A Role for Thiopurine Therapy

In high school, the usual advice on multiple choice questions was to avoid picking “always” and “never” on multiple choice questions.

A recent commentary (KH de Boer et al.”Thiopurine Therapy in Inflammatory Bowel Diseases: Making New Friends Should Not Mean Losing Old Ones”Gastroenterol 2019; 156: 11-4) makes the point that “never” is probably the wrong answer with regard to thiopurine usage.

Key points:

  • “Thiopurine therapy has proven its value in maintenance of remission, decreased need for surgery, lowered colorectal cancer risk, less phenotypic disease progression, and synergistic effects when used with infliximab therapy, including increased biologic drug levels and less antibody formation.”
  • “Notwithstanding the extensive experience by many physicians, the clinical use of conventional immunosuppressive therapies has been questioned in recent years.”
  • “In this issue of Gastroenterology, Hanauer et al share their expert opinion on the evolving use of thiopurines and methotrexate in daily practice. In their literature review, the importance of assessing the risks (infections and cancer risk) and benefits (maintenance of remission) of thiopurine therapy is highlighted”
  • Lymphoma risk: “The recent nationwide cohort study based on French National Health Insurance databases is illustrative. Including 189,289 patients, it was demonstrated that both thiopurine (adjusted hazard ratio of 2.6) and anti-TNF monotherapy (adjusted hazard ratio of 2.4) were associated with a similar small but statistically significant increased risk of lymphoma. Furthermore, combination therapy of thiopurine and anti-TNF was associated with a higher chance of developing a lymphoma (adjusted hazard ratio of 6.1).”
  • “The individual absolute risk remains low, especially in patients without additional risk factors such as a young age in male patients and negative Epstein-Barr virus serology.”

The author’s conclusion: “The thiopurines are not perfect regarding both efficacy and toxicity, but in recent years they may have been portrayed in a worse light than they deserved. No doubt, the thiopurines will be surpassed eventually by newer safe and economical (oral) therapies, but it is too early to discard these old friends.”

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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.

Monticello

 

#NASPGHAN17 IBD Treat to Target and Tight Control

More information from this year’s annual NASPGHAN meeting.

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

IBD Treat to Target: Treat the Patient or Treat the Disease

Robert Baldassano  Children’s Hospital of Philadelphia

I missed the first few minutes of this presentation, even though I had highlighted this as one of my top priorities.  So, if anyone reading this post has some additional comments, they are certainly welcome.

Key points:

  • Do not rely on symptoms alone to assess patient improvement.
  • Best surrogate marker: calprotectin.  Frequent calprotectin levels can help determine objective improvement; it is much more helpful than CRP as ~25% of patients do not elevate their CRP levels
  • Therapeutic drug monitoring is important in improving outcomes. Dose optimization improves response rate and durability of infliximab response.
  • Evolving targets in ulcerative colitis.  Even histologic activity, in the absence of endoscopic activity, is associated with relapsing disease
  • Dr. Baldassano indicated that he no longer is starting patients on thiopurine therapy. There are “36 phase 3 trials underway.” Thus, many promising options for those who may burn through current treatments
  • This lecture reviewed data from the RISK study showing that early (1st 90 days w/in diagnosis) TNF therapy helps prevent penetrating disease (related post: CCFA Update 2017/RISK study)

Another presentation by Philip Minar et al (Cincinnati Children’s Hospital Medical Center) shows that CD64 suppression is an early biomarker of response to infliximab therapy.

#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.

 

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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.

Infliximab Not Associated with Malignancy

JS Hyams et al. Gastroenterology http://dx.doi.org/10.1053/j.gastro.2017.02.004

Using the DEVELOP registry, a prospective study showed no increased risk of malignancy among 5766 pediatric participants with inflammatory bowel disease.

Link: Full Abstract

Immunosuppressive therapy for inflammatory bowel disease (IBD) in pediatric patients is thought to increase risk of malignancy and lymphoproliferative disorders, including hemophagocytic lymphohistiocytosis (HLH). We compared unadjusted incidence rates and of malignancy and HLH in pediatric patients with IBD exposed to infliximab compared with patients not exposed to biologics and calculated standardized incidence ratios (SIRs).

Methods

We collected and analyzed data from 5766 participants in a prospective study of long-term outcomes of pediatric patients with IBD (NCT00606346), from 2007 through 30 June 2016. Patients were 17 years old or younger and had Crohn’s disease, ulcerative colitis, or IBD unclassified with 24,543.0 patient-years of follow-up. We estimated incidence rates for malignancy and HLH as events/1000 patient-years of follow-up. We calculated age-, sex-, and race-adjusted SIRs, with 95% CIs, using the Surveillance, Epidemiology, and End Results Program (SEER) database.

Results

Thirteen of the 15 patients who developed a malignancy and all 5 of the patients who developed HLH had been exposed to thiopurine; 10 patients with malignancy patients had also been exposed to a biologic agent. Unadjusted incidence rates showed no increased risk of malignancy (0.46/1000 patient-years) or HLH (0.0/1000 patient-years) in patients exposed to infliximab as the only biologic vs those unexposed to biologics (malignancy: 1.12/1000 patient-years; HLH: 0.56/1000 patient-years). SIRs did not demonstrate an increased risk of malignancy among patients exposed to infliximab (SIR; 1.69; 95% CI, 0.46–4.32) vs patients not exposed to a biologic agent (SIR, 2.17; 95% CI, 0.59–5.56), even when patients were stratified by thiopurine exposure.

Conclusions

In determination of age-, sex- and race-adjusted SIRs using data from a large clinical trial and the SEER database, we found that infliximab exposure did not associate with increased risk of malignancy or HLH in pediatric patients with IBD. Thiopurine exposure is an important precedent event for the development of malignancy or HLH in pediatric patients with IBD.

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Support for Step-Up Therapy and Thiopurines

A retrospective study (H Bar-Yoseph et al. Clin Gastroenterol Hepatol 2017; 15: 69-75) indicated that thiopurine use before infliximab (IFX) was associated with the prevention of antidrug antibody formation in patients with Crohn’s disease.

The authors had 207 eligible patients which included 93 who received IFX monotherapy, 52 who received combination therapy after response to thiopurine, 34 who received IFX after lack of response to thiopurines (but continued with combination treatment), and 28 who received de novo combination therapy.  The total number of patients followed in these centers is much higher, but they excluded those with episodic infusions and for other reasons that could affect their conclusions.

Key findings:

  • Prior thiopurine therapy was associated with lower antidrug antibodies (ADA). At 1 year, past thiopurine responders had 19.3% ADA, past thiopurine failures had 16.1% ADA; both were much lower that the monotherapy rate of 46.6%  The de novo combination group had a rate of 21.9% which did not reach significance.
  • Interestingly, after the first 5 months, the de novo combination group did not develop further ADA but during the first 5 months the rate of ADA was quite similar to the monotherapy rate. This could be related to the notion that thiopurines may take 3-6 months to achieve full effect.
  • Combination therapy (compiled)  was associated with higher rates of clinical remission (58.8% vs 40.9%) and lower rates of active disease (8.8% vs. 21.5%).

Overall, this study showed high rates of ADA compared to many studies but the conclusions are similar to other published studies.  It could be that many of those with positive ADA were lower antibody levels and that many of these levels may not be clinically significant. The study has limitations mainly related to being a retrospective study.

My take: This study supports the following:

  1. Combination therapy is more effective than monotherapy
  2. Using an immunomodulator before starting infliximab may reduce ADA formation more effectively than starting combination therapy de novo.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing/usage 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.

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Cost Effectiveness & Underpowered Studies

A recent study (ALT Ma et al. J Pediatr 2016; 179: 216-8) reaches a conclusion that questions the cost-effectiveness of pretreatment TPMT activity in pediatric patients. In my opinion, this retrospective study is ridiculous. Here’s why:

The authors examined thiopurine transmethyltransferase (TPMT level) in 228 children before starting a thiopurine. They found the following:

  • Only 2 patients experienced mild neutropenia
  • 12% of their cohort had intermediate activity and 88% normal TPMT activity

I agree with their conclusion that routine blood tests are needed following institution of thiopurines, I think stating that “from an economic point of view –the cost for testing TPMT enzyme activity was high without major clinical benefit” cannot be made with such a small study.  Deficient TPMT activity occurs in about 1 in 300.  If a single patient develops bone marrow suppression due to a thiopurine medication, this can lead to a horrific and prolonged hospitalization.  The cost of such a hospitalization, both economically and emotionally, is enormous.

My take: If I were taking a thiopurine, I would want to know if I metabolized this medication at a slower rate and was at increased risk for bone marrow suppression.  My hunch is the authors would not forgo checking a TPMT level on themselves despite their study’s conclusion, particularly if they have ever witnessed a patient with thiopurine-induced bone marrow suppression.

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One Proposal to Reduce Thiopurine Combination Therapy

A recent review (X Roblin et al. Inflamm Bowel Dis 2016; 22: 1496-1501) provided a useful review of thiopurine/biologic combination therapy.  The part of this review that I found intriguing was their Figure 3: “Proposed algorithm that may guide drug discontinuation or de-escalation in patients with IBD who achieved sustained deep remission while on combination therapy.”

  • In those (in sustained deep remission) with an infliximab trough level >5 mcg/mL, this algorithm recommends discontinuation of thiopurine.
  • In those with an infliximab trough level 3-5 mcg/mL and with 6-TGN >250, this algorithm recommends reduction of thiopurine to obtain 6-TGN level >125.
  • In those with an infliximab trough level <2 mcg/mL and with 6-TGN >250, this algorithm recommends discuss stopping infliximab.

The authors acknowledge that this algorithm has not been studied and “needs to be investigated in prospective trials specifically addressing this issue.”

My take: Until more studies emerge, the best way to balance control of IBD and minimize drug toxicity remains uncertain.

Unrelated references:

  • “Crohn’s disease of the ileoanal pouch” AL Lightner et al. Inflamm Bowel Dis 2016; 22: 1502-8.
  • SZ Koh et al. Inflamm Bowel Dis 2016; 22: 1397-1402. This reference describes clinical factors associated with development of Crohn’s disease in patients with IBDU who have undergone ileal pouch (e.g. younger age).

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