Practice Tips for New IBD Therapies

A recent review provides some helpful advice: “A Practical Guide to the Safety and Monitoring of New IBD Therapies” (B Click, M Regueiro. Inflamm Bowel Dis 209; 25: 831-42).

This review discusses infection risk, malignancy risk, immunologic issues and other complications.

In terms of infection risk assessment, the authors describe a pyramid in which they stratify the risks of medications.  The safest to least safe in their assessment: vedolizumab –>ustekinumab–>anti-TNF monotherapy–>thiopurine or tofacintinib–>thiopurine/anti-TNF combination–>steroids.

Their Tables:

  • Table 1 lists potential infections and vaccination recommendations
  • Table 2 suggests management of active infections by IBD Medication Class
    • For anti-TNF agents and for IL12/23 agents: the authors recommend continuation of agent if viral (eg EBV, VZV, HSV) or bacterial (eg. Strep/Staph)/C difficile infections (unless severe) but holding for opportunistic infections.
    • For integrin agents, the authors recommend continuation of medications in the face of infections except “consider holding dose” during active C difficile infection
    • For JAK agents, the authors recommend stopping during viral infections and with opportunistic infections.  They recommend continuing with bacterial infections (hold if severe) and continuing with C difficile infection
  • Table 3 suggests management in the setting of active malignancy
    • Table 4 lists recommendations in the setting of immunologic complications.  Theses categories include antidrug antibodies,lupus-like reactions, demyelinating conditions, and psoriasis.
    • One of the points alluding to in this chart is that addition of methotrexate may help in patients receiving anti-TNF therapy with psoriasis.
    • No psoriatic reactions have been reported with vedolizumab, ustekinumab or tofacitinib; ustekinumab is FDA-approved for use in psoriasis and tofacitinib is FDA-approved for psoriatic arthritis.
  • Table 5 suggests recommendations in the setting of altered liver enzymes and altered lipids/creatine kinase

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#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.

Good Safety Data on Infliximab vis a vis Malignancy and Hemophagocytic Lymphohistiocytosis

Using data from 5766 pediatric participants with inflammatory bowel disease in a prospective DEVELOP study (JS Hyams, MC Dubinsky et al. Gastroenterol 2017; 152: 1901-14) provide more reassurance regarding the safety of infliximab.  This study took place between 2007 to 2016 and accounted for 24,543 patient-years of followup.  While the study examined rates of malignancy, the SEER database does not include non-melanoma skin cancer; thus, the authors did not have a suitable comparator for this outcome; there were two cases of basal cell carcinoma in the study population.  This article’s abstract was published on this blog previously: Infliximab Not Associated with Malignancy

Key findings:

  • There was NO increased risk of malignancy or hemophagocytic lymphohistiocytosis (HLH) in patients exposed to infliximab as monotherapy.
  • Malignancy risk was 0.46 per 1000 patient-years in patients with infliximab exposure compared with 1.12/1000 patient-years in patients who had no exposure to biologics.
  • HLH risk was 0 in those with infliximab monotherapy compared with 0.56 per 1000 patient-years in those who had no exposure to biologics.
  • Patients exposed to thiopurines with or without biologics did have increased risks of malignancy compared with comparative populations. 13 of 15 patients who developed a malignancy and all 5 patients who developed HLH had thiopurine exposure.
  • Thiopurine exposed patients had 0.75 malignancy events per 1000 patient-years compared to 0.27 malignancy events per 1000 patient-years for patients who had no thiopurine exposure
  • Thiopurine exposed patients had 0.29 HLH events per 1000 patient-years compared to 0 HLH events per 1000 patient-years for patients who had no thiopurine exposure
  • In their discussion, the authors note that after discontinuation of thiopurine therapy for 1 or more years, the standardized incidence ratio (SIR) for malignancy approached the non-exposed group (1.48 compared to 1.30); whereas ongoing or recent thiopurine exposure had SIR of 4.45.

Limitations: Study duration (<10 years). Hard to detect changes in rare malignancies

My take: In this largest prospective pediatric cohort to date, there is NO increased risk of malignancy (excluding non-melanoma skin cancer) or HLH with infliximab therapy; however, there is a trend towards increased risk among those with thiopurine exposure. Nevertheless, as malignancy is a rare event, very low increased risk of malignancy with infliximab cannot be entirely excluded.

Related blog posts:

For HLH:

 

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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Safer Than You Think: Biologic Therapies for IBD and Risk of Infection and Malignancy

While there have been a number of studies which have highlighted the potential risks of biologic agents, many studies have NOT identified any risk of infection or malignancy.

Another recent systematic review/meta-analysis (S Bonovas et al. Clin Gastroenterol Hepatol 2016; 14: 1385-97) provides reassuring data regarding the following biologics: infliximab, adalimumab, certolizumab, golimumab, natalizumab, and vedolizumab.

The authors identified 49 randomized placebo-controlled studies with 14,590 participants.

Key findings:

  • There was a moderate infection risk with odds ratio of 1.19 (19% increase in odds of developing an infection) and significant increase in opportunistic infections (eg. tuberculosis) OR 1.90
  • Risk of serious infections was NOT increased in patients treated with biologics with OR 0.89.  In studies with low risk of bias, the risk of serious infections had OR of 0.56.
  • No increase in malignancy risk was identified with OR 0.90 but the authors note that data was insufficient in terms of exposure and follow-up to be conclusive.

The authors note that the studies including in this review challenge some of the findings of observational studies. “However, observational studies lack the experimental random allocation of participants…the discrepancies between observational studies and randomized trial evidence might be explained by the inability of observational designs to fully address the complex and important differences between the IBD patients receiving and those not receiving biologics.”

Study limitations include “sponsorship bias -because the trials were supported by pharmaceutical companies and limited followup of 24 months. In addition, most of the trials in the meta-analysis were judged to be at high or unclear risk of bias because of their methodological characteristics.

My take: This study indicates that biologic therapies do not appear to increase the risk of serious infections and may not increase the overall risk of malignancy.

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Portland Fish Market

Portland Fish Market

 

 

Methotrexate –First Choice Immunomodulator?

In pediatric inflammatory bowel disease (IBD), there has been an uptick in the usage of methotrexate (MTX) over the last 10 years.  This coincides with malignancy concerns, particularly hepatosplenic T-cell lymphoma, with thiopurine use.  Recently, a retrospective study examines the use of MTX in a cohort of 290 patients from 19 centers. 172 received monotherapy with MTX for >3 months and had at least one year of followup.

Key findings:

  • 81 of these 172 used MTX as their first immunomodulator (IMM) (monotherapy) and this had become more prevalent towards the end of the study period (60% in 2010).  Among these 81, 27% achieved a sustained clinical remission –based on physician global assessment.
  • 35% who used MTX as their second IMM achieved a sustained clinical remission.
  • Among MTX users, 15% had increased ALT (>60 IU/L) and 12% had white blood cells <4000 cells/mL.
  • There was wide variation in usage of MTX therapy among different pediatric centers.
  • According to Figure 2, there was little difference in the usage of MTX between males and females.  Given the well-recognized teratogenicity with MTX, it is interesting that the authors did not elaborate on this finding.

One limitation of this study was the absence of data regarding route of MTX administration. Oral bioavailability is likely a little lower than with parental dosing.  Another limitation was reliance on physician global assessment without correlating a marker for mucosal healing.

Take-home message: Methotrexate is being used more frequently as a first-line IMM.  As there are no head-to-head comparison studies with thiopurines, one can only speculate whether its efficacy and safety are good enough to chosen as the first immunomodulator.

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Sticky Decisions with IBD Therapy – When an Infection or Malignancy Develops

A recent review article provides advice for management of biologics and immunomodulators when an infection or malignancy develops (Inflamm Bowel Dis 2014; 20: 926-35).  Serious infections are noted in 3-5% of adults receiving either thiopurines or anti-tumor necrosis factor agents (anti-TNFs); less than 0.1% of adults develop treatment-related lymphoma.  The recommendations are provided in 5 separate tables.

Table 1 addresses the issue of bacterial infectionsFor mild infections, the authors recommend that thiopurines (azathiopurine, 6-mercaptopurine) as well as anti-tumor necrosis factor agents (infliximab, adalimumab, certolizumab, golimumab) be continued.  Examples of these ‘mild’ infectious included E. coli UTI and strep pharyngitis.  For severe bacterial infections (eg. pneumococcal pneumonia), for both these therapies, the authors recommend: “stop, but may restart once treated.”  For bacterial opportunistic infections (eg. mycobacterium), for latent infections, “do not start until 2 to 4 wk INH” whereas for active infections, the authors recommend (for anti-TNFs) “stop, only restart after full treatment, and if IBD is severe.”

  • Table 2 addresses fungal infections.
  • Table 3 addresses viral infections (eg. CMV, EBV).  For EBV, the authors recommend stopping thiopurines and not restarting in male patients.
  • Table 4 addresses malignancy: solid tumors, hepatosplenic T-cell, EBV-associated lymphoma, and lymphoproliferative lymphoma.
  • Table 5 addresses skin cancers.

Towards the end of the review, the authors provide some context for the risks with thiopurines and anti-TNFs.  “The majority of side effects associated with thiopurines and anti-TNFs are mild, self-limited and reversible…the risk of a lymphoma developing on AZA/6-MP (4/10,000 patient-years) is comparable with the lifetime risk of dying from drowning (1/1112) or dying in a bicycle accident (1/5000).  The risk is much less than the risk of dying in an automobile accident (1/108).  Patients are willing to accept risks..if their disease is severe and the chance of a clinical response outweighs the risk.”

With regard to dual therapy, the authors note, “it has been our practice to lower the concomitant AZA/6-MP in patients on combination therapy with anti-TNF and then to stop the thiopurine in patients in deep remission for 3 years. However, this decision must be individualized, and for patients with severe, disabling disease, we generally do not alter treatment.”

Bottomline: This is a useful advice/handy reference for the sticky situation of managing IBD in the face of infections and malignancy.

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.