Tag Archives: thiopurine

Infliximab Not Associated with Malignancy

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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

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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.

Related blog posts:

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

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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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Grand Prismatic Spriing, Yellowstone

Grand Prismatic Spriing, Yellowstone

One Proposal to Reduce Thiopurine Combination Therapy

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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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Arthur Ravenel Jr Bridge

Arthur Ravenel Jr Bridge

IBD ‘Pearls’

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A clinical pearl is “a short, straightforward piece of clinical advice.” Here are a few:

2015 DDW abstract –#536 DR Hoekman et al “Non-trough IFX concentrations reliably predict trough levels and accelerate dose-adjustment in Crohn’s disease.”  This abstract examined data from 20 CD patients.  The authors noted that infliximab concentrations of 15 mcg/mL or higher at week 4 and 7.5 mcg/mL or higher at week 6 appeared to predict trough concentrations of 3 mcg/mL or higher at week 8.

U Kopylov et al. Inflamm Bowel Dis 2015; 21: 1847-53.  This nested case control study identified 19,582 eligible patients.  Key findings:

  • Treatment with thiopurines for more than 5 years did not increase the risk of lymphoma, melanoma or colorectal cancer.
  • There was an association between thiopurine use and nonmelanoma skin cancer (OR 1.78).
  • No association was found between the risk of the evaluated malignancies and anti-TNFα medications

K Huth et al. Inflamm Bowel Dis 2015; 21: 1761-68. This prospective cohort study completed over 2 successive influenza seasons showed that offering education and access to vaccination improved rates of vaccination from 47% (2011-12) to 75% (2013-14).  The education module is available: www.cheo.on.ca/en/IBDflu

KH Katsanos et al. “Review article: non-malignant oral manifestations in inflammatory bowel disease” Aliment Pharmacol There 2015; 42: 40-60. (Thanks to Ben Gold for this reference). This review article provides extensive information about oral lesions in IBD, differential diagnosis, numerous pictures, and management recommendations.  Some oral lesions are directly related to IBD, others can be induced by vitamin deficiencies or by medications.

One of my pet peeves -I avoid using straws

One of my pet peeves -I avoid using straws.  I heard this statistic several years ago and also see too many littered straws.

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.

Another Look at “Step-up” IBD Therapy

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Whether and how long to continue immunomodulators in patients who have undergone a “step-up” treatment to anti-tumor necrosis factor (anti-TNF) therapy remains murky.  This is due to conflicting data from different patient cohorts, changing treatment trends, (e.g. use of drug monitoring to enhance anti-TNF therapy), and different endpoints. With regard to the latter, dual therapy has been clearly more effective in some landmark studies (eg. SONIC, UC SUCCESS); however, there have been ongoing concerns regarding long-term outcomes and adverse effects.

Will more studies help resolve this question? Perhaps, but not today.

A recent study (MT Osterman et al. Clin Gastroenterol Hepatol 2015; 13: 1293-1301) examined a retrospective cohort of new users of anti-TNF therapy for Crohn’s disease in Medicare recipients.  The authors matched 381 combination with infliximab (ie. dual therapy) with 912 users of monotherapy. In addition, the authors did the same with adalimumab with 196 combination users and 505 monotherapy users. In their cohort, combination therapy occurred primarily as a “step-up” treatment after institution of thiopurine therapy.

Results:

  • Key outcome measures were unchanged: rates of surgery (hazard ratio [HR] 1.2, hospitalization HR 0.82, discontinuation of anti-TNF therapy or surgery HR 1.09, and serious infection HR 0.93
  • Opportunistic infections were increased in combination therapy with HR 2.64 and herpes zoster infection was increased with HR 3.16

Take-home message: This study suggests, at least in this elderly population, that once remission is achieved with anti-TNF therapy, discontinuation of thiopurine therapy or use of an alternative immunomodulator therapy may be worthwhile.  At the same time, definitive answers to these type of questions await carefully designed randomized trials.

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Not Using and Stopping Therapy in IBD

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Two recent articles show that a lot of patients are not receiving much therapy in inflammatory bowel disease.

  • Moreno-Rincon E et al. Inflamm Bowel Dis 2015; 21: 1564-71.
  • Melesse DY et al. Inflamm Bowel Dis 2015; 21: 1615-22.

In the first article, a multicenter retrospective study of 102 patients, the authors examined the relapse rates of patients with ulcerative colitis who had withdrawal of thiopurines.  They defined “significant clinical relapse” (SCR) as “the occurrence of UC typical signs or symptoms requiring a rescue therapy such as oral or intravenous corticosteroids, biological therapy, immunosuppressant drugs, recapture with TP [thiopurine] or surgery.”

Key findings:

  • Overall SCR was 32.35%.
  • Predictors of relapse included pancolitis (HR 5.01) and duration of treatment with thiopurines (HR 0.15).

Among those without relapse, the mean duration of remission prior to withdrawal of thiopurines was 54 months compared with 34 months in those who relapsed. In figure 2, the authors note that the rate of relapse was 19.2% for those who received >48 months of thiopurine treatment compared with a 45% rate of relapse for those who received treatment for 13-47 months.  The authors note that several studies have shown higher relapse rates than reported in this cohort and that interruption of therapy is associated with a considerable risk of relapse.

Limitations: small retrospective study and the expectation that their SCR would capture the true relapse rate.

The second study, using a Manitoba database, shows a strikingly-high rate of nonuse of medical therapy. Between 1996-2012, 3902 patients with IBD were identified; 47% with Crohn’s disease (CD) and 53% with ulcerative colitis (UC).  While only 11.7% of IBD patients did not have medication dispensed in the first year after diagnosis, beyond this period, “roughly half of all patients with IBD have not used IBD-specific medications in the previous year.”  The authors are not certain how much nonuse is due to nonadherence or nonprescription. They note that there was higher nonuse in patients with CD, possibly due to use of surgical treatment.  However, they note that multiple medications have been shown to reduce postsurgical relapse in CD.

My take: There are a lot of patients off therapy, both due to withdrawal of therapy when doing well and others due to nonadherence or nonprescription.  With or without overt symptoms, these studies make one wonder whether undertreatment will lead to long-term complications or whether there could be a significant number of patients who are overtreated.  Either way, it remains quite difficult to predict which patients will do well off medical therapy.

Broadcasters Really Know the Key Points to Winning!

Broadcasters Really Know the Key Points to Winning!

Optimal Dose of Thiopurine When Used for Combination Therapy

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To improve long-term outcomes and response in patients with inflammatory bowel disease, many experts advocate the use of combination therapy (thiopurine with anti-tumor necrosis factor).  Thiopurine cotherapy resulted in higher response rates in pivotal studies (eg. SONIC, UC Success), likely due to lower rates of antidrug antibody (ADA) and higher serum levels of biologic agents (e.g. infliximab).  To achieve these advantages, it is not clear whether a lower dose of a thiopurine may be similarly effective as a higher dose.  If a lower dose could result in a similar effect, it would likely result in fewer adverse effects.

A recent study (Yarur AJ, et al. Clin Gastroenterol Hepatol 2015; 13: 1118-24) provide some data to address the issue of optimal dosing of thiopurines.  The authors performed a cross-sectional study of 72 patients receiving infliximab (IFX) and a thiopurine.

Key findings:

  • The thiopurine metabolite 6-thioguanine (6-TG) that “best predicted a higher level of infliximab was 125 pmol/8 x 10 to the 8th RBCs.”
  • Only 8 patients (11%) had detectable antibodies to infliximab (ATI)
  • Patients with 6-TG <125 were more likely to have ATI (OR 1.3)
  • Higher 6-TG levels did not confer additional benefit

This study had many limitations including the small number of patients and the cross sectional design.  In addition, the patients may not be representative of typical patients; more than 50% were in endoscopic remission. A randomized controlled trial with larger number of patients is needed for a more definitive answer.

Take-home message: (from authors); “6-TGN metabolite levels rather than weight-based dosing may assist clinicians in optimizing treatment when using thiopurines in combination with IFX…lower target 6-TGN levels (125-176 pmol/8 x 10 to the 8th RBCs) may be adequate to maximize IFX levels and reduce immunogenicity while potentially minimizing toxicity.”

Briefly noted:

Ananthakrishnan AN et al. Clin Gastroenterol Hepatol 2015; 13: 1197-1200.  In this prospective study with 1659 patients with Crohn’s disease (CD) and 946 patients with ulcerative colitis, the authors found wide variation among the 7 participating academic centers, particularly with regard to CD treatment.  Comparing the site with the lowest usage to the highest usage, for CD:

  • Oral mesalamine 13% vs. 46%
  • Immunomodulator use 16% vs. 56%
  • Anti-TNF use 31% vs 60%
  • Combination therapy 8% vs 32%
  • Immunomodulator-naive anti-TNF use 10% vs. 17%
  • Surgery 32% vs 55%

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Cumberland Island

Cumberland Island

Toronto Consensus: Practice Guidelines for Nonhospitalized Ulcerative Colitis

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A group of 23 experts followed a rigorous process over a 1-year period to assess the quality of evidence and develop consensus statements regarding the medical management of ulcerative colitis (UC) in adults (Bressler B, Marshall JK et al. Gastroenterol 2015; 148: 1035-58, editorial 877-80).

The need for updated guidelines has emerged due to practice variation related in part to a wider availability of treatments and diagnostic tools. It is recognized that early institution of effective therapy is associated with the best outcomes.  In addition, due to the chronic nature of ulcerative colitis and the potential for reduced durability of biologic agents, careful decision-making can improve response.

Table 4 in the article summarizes the recommendations.  I will list a few:

1. Thiopurines:

  • “In patients with UC, we recommend against the use of thiopurine monotherapy to induce complete remission.”
  • In selected patients, “we suggest thiopurine monotherapy as an option to maintain complete corticosteroid-free remission.”

2. Anti-TNF therapy:

  • “In patients with UC who fail to respond to thiopurines or corticosteroids, we recommend anti-TNF therapy to induce complete corticosteroid-free remission.”
  • “When starting anti-TNF therapy, we recommend it be combined with a thiopurine or methotrexate rather than used as monotherapy to induce complete remission.”
  • For UC patients with suboptimal response or for those who lose response to anti-TNF therapy, “we recommend dose intensification.”  Dose optimization should be informed by therapeutic drug monitoring.

3. Vedolizumab

  • Vedolizumab is recommended with primary anti-TNF failure (rather than switching to an alternative anti-TNF), whereas either a 2nd anti-TNF or vedolizumab is recommended with secondary anti-TNF failure based on therapeutic drug monitoring.

4. Fecal microbial transplant (FMT)

  • “We recommend against FMT…outside the setting of a clinical trial.”

5. 5-ASA and Corticosteroids

  • Rectal 5-ASA is recommended at 1 g daily for mild-to-moderate ulcerative proctitis.  5-ASA enemas are recommended for mild-to-moderate left-sided ulcerative colitis.
  • In patients with moderate-to-severe UC, corticosteroids are recommended as 1st line therapy for induction of remission but not for maintaining remission.  In addition, corticosteroids are recommended as 2nd-line agents for inducing remission in those with mild-to-moderate disease who do not respond to 5-ASA products.

With all of the treatments, the authors recommend followup to assure response to therapy; this followup ranges from within 2 weeks for steroids, to 4-8 weeks with 5-ASA products, to 8-14 weeks for biologic agents.

Overall, the emphasis of this consensus statement is on maximizing the response to biologic agents.  By optimizing dosing and using combination therapy, the treatment guidelines aim to lower rates of antidrug antibody formation.  This in turn should improve results and is in agreement with data from both the SONIC study and the UC-SUCCESS study.

The editorial comments that methotrexate “may be an attractive option for young male patients;” however, “the absence of data on risk of malignancy with methotrexate in IBD may reflect lower frequency of use for this indication.”

While these guidelines will be useful, there are many unanswered questions (discussed in editorial).

  • In patients on combination therapy, what is the optimal dose of the immunomodulator?
  • When or Should the immunomodulator be withdrawn?
  • For secondary failure, should a 2nd anti-TNF be used prior to vedolizumab?
  • How should these guidelines be tailored for the pediatric population (or the elderly)?
  • What is the optimal monitoring for UC patients with regard to biomarkers and endoscopy?
  • What is the appropriate role of therapeutic drug monitoring?

Bottomline: These guidelines are likely to promote the use of more combination therapy and help define the current role of vedolizumab.

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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.

Don’t be Fooled About Withdrawing Immunomodulator Cotherapy -Look Past the Headline

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The coverage on a recent study (Clinical Gastroenterology and Hepatology 2015: 13(3): 514-521.e4) suggests that it should be fine to stop immunomodulator co-therapy.  I recommend reading the entire study (or at least this blog post)–you will probably come to a different conclusion.
Brief summary from AGA website: Withdrawal of Immuonomodulators after Co-therapy Does Not Reduce Trough Level of Infliximab in Crohn’s Patients

“The addition of immunomodulators increases the efficacy of maintenance therapy with infliximab for up to one year in patients with Crohn’s disease who have not been previously treated with immunomodulators. However, there are questions about the effect of withdrawing immunomodulator therapy from these patients. David Drobne and colleagues studied the effects of treatment with infliximab and immunomodulators (co-treatment) and then immunomodulator withdrawal on long-term outcomes of patients, as well as trough levels of infliximab and formation of anti-infliximab antibodies (ATI). Reporting in Clinical Gastroenterology and Hepatology, they find that, in a retrospective analysis, withdrawal of immunomodulators after at least six months (median, 13 months) of co-treatment with infliximab does not reduce the trough levels of infliximab in patients with Crohn’s disease. Detectable trough levels of infliximab at the time of immunomodulator withdrawal are associated with long-term response.”

Clinical Gastroenterology and Hepatology 2015: 13(3): 514-521.e4

Some additional details:

This was a retrospective open-label cohort study with 223 patients and median followup of 34 months. At baseline, 65 received infliximab (IFX) monotherapy and 158  received co-therapy with an immunomodulator (46 methotrexate, 112 thiopurine).  Immunomodulators were withdrawn “only in patients with durable response (ongoing clinical benefit with lasting disease control with low C-reactive protein [CRP] [below 10 mg/L]).”  Among the 158 on co-therapy, 117 reached a durable response and had withdrawal of immunomodulator after >6 months of combination therapy (median time 13 months).

Key findings:

  • At baseline, co-therapy patients, compared to monotherapy patients, had higher IFX trough levels (adjusted mean increase of 1.44-fold) and lower likelihood of antibodies to infliximab (ATI): 35/158 (22%) compared with 25/65 (38%), P=.01.
  • When immunomodulator was withdrawn, IFX levels remained stable: before 3.2 mcg/mL compared with after 3.7 mcg/mL. However, 45 of 117 (38%) required increasing doses of IFX and 21 of 117 (18%) discontinued IFX.
  • Trough levels of IFX and CRP  were most strongly associated with response to IFX dosing on monotherapy.
  • “Only 9 of 74 patients (12%) with detectable IFX trough levels at the time of immunomodulator withdrawal developed undetectable IFX trough levels during the subsequent follow-up.”
  • None of the 27 patients with IFX trough level >5 mcg/mL at time of immunomodulator withdrawal lost response to IFX during median follow-up of 29 months.

Though the headlines covering this article have suggested that IFX levels will stay stable when immunomodulators are withdrawn after >6 months, the authors proposed algorithm only recommends withdrawal for those with IFX trough level >5 mcg/mL.  In addition, the data showed that a large number of patients required dose escalation and/or lost detectable IFX levels. Despite their proposed algorithm to withdraw in this small group, the authors further backtrack in their conclusion:  “a prospective parallel group trial during a period of 5-10 years in a large group of patients is required to ascertain the real long-term benefit to risk ratio of continuing combined infliximab and immunomodulator treatment.”

Bottomline: If a patient is doing well, withdrawing immunomodulator co-therapy still has risks. I worry that the misleading reporting of this article will result in detrimental outcomes.

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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.