Combination Therapy Associated with Treatment Persistence

Another large retrospective ‘real-world’ study (C Chen et al. Inflamm Bowel Dis 2019; 1417-27) examined persistence profiles of biologic therapies in newly diagnosed IBD patients.  This study, based on Truven Health MarketScan data (2008-2015) included 5612 patients with Crohn’s disease (CD) and 3533 with ulcerative colitis (UC). There were 1156 persons (20.6%) in the pediatric age range (0-18)

Key findings:

  • Less than half of the patients continued using their initial biologic treatment after 1 year (48.5% of CD cohort and 44.8% of UC cohort).
  • For infliximab (IFX) in the CD cohort, the 1 year continued rate was 47.6% and the 5 year rate was 20.0%. In the UC cohort, the rates were 44.9% and 15.7% respectively.
  • For adalimumab (ADA) in the CD cohort, the 1 year continued rate was 50.9% and the 5 year rate was 9.1%. In the UC cohort, the rates were 45.4% and 7.7% respectively.
  • Combination therapy with immunomodulators (IMM) significantly decreased the risk of discontinuation, especially if IMM was started more than 30 days before the biologic agent (HR 0.22).  Simultaneous starting had HR of 0.32.
  • The major predictors for noncompliance included infection and hospitalization.

Why did combination therapy result in higher medication persistence rates?

  • Potential reasons included improved efficacy by direct inflammatory effects and reduced drug antibodies to TNF antagonists.  It is possible that patients receiving combination therapy had more severe disease and thus less likely to discontinue therapy.

Limitation: This study may overestimate drug discontinuation as some patients may simply have had a dosing delay.

My take: This study shows a higher-than-expected rate of drug discontinuation indicating dissatisfaction related to efficacy, cost or complications. Those receiving immunomodulators (combination therapy) were much less likely to discontinue treatment.

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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

Combination Therapy Still Works for Inflammatory Bowel Disease (Part 1)

There is speculation that the use of therapeutic drug monitoring (TDM) may obviate the advantages of combination therapy. However, there is plenty of data supporting combination therapy including a recent retrospective population-based study (LE Targownik et al. Clin Gastroenterol Hepatol 2019; 17: 1788-98).

This ‘real-world’ study (2001-2016) utilized the Manitoba IBD database and included 852 persons with Crohn’s disease (CD) and 303 with ulcerative colitis (UC).

Key findings: 

  • In persons with CD, combination therapy (immunomodulator with a TNF antagonist) was associated with lower treatment ineffectiveness with an adjusted hazard ratio (aHR) for ineffectiveness at 0.62.  The ineffectiveness in UC persons was lower at 0.82 but did not reach statistical significance.
  • When looking at specific time frames, among patients with CD, at 1 year, combination therapy the rate of ineffectiveness-free treatment was 74.2% for combination therapy compared to 68.6% for monotherapy; at 2 years, the rates were 64.0% and 54.5% respectively.
  • Combination therapy in CD was associated with increased time to first IBD-related hospitalization with aHR of 0.53 and with lower rates of switching anti-TNF agents (aHR 0.63).  Lower rate of surgery (aHR 0.76) did not reach statistical significance.
  • The choice of immunomodulator (6-MP/AZA vs MTX) and the choice of anti-TNF agent (IFX or ADA) did not significantly influence the overall benefit of combination therapy.  Though, AZA was the main concomitant treatment (92%).
  • 90% of the patients in the study who received combination therapy had received immunomodulator therapy prior to combination therapy.  This is in contrast to the SONIC study in which patients were naive to both agents.
  • 57% of IFX users and 43% of ADA users received concomitant therapy.

My take: Combination therapy has been associated with higher response rates to IBD therapy.  This advantage has to be weighed against potential adverse effects.

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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.

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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.

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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.

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Can Therapeutic Drug Monitoring with Monotherapy Achieve Similar Results as Combination Therapy for IBD?

A recent retrospective study (S Lega et al. Inflamm Bowel Dis 2019; 25: 134-41) suggests that proactive therapeutic drug monitoring (pTDM) with infliximab (IFX) helps achieve similar outcomes as combination therapy (with immunomodulator) in patients with inflammatory bowel disease.

Before reviewing the key findings, it is important to emphasize a few crucial limitations/methods:

  • The study enrolled 83 patients; only 16 received were in the monotherapy pTDM group.
  • This was a retrospective study
  • The authors utilized TDM at week 10.  If the IFX level was <20 mcg/mL, the dose and frequency of infliximab were both adjusted. If the level was between 20 & 25, either the frequency was adjusted or no adjustment, and if the level was >25, then no adjustment in dosing was performed.

Key findings:

  • The frequency of infliximab discontinuation with mono therapy in those with pTDM was lower than in those with ‘standard of care’ TDM (P=0.04) but did not differ from patients receiving combination therapy
  • Overall 9 of the 83 patients (11%) discontinued IFX during the 1-year study

In the discussion, the authors suggest that week 14 TDM may be suboptimal as this is the first time patients have an 8-week interval.

My take: The jury is out with regard to whether pTDM can negate the need for combination therapy  –a prospective trial is needed; however, the idea of getting TDM a bit earlier is intriguing, particularly as it has been shown that a high percentage of pediatric patients are receiving an insufficient dose of infliximab (Is Standard Infliximab Dose Tool Low in Pediatrics?)

Key words: 10 weeks, therapeutic drug monitoring, infliximab, trough

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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.

View from Artist’s Drive, Death Valley

IBD Shorts August 2018

Vitamin D Receptor Signaling in IBD. Inflamm Bowel Dis 2018; 24: 1149-54.  This article reviews the ways vitamin D/vitamin D receptor may contribute to the genetic, environmental, immune, and microbial aspects of IBD.

LY Chi et al. Inflamm Bowel Dis 2018; 24: 1344-51. This study with 223 pediatric patients & young adults found that current or prior combination therapy with infliximab, compared to monotherapy resulted in higher infliximab levels and lower antibody formation. Combination agent was mainly methotrexate (n=71) rather than thiopurine (n=13). In those with infliximab dose <10 mg/kg, those currently receiving combination therapy had median level of 11.1 compared with 7.0 for prior combination and 5.86 for monotherapy (never combination).

CM Johnson et al. Clin Gastroenterol Hepatol 2018; 16: 900-7.  In this retrospective study with 1466 patients with Crohn’s disease, the subset of patients with granulomas (n=187, 12.8%) were associated with a more aggressive phenotype and a younger age at diagnosis (23.6 years compared with 27.9 years; P= .0005). These patients had higher rates of steroid use, narcotic use, more stricturing and penetrating disease along with increase rates of surgery.

 

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.

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I have not independently verified the claims on this tweet

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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