Tag Archives: thiopurine

Anti-Tumor Necrosis Factor Therapies and Cochrane Reviews

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A recent article (Inflamm Bowel Dis 2014; 20: 2132-41) reviews the best available evidence on anti-TNF therapies.  This article emerged from a Cochrane collaboration session at Digestive Diseases Week (DDW) in 2013.

Key points:

  • “There is insufficient evidence to recommend ECI (early combined immunosuppression)) for every newly diagnosed patient, although it may be justifiable in some “high-risk” patients.”
  • With Crohn’s disease, combination of infliximab and azathioprine significantly improved remission, steroid-free remission, and mucosal healing rates compared with infliximab alone.
  • “A recent Cochrane review has shown that infliximab, adalimumab, and certolizumab are all effective…The choice of TNF-α antagonist depends on adherence, patient preference, mode of delivery, and cost.“
  • Elective switching of TNF-α antagonists: in patients who are doing well, elective switching “may be associated with loss of both tolerance and efficacy.”  “Dose intensification or early treatment termination was observed in 47% of patients who switched to adalimumab after an ongoing response to scheduled maintenance infliximab therapy compared with 16% of patients who remained on infliximab maintenance therapy.” 28% of ADA patients discontinued therapy compared with 2% of IFX patients.
  • When to stop therapy: among patients in deep remission >6 months who stopped, relapse occurred in 43.9% over 1 year.
  • Patients who take thiopurines or biologics (IFX or ADA) have an increased risk of nonmelanoma skin cancer. Odds ratio, compared to controls, as high as 6.75 for combination therapy (>365 days).
  • Lymphoma: the Cochrane review “found no statistically significant difference in the incidence of lymphoma between biologics and control treatment…and data from the TREAT registry also demonstrated no apparent signal for TNF-α antagonist (i.e. infliximab)-related lymphoma or overall malignancy.”
  • There has been incremental risk of Non-Hodgkin’s lymphoma and hepatosplenic T-cell lymphoma with azathioprine (thiopurines).

Related blog posts:

Other articles briefly noted:

Inflamm Bowel Dis 2014; 20: 2142-50. “Approach and management of patients with chronic hepatitis B and hepatitis C during the course of inflammatory bowel disease.”

Inflamm Bowel Dis 2014; 20: 2151-56.  Use of cyclosporin and tacrolimus in inflammatory bowel disease.  Checking hepatitis B surface antigen, surface antibody, and core antibody are recommended at the time of diagnosis of IBD. Algorithm for managing hepatitis B serology is given in Figure 1.

Thiopurines = Low Efficacy for Crohn’s

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The enthusiasm for thiopurine therapy for Crohn’s disease (CD) had already dropped a lot before two pivotal articles were recently published that confirmed the modest efficacy:

  • Cosnes J, et al. Gastroenterol 2013; 145: 758-65
  • Panes J, et al. Gastroenterol 2013; 145: 766-74
  • Gastroenterol 2013; 145: 714-16 (editorial)

The Cosnes study (from the GETAID group) reports an open-label randomized trial in 147 adult patients with newly diagnosed CD (from 2005–>2010) and risk factors for disabling disease who were recruited from 24 French centers.  Risk factors for disabling disease:

  • Age <40 years
  • Active perianal lesions
  • Corticosteroid use within 3 months of diagnosis

The characteristics and Paris classification are detailed in the paper’s Table 1. Patients were divided into early azathioprine or “conventional” treatment. Patient’s were followed for 3 years.  Azathioprine was dosed at 2.5 mg/kg/day.  The primary endpoint was the proportion of trimesters spent in corticosteroid-free and anti-tumor necrosis factor (TNF)-free remission.

Results:

  • 67% of azathioprine group achieved the primary endpoint compared with 56% in the conventional group.  The difference in achieving the primary endpoint was not statistically significant between the two groups.  Also, 41 (61%) of the conventional group were placed on azathioprine (mean time 11 months after enrollment).
  • The azathioprine group patients were more likely to not have perianal surgery (96%) compared with the conventional group patients (82%).
  • Adverse events included pancreatitis in 7 (10%) of azathioprine group compared with 1 (1%) of conventional group.  Elevated liver function tests were noted in 3 (4%) compared with 1 (1%) respectively.  No cases of neutropenia were noted in early azathioprine group.

The latter finding is interesting especially as the authors did not check thiopurine methyltransferase (TPMT) assays in a systematic manner.

Panes et al (for the AZTEC study group) performed a prospective double-blind trial of adult patients with a recent CD diagnosis (<8 weeks).  This study enrolled 131 patients from 31 centers in Spain.  68 received azathioprine (2.5 mg/kg/day) and 63 received placebo.

Results:

  • After 76 weeks of treatment, 30 (44.1%) azathioprine patients and 23 (36.5%) placebo-treated patients were in sustained corticosteroid-free remission (P= .48).
  • Relapse rates were lower in azathioprine group compared with placebo: 11.8% vs 30.2%.
  • Serious adverse effects were more frequent in the azathioprine group compared with placebo: 20.6% vs. 11.1% (P= .16).  In the azathioprine group, 7 (10%) developed pancreatitis, 16 (24%) developed leukopenia, 9 (13%) developed anemia, and 9 (13%) developed abnormal liver function tests.  Infections were more common in the placebo-treated group (24%) compared with 12% in the azathioprine group

The accompanying editorial should be mandatory reading for all health care providers who help manage inflammatory bowel disease (IBD) patients.  The editorial traces how thiopurines (azathioprine and 6-mercaptopurine) became an accepted cornerstone of IBD treatment.  In adults, after initial disappointing results from Summers et al (Gastroenterol 1979; 77: 847-69), efficacy was demonstrated in a seminal study by Present et al (NEJM 1980; 302: 981-87).  However, the authors note that a recent Cochrane review reported that “thiopurines are not effective for induction of remission, but are effective for maintenance of remission.”

The editorial notes that a high degree of efficacy was demonstrated from a small but influential pediatric study of 55 patients.  After a high remission rate (89%) for all patients, this study showed that among those in remission, “1 patient (4%) in the 6MP group had a relapse within 180 days of achieving remission, compared with 7 patients (28%) in the placebo group.”

The editorial draws the following conclusions from the current studies:

  • “The remaining indications for primary therapy with thiopurines are maintenance of steroid-induced remission/steroid sparing in patients with CD that is not newly diagnosed, and prevention of postoperative recurrence.”
  • “The strongest indication for thiopurines may be as part of combination therapy.”
  • “If TNF antagonists had a similar low cost as generic thiopurines, there would likely be little debate regarding an evolution toward treatment of CD with TNF antagonists, either as monotherapy or ideally as combination therapy.  Currently, the annual costs of TNF antagonists is 10-20 times that of thiopurines.”
  • Because of the difference in cost.., “the use of thiopurines in CD is likely to persist, despite the shrinking number of indications, the modest effect size, and the suboptimal safety profile.”

Related blog posts:

Thiopurines associated with reduced risk of colon cancer

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A recent study provides some good news for those using thiopurines (6-mercaptopurine and azathioprine) (Gastroenterol 2013; 145: 166-75).

Using the observational cohort enrolled in the French CESAME study (Cancers et Surrisque Associe aux Maladies Inflammatoires Intestinales En France), the authors followed 19,486 patients with IBD.  60.3% had Crohn’s disease, and 30.1% were receiving thiopurine therapy.  The study period was 2004-2007.  At the start of the study, 2841 patients (14.6%) had long-standing extensive colitis.

Among patients with long-standing extensive colitis, the hazard ratio for colrectal high grade dysplasia and cancer was 0.28 for those who received thiopurine therapy compared with those who never received thiopurine therapy.

Thus, this prospective study showed that while colorectal cancer (CRC) was increased in IBD patients with long-standing colitis, this risk was less among the subset who were treated with thiopurines.  Some previous studies have not found a reduction in CRC risk, though they may have been underpowered and biased as these studies came from referral centers.

The authors also cautioned that more than 1/3rd of CRC cases occurred in those without extensive colitis which may necessitate a lower threshold for screening colonoscopy.

Related blog posts:

Mixed-review for Thiopurines

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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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Switching from Thiopurines to Methotrexate

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Data regarding methotrexate treatment for Crohn’s disease (CD) is limited.  A fairly large retrospective study provides a better idea about its effectiveness over a five-year period (Clin Gastroenterol Hepatol 2013; 11: 667-72).

In total 174 consecutive CD patients (age 35 ±12 y) from 3 hospitals were analyzed.  All of these patients received methotrexate (MTX) after thiopurine therapy. 23% had not responded to an anti-TNF agent.  Most of the patients who had failed thiopurine treatment had an intolerance to thiopurine rather than loss of clinical response.  Data on patient characteristics including smoking status, disease behavior/location, previous treatments, and indication for MTX are detailed in Table 2.  Interestingly, 113 patients were female.  The authors noted that 90% of their patients received MTX parenterally.

Key findings:

  • Patients with sustained clinical benefits from methotrexate monotherapy:  98 (86%) at 6 months, 50 (63%) at 12 months, 27 (47%) at 24 months, and 3 (20%) at 60 months.
  • 45 (26%) discontinue methotrexate due to intolerance, mostly within the first 6 months.  However, adverse effects were generally mild.  Only one patient required hospital admission for an infection (cytomegalovirus).

There are many limitations of this retrospective study.  Nevertheless, a significant portion of patients derived clinical benefit for at least 2 years.

Related blog posts:

Thiopurine Metabolite Testing -NASPGHAN Consensus Recommendations

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The inflammatory bowel disease committee of NASPGHAN has published a review and recommendations for the use of thiopurine metabolite testing (JPGN 2013; 56: 333-40).

The effectiveness of thiopurines is reviewed with a few key points:

  • Cochrane reviews have shown that azathioprine and 6-mercaptopurine are effective in inducing remission in Crohn’s disease.  For active disease the overall response rate has been reported as 54% compared with 33% for placebo.
  • For ulcerative colitis, a Cochrane analysis deemed the methodologic quality of 4 of the 6 studies as unsatisfactory and that all studies were small.  “The reviewers concluded that azathioprine may be effective treatment for patients with ulcerative colitis.”

The review covers the potential adverse effects of the thiopurines: myelosuppression, pancreatitis, elevated transaminases, susceptibility to infection, and malignancy.  The review suggests that the risk of non-Hodgkin lymphoma is probably increased up to 4-fold. Though, it is difficult to determine how much of the risk is truly due to the usage of thiopurines or other confounding factors.  The studies about the risk of non-melenoma skin cancer are not discussed.

Other covered topics: advantages of thiopurine metabolite testing (6-thioguanine [6-TGN] and 6-methylmercaptopurine[ 6-MMP]), potential disadvantages of metabolite testing (e.g.. cost), use of genotype versus phenotype (phenotypic testing is generally preferred), thiopurine metabolism, devising target levels, use of allopurinol, and misinterpretation of metabolite testing.

Specific Consensus Recommendations:

  • Obtain thiopurine methyltransferase (TPMT) testing prior to initiation of thiopurines.
  • Avoid use of thiopurines in individuals with extremely low TPMT activity or who are homozygous recessive for TPMT activity
  • TPMT testing does not predict all cases of leukopenia.  All individuals receiving thiopurines should have routine monitoring with CBCs.  “Most adverse effects from thiopurines are not directly related to 6-TGN or 6-MMP levels.”
  • Metabolite testing can help determine adherence to therapy
  • Metabolite testing may be helpful in guiding dose adjustment and/or adding allopurinol treatment
  • Routine and repetitive testing of metabolites is not recommended in patients who are doing well on an acceptable thiopurine dosage.

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Quality improvement and better outcomes in Pediatric Inflammatory Bowel Disease

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More information on outcomes and quality improvement (QI) efforts are available from Cincinnati Children’s Hospital (JPGN 2012; 55: 679-88).  The QI efforts at Cincinnati are part of a broader effort in QI in pediatric IBD that has been discussed on a previous post (see below).

Our group has rejoined Improve Care Now (ICN) and I look forward to gaining more first hand experience.  Some of the ICN target goals:

  • 80% remission rate among each center and sustained remission rate of 45%
  • 76% steroid-free remission
  • 90% checking TPMT if using thiopurine
  • 95% checking PPD/chest xray if using biologic therapy
  • 95% using accepted methotrexate dosing

As I look at these goals, I wonder whether the remission rate is feasible and about the variation in different centers. For example, among the groups with >75% enrollment of their patients, one center reports a 89% remission rate and another center 64% remission rate.  Given the limited number of therapeutic agents, how could there be such a difference?  Some explanations could include variation in the use of more potent biologic agents as well as capturing/assuring followup of more patients who are doing well.

Given this backdrop, I looked at this most recent publication to learn how their QI practices could translate into better care for my patients.

In this retrospective chart review study of 505 patients, who were followed from 2007-2010 at the IBD center, the remission rate increased from 59% to 76%.  The data were captured prospectively.  This corresponded to improved patient global assessment (>7) from 69% to 80%.  Repeated steroid use dropped from 17% to 10%.  Vitamin D (25-OH D) improved and this also correlated with quiescent disease.

Remission rates were defined by a pediatric Crohn clinical disease index, the sPCDAI, or PUCAI for Ulcerative colitis.

Key observations:

  • There was a trend towards increased use of anti-TNFα therapy (along with decreased use of 6-mercaptopurine) during the study period, but this did not reach statistical significance. No statistical difference was identified in the use of any major IBD medication class.
  • Despite target goals, the only drug class with a statistically significant change in dosing was 5-ASA (from 42 mg/kg to 50 mg/kg).
  • Fecal calprotectin monitoring increased.  The QI team recommended that IBD patients with ‘inactive’ disease have a fecal calprotectin measured every 6 months.  Those with elevated values had therapeutic drug monitoring implemented.  “Fecal calprotectin >400 μg/g is associated with a higher chance of relapse in a pediatric cohort.”
  • Starting in 2009, increased vitamin D monitoring was implemented (every 6 months).  In patients with a serum 25-OHD level < 30 ng/mL, treatment with 50,000 units weekly (for 6-8 weeks) was recommended (8000 units if weight <20 kg).  Once serum 25-OHD was >30 ng/mL, patients were maintained on monthly dosing.
  • Preclinic planning also increased and corresponded to improved remission rates which were 67% in 2009 and 76% in 2010.
  • The authors conclude: “Our results show that significant improvement in patient outcomes were achieved following QI efforts that did not rely on new medications or therapies, rather through initiating novel care processes and standardization of care.”

I think this conclusion is misleading.  First of all, as the authors point out, they did change their therapeutic approach.  They started vitamin D in more patients, used anti-TNFα therapy in more patients, and increased dosing of 5-ASA agents.  Other gains in remission rate could have been related to improved followup of patients who were doing well.

Despite my skepticism about the conclusion, I think the overall achievements are laudable.  Decreasing variation of care and assuring that all patients receive the best care possible with our diagnostic tests and current therapies is certainly worthwhile.  When patient care is studied carefully, this makes sure that “standard” practice like checking TPMT status before thiopurine use, checking PPDs before anti-TNFα therapy, and using optimal drug dosing occur in virtually all patients.

Developing a checklist for each patient can help assure that best practices occur.  For those with electronic medical records, this may mean putting in more “hard stops.”  A hard stop means the physician cannot sign out of a chart without paying attention to a specific detail.  For example, if a physician orders methotrexate, a “hard stop” could come up if the dosing was not in the typical target range.

Useful link:

Link for disease classification (quiescent, mild, moderate, severe):

http://links.lww.com/MPG/A129

Related blog entries:

Assessing and discussing risk of lymphoma in IBD

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A recent article has shown that the absolute lymphoma risk from medications in children and young adults with IBD is quite low (Inflamm Bowel Dis 2012; 18: 838-43).

In this single center study from 1979-2008, 1374 pediatric IBD patients had charts reviewed to determine whether lymphoma developed.  In total, two male patients who had received thiopurines developed lymphoma (one Hodgkin, one anaplastic large cell) in 6624 patient-years of follow-up.  Both patients are alive after chemotherapy.  Mean follow-up was 4.8 years per patient.  The absolute lymphoma incidence rate was 3 per 10,000 patient-years; after thiopurine exposure, the rate was 4.5 per 10,000 patient-years compared to an expected 0.58 per 10,000 patient-years.

In this study, 22% of the patients had received TNF inhibitors.  None developed lymphoma.  The risk of biologics could not be fully assessed due to a limited study period: 713 person-years taking the medication.

The risk of thiopurine-associated lymphoma was similar to previous studies but did not reach statistical significance.  As related in other studies, the risk of biologic agents, like Remicade, Humira, and Cimzia, is heavily influenced by whether patients had also received immunomodulators.

One useful way to try to convey this risk has been with diagrams.  One useful diagram is a palette of one thousand people or of 10,000 people showing the absolute risk and one showing the risk for other complications like infection.  You can make your own by going to the following link:

Download Communication Tools

RiskComm

Additional references/blog entries:

Only one chance to make first impression

Biologics | Living Longer | Arthritis Today Magazine -From Arthritis magazine: biologics improve survival in Rheumatoid arthritis