Tag Archives: infliximab

Drug levels for inflammatory bowel disease

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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)05246-0. PMID 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).

TNF antagonists and UC

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In my fellowship (15 years ago), the use of thiopurines (eg. azathioprine, 6-mercaptopurine) for ulcerative colitis was debated.  Many physicians urged colectomy rather than using these drugs which could have long-term consequences.  At the time, the risk of thiopurines was less well-understood.  Over time, the use of these agents has become common when mesalamine products were ineffective.  The same issue comes up with TNF antagonists versus colectomy.

A recent study provides more information on the effectiveness of adalimumab for patients with moderate-to-severe UC but does not settle this debate (Gastroenterology 2012; 142: 257-65).  In this study, termed ‘ULTRA-2’ (Ulcerative colitis long-term remission and maintenance with adalimumab 2), the  efficacy of adalimumab for induction & maintenance of remission was studied in 494 patients.  This was a randomized, double-blind, placebo-controlled study; average age was 40 years.

Clinical remission in the adalimumab group were 16.5% at 8 weeks (9.3% placebo).  At 52 weeks, 17.3% in the adalimumab group were in remission (8.5% placebo).  Among patients naive to anti-TNF agents, the response rate was 21.3% at week 8 & 22% at week 52.  Safety overall was similar in both groups; however, in the adalimumab group one patient developed gastric cancer and one developed squamous cell carcinoma.

The authors conclude that adalimumab is safe and more effective than placebo in inducing and maintaining remission among patients with moderate-to-severe UC.

A second study, also published this past month, looks at the use of infliximab for maintenance therapy for UC (Inflamm Bowel Dis 2012; 18: 201-11).  Patients who had achieved benefit from ACT-1 and ACT-2 studies were followed for three years.  Dosage of infliximab could be adjusted.  A total of 229 patients entered the study.  During the study, 70 patients (30.6%) discontinued infliximab due to adverse effects (10.5%), lack of efficacy (4.8%) or other reasons (15.2%); the majority were able to continue infliximab.  The authors indicate that no new safety issues were identified. Yet, there were two deaths among the infliximab group including a 19 year-old nonsmoker who developed lung cancer and a lethal case of histoplasmosis.

Because the improvement compared to placebo is modest with both of these agents, the question about whether to use these medications or proceed to surgery in UC patients is unanswered.

Additional references:

  • -Aliment Pharmacol Ther. 2008 Oct 15;28(8):966-72. Epub 2008 Jul 24.  Long-term outcome of adalimumab therapy for ulcerative colitis with intolerance or lost response to infliximab: a single-centre experience.
  • -Am J Gastroenterol (Oussalah A et al) 2010; 105: 2617-25. Multicenter study of IFX for UC
  • -Gastroenterology 2010; 138: 2282. Severe pediatric UC. 25/33 responded to IFX. colectomy rate 19% at 1 year.
  • -Gastroenterology 2009; 137: 1204 (ed), 1250. lower colectomy rates at 54wks in IFX vs placebo (+concomitant meds): 10% vs. 17%.
  • -Clin Gastro & Hep 2008; 6: 1112. Do NOT use CYA post infliximab and vice versa. n=19. 1 death due to sepsis. Remission rates occur in ~1/3rd but are of short duration.
  • -NEJM 2005; 2462. 69% clinical response @ 8 weeks (vs. 37% placebo) & 45% at week 54 (vs. 20% placebo).
  • -JPGN 2004; 38: 298. 82% short-term response, 63% sustained response; n=16.

Only one chance to make first impression

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Infliximab (IFX) came into clinical practice in 1998 after impressive results, published in the New England Journal of Medicine, demonstrated remarkable success in refractory Crohn’s disease  and even allowed resolution of fistulas.  Due to its expense and perceived risks, IFX has been typically reserved for treatment failures & significant perianal disease.  Although there have been discussions about ‘top-down’ therapy for many years, more and more it has become apparent that the best opportunity to influence the natural history of Crohn’s disease is early in the course; and perhaps in some cases of ulcerative colitis early IFX treatment may be worthwhile.  Clinical experience and treatment trials have shown that IFX response is significantly greater in Crohn’s disease than ulcerative colitis.  
Data on the postoperative course of Crohn’s disease has been informative on this approach as have large studies demonstrating that IFX is likely at least as safe as any other medication treatments for moderate-to-severe disease (eg. thiopurines, corticosteroids, methotrexate, tacrolimus).  With regard to postoperative Crohn’s disease, it has been shown that microscopic disease may develop within one week of intestinal resection.  More than 70% of postoperative patients develop significant mucosal recurrence within 12months (i2 or greater); yet, symptoms may not develop for a much longer time.  When significant mucosal disease is present, it may already be too late to achieve optimal response to IFX and similar agents due to remodeling of the intestinal submucosa.  Early in the course of Crohn’s disease, the vast majority of patients have an inflammatory phenotype (Cosnes J, et al. Inflamm Bowel Dis. 2002; 8:244-25), whereas later in the course, stricturing and penetrating disease are increasingly common.  

Postoperative mucosal scoring system:

• i1 – 5 or fewer apthous lesions

• i2 – more than 5 apthous ulcers with normal mucosa between, or skip areas of larger lesions

• i3 – diffuse apthous ileitis with diffusely inflamed mucosa

• i4 – diffuse inflammation with large ulcers, nodules or narrowing

 Rutgeerts et al. Gastroenterology 1990;99:956-83

Top-down approach:

Benefits: higher efficacy, lower disease-related complications, decrease surgery, improvement in catchup growth/bone formation (both not shown in AZA trials)

Risks: higher costs (but probably cost-effective)

**IFX therapy early may save health care costs by reducing surgery/hospitalizations:  Jewell DP et al, Eur J Gastroenterol Hepatol 2005, Leombruno JP et al Pharmacoepidemiol Drug Saf 2011

Conventional approach with accelerated step-up:

Risks: lower efficacy, higher infection risk/mortality with repeated steroids

Benefits: possibly lower cost

Potential drawbacks with azathioprine or 6-mercaptopurine (thiopurine class):

  • IBD 2011; 17: 2138. AZA can achieve remission in only ~30%.
  • Canc Research 2009; 69: 7004.  AZA is carcinogen– incorporated into DNA & changes sun absorption.  Skin cancer risk never drops when stopping med.
  • Gastro 2011; 141: 1621: CESAME (n=19,486)  thiopurines associated with NHL risk.  HR 5.28.
**Much of the information on this posting was influenced by presentations at “Advances in IBD 2011.”  Specific speakers that influenced this posting include Robert Baldassano, Marla Dubinsky, and Miguel Regueiro.

Additional References:

  • IBD 2009; 15: 1583. Postoperative mgt: low risk (1st surg, short stricture) –>no Rx; moderate risk (<10yrs of dz, long stricture, inflammatory dz)–>6MP; high risk (penetrating dz, >2 surg) –>IFX.  Post-op scope @6-12mo
  • JPGN 2009; 48 suppl 2: S72
  • Clin Gastro & Hep 2009; 7:183. Long term results with surgery for small bowel Crohn’s. n=865 surgeries. Risk for repeat surgeries: younger age, upper small bowel location, stricturing
  • Gastroenterology 2009; 136: 441. IFX prevents recurrent Crohn’s post-op. n=24. 1/11 w recurrence vs 11/13 control patients.
  • Am J Gastro 2008; 103: S412 (abstract 1054) IFX reduces post-op recurrence. clinical recurrence 0% at week 54 vs 39% of controls. n=23. 90% in IFX group with endoscopic remission vs 15% of placebo group.
  • Lancet 2008; 371: 660-667.   top-down strategy more likely to achieve endoscopic remicssion after 2yrs: 73% vs 30%. n=129.
  • NEJM 2010; 362: 1383. Sonic study. Combination AZA/IFX with greater efficacy. 56.8% remission in combo Rx vs IFX monotherapy.
  • Gut 2010; 59: 1363.   n=121.  Co-treatment helpd reduce complications & flares relative to monotherapy (& azathioprine appeared to be more effective than methotrexate).
  • JPGN 2009; 49: 183.  REACH pediatric trial showed good perianal dz response to infliximab.

Deadly consequences of pain management

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A big part of a pediatric gastroenterologist’s daily practice is trying to help patients with recurrent abdominal pain.  The goals are to determine the reason for the pain and then to offer the best therapy.  In many cases, these goals can be quite difficult.  With regard to diagnosis, the majority of patients have ‘functional’ pain and the diagnosis is in part a diagnosis of exclusion, trying to rule out other potential etiologies.  With regard to treatment, this is also difficult.

Narcotics are not often given for pediatric abdominal pain, but are used under certain circumstances.  These medications can have unintended consequences.  One consequence of frequent narcotic usage is that individuals may tolerate pain more poorly after receiving narcotics.  A useful review of narcotic overuse was published in the New England Journal of Medicine in 2010.  (NEJM 2010; 363: 1981).

“Deaths from unintentional drug overdoses in the United States have been rising steeply since the early 1990s …and are the second-leading cause of accidental death, with 27,658 such deaths recorded in 2007.”  11,499 of the deaths in 2007 were due to unintentional narcotic overdose.  In comparison, in the same year, there were about 6,000 deaths from cocaine & 2,000 deaths from heroin.

Besides the number of deaths, the other alarming factor has been a sharp rise (10-fold since 1990) in the usage of narcotics in the past two decades.  One of the factors driving this increase has been a compassionate interest in relieving pain.  The availability of these drugs throughout the country even in remote regions allows these abusable drugs to be more accessible than illicit drugs like cocaine and heroin.   While the availability of these medications may increase the rates of suicide, most opioid-overdose deaths are tragic accidents. Often, laboratory tests identify one or more substances in addition to the opioid, indicating that the depressant effects of alcohol or other drugs were additive  in causing death.

With regard to gastroenterology/pediatric gastroenterology, another important aspect of narcotics use is the association of increased mortality risk with inflammatory bowel disease.  This has been shown by analyzing a registry for infliximab (IFX) (Lichtenstein G, DDW 2010, abstracts#T1039 & T1040.).  In the TREAT registry with 6273 patients (3334 treated with IFX), the only risk factors for increased mortality/increased infections were steroids and narcotics.  This study also showed that IFX did not increase mortality, serious infections, malignancy or lymphoma in this cohort.

Additional Reference:

Clin Gastro & Hep 2008; 6: 978. Refractory abdominal pain review.  ‘Narcotics over time increase frequency, duration and intensity of pain.’ Practical recommendations:
treat constipation, withdraw narcotics, consider mental health (CBT/hypnosis/psychotherapy/stress mgt), and possible TCA or SNRI therapy.