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 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.

CCFA Conference Notes 2016 (part 3) -Malignancy and IBD

This blog entry has abbreviated/summarized this terrific presentation; most of the material has been covered in this blog in prior entries but still this was a useful review. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

3rd Lecture: Prevention and management of malignancy in IBD –Dr. Thomas Ullman

Malignancy risk (colorectal cancer [CRC]) is present with prolonged ulcerative colitis, though more recent studies have shown lower risk than in the past –not much higher than the general population.

Screen Shot 2016-04-17 at 12.02.04 PM

  • CRC surveillance–colonoscopy monitoring after 8-10 years. Typically colonoscopy every other year for most patients, every year in higher risk patients (eg. PSC).

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  • Unclear if chemoprevention is effective (5-ASA, thiopurines, others).
  • Chromoendoscopy “has not been consensus on its use in our field (yet).” It is time consuming and expensive and unclear if it will improve outcome.

Does medical therapy for IBD predispose to developing cancer?

  • Thiopurines increase the risk of malignancy. (Pasternak et al) though the risk returns to near baseline when stopped according to study below.

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  • No overall increased risk with anti-TNF agents with RCTs (may not follow patients long enough) but also not seen in Danish registry either (JAMA study)
With Anti-TNFs

No increased risk of malignancy in this study with Anti-TNFs

  • Lymphoma risks: age, immunodeficiency, EBV
  • EBV negative are at risk for HLH with thiopurines
  • HTSCL ~200, >90% men and >90% <35 years. NOT EBV-related. Has not been identified in anti-TNF monotherapy.

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  • Skin cancer –main concern is in non-melanoma skin cancer (possibly melanoma too). Skin cancer increase has not been noted with methotrexate. Prevention: Skin care, and annual dermatology visits.
  • Cervical cancer—likely increased risk in IBD, probably due to thiopurine exposure and reduced immune surveillance. Prevention: HPV vaccination, Pap testing.
  • Urinary Tract cancers –especially in those >65 years with thiopurine exposure

 

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.

 

Malignancy Risk with Thiopurines

Based on a large retrospective, nationwide cohort study, it has been estimated that patients with ulcerative colitis have a 4-fold increase in the risk of lymphoma compared with patients who have not been treated with thiopurines (Gastroenterol 2013; 145: 1007-15).  While this study enrolled data from 36,891 patients followed for a median of 6.7 years, this study should not be interpreted in isolation.  The editorial (pages 927-30) provides some important context.

Besides the risk of lymphoma in patients treated with the thiopurines, the editorial briefly states the potential for life-threatening infections, primarily varicella and hemophagocytic lymphohistiocytosis which may complicate primary EBV infection.  The latter is much more common in younger patients.

With regard to malignancy, besides lymphoma, thiopurines also increase the frequency of nonmelanoma skin cancer.  Since these are not life-threatening, in many patients the risk of lymphoma is “the major limiting factor for the prolonged use of thiopurines.”  Furthermore, the risk of lymphoma may increase relative to treatment duration according to the above-referenced study. The editorial notes that there are three types of lymphoma to be considered:

  1. Posttransplant-like lymphoma associated with EBV seropositivity. Absolute risk in all IBD patients ~ 1 per 1000 patient-years.  All EBV-seropositive patients are at risk.
  2. Early post-mononucleosis lymphomas. Absolute risk in all IBD patients ~0.1 per 1000 patient-years; however, the risk in young men who are seronegative for EBV (<35 years) is ~3 per 1000 patient-years.
  3. Hepatosplenic T-cell lymphomas.  Absolute risk in all IBD in all IBD patients ~0.05 per 1000 patient-years; again, in young patients (mostly men) the risk is ~0.1 per 1000 patient-years.

The second and third types of lymphomas can be reduced by limiting thiopurines in young men.

Despite the risks posed by thiopurines, the overall benefit-risk balance needs to consider the fact that the risk of colorectal cancer “is markedly reduced in patients with long-standing extensive colitis exposed to thiopurines.”  Thus, the lowered risk of colorectal cancer “may outweigh the excess risk of lymphoma.”

Also, in considering thiopurines:

Inflamm Bowel Dis 2013; 19: 2801-08.  “Thiopurines are Associated with a Reduction in Surgical Re-resections in Patient’s with Crohn’s Disease.”  This study was a retrospective review of 567 patients of whom 237 (41.8%) developed a surgical recurrence after a median of 70 months.  Taking thiopurine was associated with a hazard ratio of 0.51.  Due to small numbers, the results with anti-TNF therapy was not conclusive, but “seems promising as well.”

Related blog posts:

Risk from CT scans -Best Data to Date

Thanks to Mike Hart for forwarding the following reference:

BMJ 2013; 346: f2360 doi: 10.1136/bmj.f2360

This study examines the risk of cancer among a cohort of nearly 11 million Australian children and adolescents since 1985.  Among this cohort, 680,000 (6.2%) pediatric patients were identified who had been exposed to a CT scan. This study was accomplished by analyzing CT scans funded by the Australian Medicare system which provides health services for all Australians.

One of the remarkable aspects of this study was the efforts the authors took to exclude reverse causation.  First of all, the data was analyzed with an exclusion period of a year “because of the possibility that the scan was part of the cancer diagnostic procedure…but we repeated the main analyses with lag periods of five and 10 years to explore the possibility of reverse causation.”  In addition, the authors analyzed all non-brain cancers in patients who had had cranial CT scans.  Despite all of the parameters, an increased risk of cancer was maintained among those who had prior CT and the risk was heightened by obtaining studies at younger ages and by having increased number of CT scans.

Key findings:

  • Almost 60% of CT scans were of the brain. Only 5% of CT scans were of abdomen or pelvis.
  • CT scan incidence increased over time.  Between 1985-89, 95,249 (14%) CT scans were ordered.  Whereas between 2000-2005, 266,971 (39%) were ordered.
  • The average CT dose was about 4.5 mSv per scan.
  • The increased relative risk (IRR) for brain cancers after a scan to a site other than the brain was 1.51 (confidence interval 1.19-1.91).
  • Each seivert (Sv) of effective dose was associated with 0.125 cancers; thus, by 2007, with average followup of 9.5 years, one cancer resulted from every 1800 CT scans.  This number is likely to climb with more time.
  • Among brain CT scans, the numbers are trickier due to the possibility of slow-growing tumors (which could trigger symptoms for imaging and still be difficult to detect).  However, up to one excess brain cancer would occur for every 4000 brain scans.
  • All solid cancers IRR 1.25, All lymphoid/hematologic cancers IRR 1.19, Brain cancers after CT IRR 2.44, Brain cancer after other scans 1.51.

There are several limitations to the study including the difficulty of knowing specific doses of radiation at various CT scanners, the possibility of CT scans funded outside the Australian Medicare system, or obtaining screening scans due to precancerous genetic conditions. Nevertheless, the magnitude of the cohort in this study along with its general agreement with a number of other studies provide ample evidence that these risks are real.

Take-home point: While CT scans have the potential for great benefits, they increase the risk of developing cancer; in many cases, an MRI or an ultrasound can provide similar information without this risk.  In this study, for lag (exclusion) period of one, five, and 10 years, the incidence rate for all cancers combined increased by 24%, 21%, and 18% respectively in the CT exposed group.  Eventual lifetime risk is likely to climb with longer followup.

Related blog posts:

Mixed-review for Thiopurines

In this era of biologic agents for inflammatory bowel disease (IBD), the estimation of the risks and the benefits of thiopurines has been changing (Clin Gastroenterol Hepatol 2013; 11: 395-97).

The referenced article is an editorial that reviews new data on thiopurines as well as provide a background for their usage.

Main points:

  • After the SONIC trial, the usage of combination therapy in many IBD patients has regained favor with the main question: “How long to continue combination therapy?”
  • STORI trial evaluated withdrawal of infliximab (IFX) in patients on combined therapy.  More than 40% of patients who were withdrawn from IFX relapsed at 1 year.
  • After >20 years of thiopurine usage, more data is available on both short-term and long-term risks/benefits.  The risk of lymphoma in IBD patients on thiopurines is “4-fold increased…in the 6 evaluated studies.” Nonmelenoma skin cancer risk is increased by a hazard ratio of 5.9 in ongoing users and 3.9 in past thiopurine users.
  • At the same time, more recent studies have lowered the expectation of benefit for thiopurines (AZTEC trial, Cosnes study).

Related references:

  • Cosnes et al. Gastroenterol 2012; 142: s161.
  • Gastroenterol 2012; 142: 63-70.
  • Med Clin North Am 2010; 94: 93-113.

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