Three Studies Show Benefit of Concomitant Therapy for Inflammatory Bowel Disease (Part 1)

In the first study (J Cheng et al. Inflamm Bowel Dis 2017; 23: 1762-73), the authors retrospectively reviewed 148 children (113 with Crohn’s disease, 35 with ulcerative colitis). 90 patients received concomitant therapy (infliximab with either a thiopurine [n=67], methotrexate [n=23]) and 58 received infliximab monotherapy. Key findings:

  • Concomitant therapy >6 months  significantly lowered the risk of secondary loss of response in Crohn’s disease (CD) (HR =0.39) compared to monotherapy.   A similar trend was noted with ulcerative colitis (UC) but did not reach statistical significance.
  • Steroid-free remission rates at 1 year were 78% for CD patients with concomitant therapy compared with 54% on monotherapy
  • Among primary nonresponders, 67% of CD patients and 75% of UC patients were receiving IFX monotherapy.
  • No differences in adverse events were evident between patients receiving monotherapy compared with concomitant therapy. One patient (receiving azathioprine) developed a follicular lymphoma; this patient was well 10 years later.

The second study (Y Qui et al. Clin Gastroenterol Hepatol 2017; 15: 1359-72) was a systemic review of 35 studies that met the authors’ inclusion criteria. In total, 6790 patients with inflammatory bowel disease were enrolled in these studies. This study looked at multiple anit-TNF agents including infliximab, adalimumab, certolizumab, and golimumab. Key finding:

  • Antidrug antibodies were reduced by 51% in patients receiving concomitant therapy
  • Conclusion from authors: “concomitant use of immunomodulators should be considered in patients treated with anti-TNF 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.

More on this topic tomorrow.

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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.


Top Anti-TNF for Ulcerative Colitis

A recent retrospective cohort study (S Singh et al. Clin Gastroenterol Hepatol 2017; 15: 1218-25) compared infliximab and adalimumab in a nationwide Danish cohort of adults with ulcerative colitis (UC) from 2005-2014. The authors used propensity score and selected 171 patients who received infliximab (IFX) from a total of 1580 and 104 patients who received adalimumab (ADA) among a total of 139.

Key findings:

  • Patients who received ADA had higher hospitalization rates (HR 1.84) and a trend toward higher UC-related hospitalization (HR 1.71, CI 0.95-3.07) compared to IFX
  • Risk of abdominal surgery was not significantly higher in ADA patients (HR 1.35) compared to IFX
  • Serious infections were higher in ADA group, HR of 5.11 of needing hospitalization due to infections

There have been no randomized clinical trials  to determine if a specific anti-TNF agent is superior to another. In an associated editorial (MT Osterman, GR Lichtenstein, 1197-99), the authors note that while we don’t know which agent is superior, by comparing similar trials (ACT 1 & 2 for IFX and ULTRA 1 & 2 for ADA), “raw week 8 induction rates of clinical remission, clinical response, and mucosal healing are approximately 16%, 18%, and 19%, respectively, higher for infliximab”..”less dramatic differences favoring infliximab (approximately 9%, 13%, and 15%, respectively) are seen during maintenance at 1 year.”

My take: Due to the lack of randomized head-to-head studies, we do not know with certainty which anti-TNF is best for UC.  However, the data we have from retrospective cohort studies and from using raw data from prospective studies suggests that infliximab is effective in more patients.

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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.

Combination Therapy with Adalimumab -Is it Helpful?

A recent study (JM Chalbhoub et al. Inflamm Bowel Dis 2017; 23: 1316-27) performed a systematic review and meta-analysis to examine the effectiveness of Adalimumab (ADA) combination therapy compared with monotherapy.  With infliximab (IFX), the SONIC study, showed that combination therapy with an immunomodulator (IMM) (azathioprine) improved response; combination therapy resulted in reduced immunogenicity, lower rates of infusion reactions, and higher IFX levels.

With the advent of widespread use of therapeutic drug monitoring, some have questioned the need for combination therapy with IFX.  The need for combination therapy for ADA is also a matter of debate.  ADA has less immunogenicity than IFX and it is unclear if combination therapy will improve outcomes. There have been conflicting studies regarding combination therapy with ADA, prompting the current meta-analysis.

The authors identified 24 articles for inclusion from an initial pool of 1194. Key findings:

  • No significant difference between combination therapy and monotherapy was noted for induction of remission (OR 0.86) or response (OR 1.01). The induction of remission is based on data from 3096 patients (1400 on combination treatment).
  • No difference was noted for maintenance of remission (OR 0.97) or response (OR 0.91). The maintenance of remission is based on data from 1885 patients (859 on combination treatment).
  • Patients receiving combination therapy had lower odds of developing antidrug antibodies (OR 0.24)
  • Subgroup analysis in anti-TNF experienced patients showed improved successful induction of remission (OR 1.26) but also more frequent opportunistic infections (OR 2.44)

Overall, the authors conclude that “combination of ADA and immunomodulators does not seem superior to ADA monotherapy for induction and maintenance of remission and response to Crohn’s disease.” They do comment on the recent DIAMOND study which was a randomized open-label top-down strategy trial in anti-TNF-naive and IMM-naïve patients.  While no overall advantage of combination therapy was evident, better endoscopic response (84% vs. 64% with monotherapy) was seen at 26 weeks (but not at 52 weeks).

This study has several limitations.  Overall, there were a small number of randomized trials and the trials had significant heterogeneity.

My take (borrowed from authors): “It is unclear whether the addition of IMM impacts the efficacy of a less immunogenic anti-TNF biologic such as ADA in CD.” Though, in the subgroup of anti-TNF exposed patients, “combination therapy was associated with higher odds of induction of remission.”

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Adalimumab Can Reverse Growth Failure in Pediatric Crohn’s Disease

In an industry-sponsored study (TD Walters et al. Inflamm Bowel Dis 2017; 23: 967-75), adalimumab (ADA) was shown to be effective agent in reversing growth failure associated with pediatric Crohn’s disease (CD).

Background:  About one-third of children and adolescents with CD suffer from growth failure and delayed puberty.  Several prior studies have shown that anti-TNF therapy can improve height velocity and that early treatment with anti-TNF therapy (≤3 months after diagnosis) leads to greater improvement in height obtained, if initiated before puberty or early into puberty. This study examines the effectiveness of ADA in children from the IMAgINE 1 trial.

The authors identified 73 participants with growth delays (& adequate data) along with 27 participants with no growth delays.

Key findings:

  • ADA therapy significantly improved and normalized growth rates at 26 and 52 weeks in patients with baseline linear growth impairment.
  • At week 26, height velocity z-score was 1.33 among 23 children in remission compared with -0.78 (n=29) among “nonremitters”
  • At week 52, height velocity z-score was 2.17 among 27 children in remission compared with -1.57 (n=17) among “nonremitters”

My take: In moderate to severe CD, anti-TNF agents have been demonstrated to reverse growth failure; though, this is expected to occur only in patients with clinical response. To my knowledge, no other CD medical therapies have been proven to reverse growth failure (surgical treatment can improve growth as well).

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Hepatitis B Reactivation Due to Immunosuppressive Therapies

The topic of Hepatitis B virus (HBV) reactivation has been discussed on this blog before (see link below).  Another excellent review on this topic (R Lomba, TJ Liang. Gastroenterol 2017; 152: 1297-1309) has been published.  The authors examine the course and mechanisms of HBV reactivation.  They divide the risk of reactivation into three groups: high, moderate and low risk and proposed management.

High risk groups, which have >10% risk of reactivation) include the following

  • B-cell-depleting agents including rituximab, ofatumumab, alemtuumab, and ibritumumab
  • High-dose corticosteroids (>20 mg/day in adults)
  • Antracyclines including doxorubicin
  • Potent TNF-α inhibitors: infliximab, adalimummab, certolizumab, and golimumab
  • Local therapy ofr HCC including TACE (transarterial chemoembolization)

Moderate groups (1-10% reactivation) include cytokine-based Rx (eg. abatacept, ustekinumab, natalizumab, vedolizumab), cyclosporine, systemic chemotherapy, moderate corticosteroid dosing

Low risk groups (<1% reactivation) include thiopurines (azathioprine, 6-mercaptopurine), and methotrexate as well as short-term low-dose corticosteroids.


  • For HBV screening, the authors recommend HBsAg and anti-HBc testing
  • Prophylactic therapy with potent oral anti-HBV therapies are recommended for those at moderate or high risk of reactivation.  In those at low risk, the options include prophylactic treatment or watchful monitoring.
  • A more detailed algorithm is provided in Figure 3.  In those with HBsAg positivity, if HBV DNA is less than 2000 U/mL, this algorithm suggests monitoring labs (HBsAg, ALT, HBV DNA every 3 months)

Mechanisms of HBV reactivation are discussed.  For example, with TNF-α inhibitors “can activate a unique host antiviral pathway, the APOBEC (apolipoprotein B mRNA editing enzyme, catlytic polypeptide-like) proteins, that cause the degradation of cccDNA in HBV-infected cells. Thus, blocking this endogenous antiviral pathway may lead to a higher HBV replication state and HBV reactivation.”

My take: In pediatric gastroenterology, we do not see a lot of HBV reactivation. Nevertheless, we do use many of the medications which can trigger HBV reactivation and need to keep these recommendations in mind.

Related blog post: What HBV Testing is Needed Before TNF Inhibitor Therapy

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Surgical Reset for Anti-TNF Therapy with Crohn’s Disease

A recent study (A Assa et al. Inflamm Bowel Dis 2017; 23: 791-97) indicates that after surgery, anti-TNFα treatment is worth another try.

In this retrospective study with 53 children, 18 had “pharmacodynamic failure” with anti-TNFα medications (PK group) and 35 were controls. “Phamacocynamic failure is characterized by either a lack of improvement of CD symptoms or  loss of response after initial improvement in the setting of adequate serum drug levels without ADAs” [antidrug antibodies].

Key findings:

  • Mean age at time of intestinal resection was 14.8 years
  • Median time from resection to anti-TNF initiation was 8 months
  • Compared to the control group, the PK group had similar response to anti-TNF therapy.   “Similar proportions of patients from both groups were in clinical remission on anti-TNF treatment after 12 months and at the end of follow-up (1.8 years)”
  • At 12 months, remission rates were 89% (PK) versus 88.5% (control)

The authors propose an explanation: “A plausible explanation for this finding is that in severely inflamed tissue with high inflammatory burden, local high levels of TNFα serves as a sink for anti-TNFα antibodies and that tissue injury and local hypoxia might further limit drug penetrance to its target.”

My take: This information is useful.  Many patients who have surgery may respond to anti-TNFα therapy subsequently.  The unanswered question: Could more frequent dosing of anti-TNFα therapy have averted surgery in some patients by overcoming areas of intense disease?


Safety of Long-term Adalimumab in Pediatrics; Weighted PCDAI

A recent study (W Faubion et al. Inflamm Bowel Dis 2017; 23: 453-60) reports on the long-term safety/effectiveness of Adalimumab in pediatric patients entering the IMAgINE 2 trial (& who completed the 52 week IMAgINE 1 trial).

Patients with a PCDAI <10 were considered to be in remission and those who had a drop in PCDAI of 15 or more were considered to have had a treatment response.

Key findings:

  • Of the 100 patients enrolled in IMAgINE 2, 41% achieved remission and 48% had a treatment response at week 240.
  • >80% of patients were “able to discontinue use of corticosteroids.”
  • Adalimumab treatment was associated with growth normalization.
  • No new safety signals were identified.

While this study provides some reassurance regarding long-term adalimumab use, it should be noted that the instruments used to assess efficacy in this trial (& many others) are suboptimal.

A recent study (D Turner et al. JPGN 2017; 64: 254-60) showed that PCDAI (and several similar versions) had “poor correlation with calprotectin” and none of the PCDAI versions “can give a valid assessment of mucosal healing.”  This study had used prospectively collected data from the ImageKids study of 100 children with Crohn’s disease.  For the weighted PCDAI, the “best cut-off to identify endoscopic mucosal healing was <12.5 points” with a sensitivity of 58% and specificity of 84%.\


History: (recall 1 week):

  • Abdominal Pain  0=None, 10=Mild (does not interfere with activities, brief), 20=Moderate/Severe
  • Patient functioning 0=No limitations, 10=Occn difficulty with activities (below par), 20=frequent limitations
  • Stools per day 0=0-1 liquid stools, no blood, 7.5=up to 2 semiformed stools with blood or 2-5 liquid nonblood, 15=Gross bleeding or ≥6 liquid stools or nocturnal diarrhea


  • ESR 0 points if <20, 7.5 points if 20-50, 15 points if >50
  • Albumin 0 points if ≥3.5 g/dL, 10 points if 3.1-3.4 g/dL, and 20 points if ≤3.0 g/dL


  • Weight 0= Weight gain or stable or voluntary weight loss, 5=involuntary weight loss 1-9% or involuntary weight stable, 10= weight loss ≥10%
  • Perirectal Disease 0=None or asymptomatic tags, 7.5= 1-2 indolent fistula, scant drainage, no tenderness, 15=active fistula, drainage, tenderness or abscess

Extraintestinal Manifestatons: Fever for 3 days (≥38.5), definite arthritis, uveitis, erythema nodosum, or pyoderma gangrenosum

  • Points: 0=None, 10 ≥1

Total Score 0-125: ______________________

As compared with PCDAI, the weighted PCDAI drops height velocity, abdominal examination, and hematocrit.  Turner et al note “their exclusion does not mean that they have no role in reflecting disease activity, but that the other included items, as a whole, are inclusive of the contribution of the 3 items.” Also, the weighted PCDAI simplifies the “extraintestinal manifestation” into a simple choice; overall, this affects few scores due to the low frequency of these manifestations.

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