problem affects about 5% of patients treated with anti-TNF agents.  The authors found that IL-36γ and IL-17C are increased in anti-TNF-induced psoriasiform skin lesions of patients with Crohn’s disease (n=13 patients).  An important clinical point was that 7 of these patients with “severe anti-TNF induced skin lesions were successfully treated with the IL-12/IL-23 neutralizing antibody ustekinumab.”  This was superior to topical steroids or topical tacrolimus.

The second article is a proof-in-principle type article showing that proactive measurements of infliximab (IFX) levels may improve outcomes.  This retrospective observational study examined 48 patients who had proactive IFX levels. In 12 of 48, IFX dosing was escalated after the first proactive monitoring.  In addition, over the study period, 15% of patients had their dosing lowered. In those with proactive monitoring, the probability of remaining on IFX was >80%.  Those patients who achieved trough levels >5 mcg/mL had >90% probability of remaining on IFX therapy.  The authors hypothesize that better IFX levels may reduce anti-infliximab levels.

The third article examines carbohydrate intake in relation to the development of Crohn’s disease (CD) and ulcerative colitis (UC). The authors utilized the “EPIC” cohort (European Prospective Investigation into Cancer and Nutrition) (Public Health Nutr 2002; 5: 1113-24).  among 401,326 enrollees at recruitment, the dietary intakes of carbohydrates were measured using validated food frequency questionnaires. In this cohort, 110 developed CD and 244 developed UC during followup. Key finding: there was no significant risk for IBD based on total carbohydrate intake.  This study does not exclude the possibility that specific carbohydrates could have an etiological role.

The fourth article, a case-control study (2002-2011),  examines risk factors for endoscopy-associated perforation and perforation-associated complications (PAC) in patients with and without IBD. n=217,334 lower endoscopies (with 9518 in IBD patients).  Perforation rates: 18.91 per 10,000 and 2.50 per 10,000 for IBD and non-IBD endoscopy respectively.  The use os systemic corticosteroids at the time of endoscopy was associated with a 13 times greater risk for PAC.

Related blog posts:

More Lessons in TNF Therapy (Part 2)

Another useful study (Clin Gastroenterol Hepatol 2014; 12: 1474-81, editorial 1482-84 [podcast available: on infliximab (IFX) usage addresses the issue of reinitiating IFX therapy after a “drug holiday.”

The authors conducted their retrospective single-center study in Belgium.  This detail is important as interruption of therapy is more common in Europe where agents like IFX are often stopped when patients are doing well.  In the U.S. stopping IFX occurs more commonly when there are antibodies to infliximab (ATIs) or increased clinical symptoms.  In this particularly study, 22% were restarted on IFX after loss of response (despite dose optimization) and the remainder had been stopped either due to remission, pregnancy or patient decision. Also, in their center, patients do not receive IFX unless they were allergic or refractory to steroids and/or immunomodulators for a minimum of 3 months.

In total there were 128 patients (105 with Crohn’s and 23 with ulcerative colitis).

Key findings:

  • Reintroduction of IFX resulted in a clinical response in 84.5% at week 14, 70% at 1 year, and 61% at more than 4 years.
  • Higher response was noted in those who discontinued because of remission: 90% at week 14, 77.5% at 1 year, and 66.6% at more than 4 years.
  • In patients with prior loss of response, 45% had response to reintroduction of IFX at 1 year.
  • 15 patients had acute infusion reactions, seven of these were severe.
  • ATI-positivity was associated with a higher risk of infusion reaction, though most ATI-positive patients did not develop a reaction.  Particularly in ATI-positive patients, the editorial recommends a “slow infusion protocol and possibly steroids before administration of the drug.”
  • The editorial states: “it seems reasonable to check drug levels and antibodies before the second infliximab dose.” Trough levels >2 mcg/mL and undetectable ATIs early after restarting the drug were associated with good responses. “For patients with high ATIs (≥9.1 U/mL), another drug should be considered.”
  • Among those with detectable ATIs, response at 1 year was noted in 54.8%.
  • Immunomodulator cotherapy had a beneficial effect.

Bottomline: This study provides useful insights for patients who need to reinitiate IFX treatment.  In addition, some IFX failures may be able to resume IFX after a drug holiday.

Related blog posts:

Overcoming ATIs

Usually, when antibodies to infliximab (ATI) develop in combination with a loss of clinical response in an individual with inflammatory bowel disease (IBD), this often indicates a need to switch treatments.  A recent study suggests that some patients can eliminate ATIs with the addition of immunomodulators (Clin Gastroenterol Hepatol 2013; 11: 444-47).

In this small retrospective study, 5 patients (18-37 years of age) who developed ATIs were able to continue infliximab therapy after instituting immunomodulator treatment (3 with thiopurines, and 2 with methotrexate).  What makes this report interesting, was that these ATIs (prior to immunomodulator use) were identified multiple times and were associated with undetectable infliximab levels.  None of these patients had dose intensification of infliximab.  After instituting immunomodulator therapy, detectable infliximab was evident and the ATIs disappeared.  According to Figure 1, the timeframe for return of response was about 10 weeks in some of these patients.

The authors note that the addition of immunomodulators can gradually eliminate a preformed memory response to infliximab antigen.  They also note that ATIs can sometimes disappear spontaneously, though this had not been noted to occur previously when mulitple ATIs levels have been identified.

While these observations are important, a larger prospective study is needed to inform how frequently this strategy could be successful.

Related blog links:

Drug levels for inflammatory bowel disease

In many conditions, drug levels are helpful to make sure the patient receives an adequate dose for the indication.  When we treat infections or seizures, drug levels predict the effectiveness of the medication and allow dosing adjustments to improve responses as well as to lower toxicity. Drug levels are helpful in inflammatory bowel disease (IBD) as well.  Drug levels may help with thiopurine dosing and with infliximab (IFX) dosing.

Infliximab (IFX) levels can guide therapy (Scand J Gastroeneterol 2011; 46: 310-18). This study examined 106 patients (85 with CD and 21 with UC) over a ten-year period. In this cohort, patients received concurrent hydrocortisone, acetaminophen, and cetirizine to prevent acute reactions and to try to limit anti-infliximab antibodies (ATI), also called anti-human antichimeric antibodies (HACA).  Infusion intervals ranged from 4-12 weeks.

69% of Crohn’s patients maintained response to IFX and 48% of UC patients.  Infliximab trough levels were significantly increased among patients who maintained their response.  A cutoff value of 0.5 μg/mL was defined as clinically relevant for IFX trough concentrations for Crohn’s patients and for UC the cutoff was 0.8 μg/mL .  Trough levels below this cutoff were 86% sensitive and 85% specific for identifying loss of response.  The overall accuracy for the test was 87% in identifying loss of response.

Also, ATIs were significantly higher in CD patients who had lost response to infliximab.  Patients who had been “re-treated,” were significantly more likely to have developed ATIs.  “Re-treated” was defined as having interruption of IFX treatment more than 6 months.

These specific cutoff values apply to the radioimmunoassay technique for measuring IFX and ATI.  These values may not extrapolate to ELISA assays.  At the same time, the findings suggest a practical approach in patients with symptoms while receiving IFX:

  • Check IFX level (at trough or at 4 weeks)
  • If low level and no ATI, likely to respond to dose escalation
  • If low level but positive for ATI, not likely to respond to dose escalation
  • Do not assume symptoms are due to drug failure; reassess with imaging &/or scope. Consider alternate etiologies (eg infections, stricture, celiac, IBS).
  • Cotherapy with an immunomodulator reduces ATIs and boosts levels of IFX.
More usage of IFX and ATI levels is likely; however, cost issues preclude frequent measurements.

Additional references:

  • Only one chance to make first impression.  Previous blog entry on use of infliximab.
  • -Clin Gastro & Hepatology 2011; 9: 395. Do not assume symptoms are due to drug failure -reassess with imaging &/or scope. Consider alternate etiologies (eg infections, stricture, celiac, IBS). Check IFX level –if >12 @ 4weeks or >1.4 mcg/mL at trough –>predicts good response.  If +HACA, ~90% response with alternative TNF.  In those with low level, 86% responded to dose escalation.
  • -DDW 2011, Abstract #772. If loss of response to IFX, **confirm active dz (labs, scope) & not due to CDT. **check HACA –if +, only 10-20% chance of responding to dose escalation; better chance of responding to similar agent **check IFX week 4 level, if low (& neg HACA) then 90% respond to dose escalation
  • -NEJM 2010; 362:1383-1395. SONIC study.  Patients with moderate-to-severe Crohn’s disease who were treated with infliximab plus azathioprine or infliximab monotherapy were more likely to have a corticosteroid-free clinical remission than those receiving azathioprine monotherapy.
  • -Gut 2010; 59: 49-54. Trough IFX levels in UC. n=115. Antibody status can only be measured at trough levels. Undetectable trough level (<1.4 mcg/mL) associated with lower remission (15% vs 69%) and lower endoscopic response (28% vs 76%) & higher colectomy rate (55% vs. 7%).
  • -Gastroenterology 2010; 139: 344 (review of above Gut article). Similar to Crohn’s disease: 82% remission with detectable trough vs 6% w/o detectable level.
  • Lancet 354 (9194): 1932–9. doi:10.1016/S0140-6736(99)05246-0PMID 10622295.”Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group”.
  • -Am J Gastroenterol 2010; 105: 1133-39. If lack/loss of response, may need dose escalation with humira or Cimzia (q2weeks):
  • -IBD 2011; 17: 141-51. Loss of response to biologics.
  • -Gastro & Hep 2008; 4: 12. “primary nonresponse can be determined after 2 doses” in table reiterating AGA consensus guidelines. 85% of responders show benefit by 2weeks & all responders benefit c/in 6 weeks (Am J Gastro 2001; 96: S303). Worsening Sx despite infliximab indicates need to look for stricture, infxn, etc.
  • -Clin Gastro & Hep 2006; 4: 1248. Clinical remission associated with measurable infliximab troughs; thus, if no measurable trough, increase dose or shorten interval. If level detected & no response, unlikely to respnd to TNF class. Also, concurrent immunomodulators were not helpful.
  • -Am J Gastro 2010; 105: 2617 (Oussalah et al). 2-3yrs 41% IFX failure in UC. withdrawal of AZA increase loss of response –7x more likely
  • -Am J Gastro ; 105: 1133-40. n=155. 23% ATI -92% respond to med change, 17% respond to dose change. Level <12 @ 4weeks, 86% respond to dose change
  • -Gut 2010; 59: 1363. n=121. Co-treatment helped reduce complications & flares relative to monotherapy (& azathioprine appeared to be more effective than methotrexate).