Combination Therapy Study Points to Central Role of Adequate Drug Levels

A recent study (JF Colombel et al. Clin Gastroenterol Hepatol 2019; 17: 1525-32) examines the effect of combination therapy and drug levels in achieving corticosteroid-free remission at week 26 (CSFR26).

The authors performed a post hoc analysis from 206 patients with Crohn’s disease (CD): 97 monotherapy with infliximab & 109 with combination infliximab/azathioprine

Key findings:

  • The proportions of patients achieving CSFR26 were not significantly greater among those receiving combination therapy vs monotherapy within the same serum infliximab concentrations
  • Mean trough infliximab concentrations in the combination therapy were higher than for monotherapy: 3.54 mcg/mL vs. 1.55 mcg/mL
  • Higher levels of antidrug antibodies were seen with monotherapy: 35.9% vs 8.3% of those with combination therapy.  Antidrug antibodies were detected only in those with lowest quartile of infliximab trough levels.

My take: This study indicates that combination therapy’s higher efficacy is due to  favorable pharmacokinetics rather than drug synergy.  If good infliximab trough levels can be achieved with infliximab monotherapy, this may obviate the need for combination therapy.  The uncertain factor is whether closer attention to trough levels will minimize the development of antidrug antibodies as effectively as the use of combination therapy.

Related blog posts:

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.

Sagrada Familia, Barcelona

Steroid-Free Approach in Autoimmune Hepatitis

A recent case report (A Wehrman et al. J Pediatr 2019; 207: 244-7) described steroid free treatment of autoimmune hepatitis (AIH) in 8 patients.

This retrospective review of all patients with AIH at CHOP between 2009-2014 compared patients who had AIH treated with (n=12) and without steroids (aka azathioprine monotherapy). Near normalization of ALT was defined as less than 2 x ULN.

Key findings:

  • All children in the steroid group had normalization of liver enzymes by 12 months of therapy compared with only 2 of 8 in the steroid-free group. Though, near normalization of ALT occurred at a median of 5.5 months in the steroid free group (compared with 1.8 months in the steroid group).
  • Adverse effects were evident in 75% of the steroid group compared with 11% of the steroid-free group

The authors conclude that “liver enzymes may take longer to normalize without steroids, but this difference was not statistically significant in our small cohort, nor did it lead to any adverse outcomes.”

My take: Standard therapy for AIH is prednisone for induction with subsequent azathioprine.  This study shows that in patients unwilling to take steroids or with intolerance that azathioprine monotherapy may be an effective alternative though liver enzymes are likely to take much longer to improve.

Related blog posts:

Barcelona/Mediterranean Sea

Sub-Analysis of DIAMOND Study

K Watanabe et al. Clin Gastroenterol Hepatol 2018; 16: 542-9.

The DIAMOND study evaluated monotherapy with adalimumab (n=85) compared with combination therapy of adalimumab with azathioprine (n=91).

Key findings:

  • In this subanalysis of patients with moderate and severe Crohn’s disease (CD), endoscopic response (defined by SES-CD drop of at least 8 points or SES-CD <4) was significantly higher at week 26: 71.6% vs 54.4%. The OR for endoscopic response was 2.12 at week 26 with combination therapy.
  • At week 52 the endoscopic response difference was not statistically significant: 60% vs. 50%.
  • Similarly, mucosal healing was more common (but not statistically significant) in the combination group compared with monotherapy: 20.9% vs 103% at week 26, and 21.5% vs 12.2% at week 52.
  •  While not statistically significant, the combination group had ADA trough that was higher (7.6 compared with 6.5).

My take: The results described above for endoscopic responses and mucosal healing rates are depicted in figure 2 (I do not have a digital copy of figure or permission to use).  After one looks at this figure, depicting the data noted above, there certainly appears to be an advantage for the use of combination therapy in patients with moderate-to-severe CD.

Related blog posts:



I have not independently verified the claims on this tweet

#NASPGHAN17 Is it time to stop using thiopurine therapy?

This blog entry has abbreviated/summarized this presentation. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

Safety in Pediatric IBD Therapy: Is it time to stop using thiopurines?

Jeffrey Hyams  Connecticut Children’s Medical Center

Key points from this lecture:

  • Dr. Hyams:  “There are better options than thiopurines in 2017 due to infrequent but serious risks”
  • The DEVEVOP study showed that anti-TNF agents did NOT increase the risk of lymphoma or hemophagocytic lymphohistiocytosis (HLH).  In contrast, these risks do occur with thiopurines –this is infrequent but remains significant.
  • Therapeutic drug monitoring may obviate the need for combination/dual therapy which has been shown to improve response rates to anti-TNF agents; methotrexate may work for combination therapy and may be safer than thiopurines
  • If a thiopurine is used as part of combination therapy, short duration (~6 months) is likely to have low risks
  • In addition to Dr. Hyams, Dr. Baldassano, in his discussion of treat to target (discussed in subsequent post), echoed the sentiment that he no longer recommends thiopurine therapy

Dr. Hyams slides list some of the relative risks of thiopurine therapy.  To understand these risks, the absolute risk is probably more helpful.

My take: This lecture did not focus on the main benefit of thiopurines which is its use in combination therapy. Many experts consider combination therapy to be the standard of care for adults with Crohn’s disease.  The advantages of combination therapy are mainly due to improved durability of anti-TNF therapy and lower antidrug antibodies.  How this benefit stacks up against the risks discussed in this lecture and whether this benefit can be supplanted by the use of therapeutic drug monitoring is uncertain.


Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  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.

6-Thioguanine Levels in Autoimmune Hepatitis

A recent retrospective study (MA Sheiko et al JPGN 2017; 65: 80-5) examines the issue of azathioprine (AZA) metabolites and outcomes in pediatric autoimmune hepatitis (AIH).

Study characteristics:

  • 66 children
  • Mean age of diagnosis 9.6 years
  • Mean follow-up 2.9 years
  • Study period 2002-2013

Key findings:

  • 79% achieved biochemical remission (defined as ALT ≤50 U/L); mean time was 6.2 months
  • 6% required liver transplantation
  • 18% were weaned off immunosuppression and remained in remission
  • 6-thioguanine (6-TGN) levels ranging from 50 to 250 (pmol/8 x 10 to 8th red blood cell count) were associated with biochemical remission

Our study suggests that AZA dosing of approximately 1.2 to 1.6 mg/kg/day will achieve 6-TGN levels of 50 to 250 pmol, which is sufficient to maintain biochemical remission in the majority of patients.

This is significantly lower than dosing recommended for inflammatory bowel disease (recommended levels 250-450). The associated editorial (pg 2-3, N Kerkar) cautions that while “lower levels are sufficient for maintaining biochemical remission…higher levels, similar to that used in IBD, are required for inducing remission.”

My take: Lower doses of azathioprine are likely to maintain biochemical remission and cause fewer side effects.  Metabolite levels can be helpful to assure reasonable levels of 6-TGN and to assure medication adherence.

Related blog entries:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  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.

Shem Creek, SC

What I did not know …a few items

  1. 6-Mercaptopurine (6-MP) often can be used when patients are intolerant of azathioprineS Hubener et al. Clin Gastroenterol Hepatol 2016; 14: 445-53.  This retrospective study showed that 15 of 20 patients with autoimmune hepatitis and prior azathioprine intolerance responded to 6-MP.  This is somewhat unexpected as azathioprine is metabolized into 6-MP.  However, rather than 6-thiouracil, the “imidazol component of azathioprine, which is cleaved off…might trigger adverse reactions.”  Another artical on thiopurines (Aliment Pharmacol Ther 2016; 43: 863-883) (thanks to Ben God for this reference) provides a thorough review of the pharmacogenetics and pharmocokinetics of these medications.  While this review reinforces the recommendation to check TPMT before treatment, it notes that only a small proportion of thiopurine toxicity is related to deficient TPMT activity.
  2. There is no formal validated or consensus definitions of mild, moderate, or severe IBD. L Peyrin-Biroulet et al. Clin Gastroenterol Hepatol 2016; 14: 348-54.  While the Lemann index measures the cumulative structural bowel disease, the authors propose criteria which involves three areas of severity: impact of the disease on the patient (eg. clinical symptoms), inflammatory burden (eg. biomarkers, mucosal disease, disease extent), and disease course (eg. structural disease, intestinal resection, perianal disease, extraintestinal manifestations)
  3. Fundic gland polyps (often associated with proton pump inhibitor therapy) are not premalignant lesions. There is an “inverse correlation between the FGPs and gastric neoplasia.” S Varghese et al. Gastroenterol Hepatol; 2016; 12: 153-4.
  4. Parents of newborns do not know how to use car seats.  BD Hoffman et al (J Pediatr 2016; 171: 48-54) showed that 95% of car seats were misused (291 families).  Serious misuse was present in 91%.


Related blog posts: Lemann index: Short Takes on IBD Articles | gutsandgrowth

Gibbs Gardens has >20 million daffodils

Gibbs Gardens has >20 million daffodils


The results of the “UC SUCCESS” trial show that combination therapy with infliximab and azathioprine is more effective than either medication as monotherapy in ulcerative colitis (UC) (Gastroenterol 2014; 146: 392-400). This study findings are similar to the SONIC trial in Crohn’s disease (CD).

Study Design: randomized, double-blind trial with evaluation at 16 weeks with a total of 239 patients.  In patients assigned to infliximab (IFX) alone, they were given daily oral placebo pills. In patients with azathioprine monotherapy (AZA), dosed at 2.5 mg/kg/day, they also received placebo infusions.  Patients had moderate to severe UC as defined by Mayo scores at baseline and had not responded adequately to a course of corticosteroids.  All patients were naive to tumor necrosis factor α antagonists (anti-TNFα).  Mean age was approximately 40 years.


  • IFX/AZA had a 39.7% corticosteroid-free remission at week 16 compared with 22.1% with IFX monotherapy and 23.8% with AZA monotherapy.
  • Mucosal healing at week 16 was evident in 62.8% of combination group compared with 54.6% IFX monotherapy and 36.8% with AZA monotherapy.
  • Serious adverse events were noted more frequently in the AZA monotherapy group, though this did not reach statistical significance.
  • A subset of patients had antibodies to infliximab (ATIs) measured.  ATI-positivity was more common with IFX monotherapy (19%, 7 of 37) than for IFX/AZA combination (3%, 1 of 31)

While this study indicates that for moderate to severe UC combination therapy with IFX/AZA was superior in this age group, there were several limitations.  Given the slow onset of action of azathioprine, more patients may have responded to this therapy if longer treatment duration was studied.

Take-home message: Combination therapy for UC, like CD, is more effective.  In this small study population, the adverse events were not increased. In the pediatric population, particularly males, the concern for malignancy in patients (especially males) treated with combination therapy may limit the frequency of combination therapy.

Related blog posts:

Other recent IBD articles of interest:

Inflamm Bowel Dis 2014; 20: 291-300. “Malignancy and Mortality in Pediatric Patients with Inflammatory Bowel Disease”  This article presented the results of a survey of 20 European countries and Israel.  Key finding: 18 cases of cancer and 31 deaths in 44 children. 5 of the deaths were due to cancer; the most common cause of mortality was infectious (n=14).  In this cohort, all HSTCL or EBV-positive lymphomas were treated with thiopurine monotherapy.

Inflamm Bowel Dis 2014; 20: 196-212.  “Opportunistic Infections Due to Inflammatory Bowel Disease Therapy”  This review article covers a broad range of pathogens and includes recommendations for prophylaxis and treatment (Table 3).  In addition the authors  provide suggestions for checking for several infections prior to treatment and vaccinations.