Tag Archives: azathioprine

What I did not know …a few items

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  1. 6-Mercaptopurine (6-MP) often can be used when patients are intolerant of azathioprine. S Hubener et al. Clin Gastroenterol Hepatol 2016; 14: 445-53.  This retrospective study showed that 15 of 20 patients with autoimmune hepatitis and prior azathioprine intolerance responded to 6-MP.  This is somewhat unexpected as azathioprine is metabolized into 6-MP.  However, rather than 6-thiouracil, the “imidazol component of azathioprine, which is cleaved off…might trigger adverse reactions.”  Another artical on thiopurines (Aliment Pharmacol Ther 2016; 43: 863-883) (thanks to Ben God for this reference) provides a thorough review of the pharmacogenetics and pharmocokinetics of these medications.  While this review reinforces the recommendation to check TPMT before treatment, it notes that only a small proportion of thiopurine toxicity is related to deficient TPMT activity.
  2. There is no formal validated or consensus definitions of mild, moderate, or severe IBD. L Peyrin-Biroulet et al. Clin Gastroenterol Hepatol 2016; 14: 348-54.  While the Lemann index measures the cumulative structural bowel disease, the authors propose criteria which involves three areas of severity: impact of the disease on the patient (eg. clinical symptoms), inflammatory burden (eg. biomarkers, mucosal disease, disease extent), and disease course (eg. structural disease, intestinal resection, perianal disease, extraintestinal manifestations)
  3. Fundic gland polyps (often associated with proton pump inhibitor therapy) are not premalignant lesions. There is an “inverse correlation between the FGPs and gastric neoplasia.” S Varghese et al. Gastroenterol Hepatol; 2016; 12: 153-4.
  4. Parents of newborns do not know how to use car seats.  BD Hoffman et al (J Pediatr 2016; 171: 48-54) showed that 95% of car seats were misused (291 families).  Serious misuse was present in 91%.

 

Related blog posts: Lemann index: Short Takes on IBD Articles | gutsandgrowth

Gibbs Gardens has >20 million daffodils

Gibbs Gardens has >20 million daffodils

UC SUCCESS

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The results of the “UC SUCCESS” trial show that combination therapy with infliximab and azathioprine is more effective than either medication as monotherapy in ulcerative colitis (UC) (Gastroenterol 2014; 146: 392-400). This study findings are similar to the SONIC trial in Crohn’s disease (CD).

Study Design: randomized, double-blind trial with evaluation at 16 weeks with a total of 239 patients.  In patients assigned to infliximab (IFX) alone, they were given daily oral placebo pills. In patients with azathioprine monotherapy (AZA), dosed at 2.5 mg/kg/day, they also received placebo infusions.  Patients had moderate to severe UC as defined by Mayo scores at baseline and had not responded adequately to a course of corticosteroids.  All patients were naive to tumor necrosis factor α antagonists (anti-TNFα).  Mean age was approximately 40 years.

Results:

  • IFX/AZA had a 39.7% corticosteroid-free remission at week 16 compared with 22.1% with IFX monotherapy and 23.8% with AZA monotherapy.
  • Mucosal healing at week 16 was evident in 62.8% of combination group compared with 54.6% IFX monotherapy and 36.8% with AZA monotherapy.
  • Serious adverse events were noted more frequently in the AZA monotherapy group, though this did not reach statistical significance.
  • A subset of patients had antibodies to infliximab (ATIs) measured.  ATI-positivity was more common with IFX monotherapy (19%, 7 of 37) than for IFX/AZA combination (3%, 1 of 31)

While this study indicates that for moderate to severe UC combination therapy with IFX/AZA was superior in this age group, there were several limitations.  Given the slow onset of action of azathioprine, more patients may have responded to this therapy if longer treatment duration was studied.

Take-home message: Combination therapy for UC, like CD, is more effective.  In this small study population, the adverse events were not increased. In the pediatric population, particularly males, the concern for malignancy in patients (especially males) treated with combination therapy may limit the frequency of combination therapy.

Related blog posts:

Other recent IBD articles of interest:

Inflamm Bowel Dis 2014; 20: 291-300. “Malignancy and Mortality in Pediatric Patients with Inflammatory Bowel Disease”  This article presented the results of a survey of 20 European countries and Israel.  Key finding: 18 cases of cancer and 31 deaths in 44 children. 5 of the deaths were due to cancer; the most common cause of mortality was infectious (n=14).  In this cohort, all HSTCL or EBV-positive lymphomas were treated with thiopurine monotherapy.

Inflamm Bowel Dis 2014; 20: 196-212.  “Opportunistic Infections Due to Inflammatory Bowel Disease Therapy”  This review article covers a broad range of pathogens and includes recommendations for prophylaxis and treatment (Table 3).  In addition the authors  provide suggestions for checking for several infections prior to treatment and vaccinations.

AGA Guidelines for the Use of Thiopurines and Anti-TNF Agents for Crohn’s

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The link (from KT Park’s twitter feed): gastrojournal.org/article/S0016-5085(13)01521-7/fulltext …

Some of the key points/recommendations for adults with Crohn’s disease:

  • In clinical practice, CD of moderate severity is defined as disease requiring systemic corticosteroids for symptom control.

For Induction of Remission:

  • We Suggest Against Using Thiopurine Monotherapy to Induce Remission in Patients With Moderately Severe CD (Weak Recommendation, Moderate-Quality Evidence)
  • We Suggest Against Using Methotrexate to Induce Remission in Patients With Moderately Severe CD (Weak Recommendation, Low-Quality Evidence)
  • We Recommend Using Anti–TNF-α Drugs to Induce Remission in Patients With Moderately Severe CD (Strong Recommendation, Moderate-Quality Evidence)
  • We Suggest Using Anti–TNF-α Drugs in Combination With Thiopurines Over Anti–TNF-α Drug Monotherapy to Induce Remission in Patients Who Have Moderately Severe CD (Weak Recommendation, Moderate-Quality Evidence)

Maintenance of Remission:

  • We Recommend Using Thiopurines Over No Immunomodulator Therapy to Maintain a Corticosteroid-Induced Remission in Patients With CD (Strong Recommendation, Moderate-Quality Evidence)
  • We Suggest Using Methotrexate Over No Immunomodulator Therapy to Maintain Corticosteroid-Induced Remission in Patients With CD (Weak Recommendation, Low-Quality Evidence)
  • We Recommend Using Anti–TNF-α Drugs Over No Anti–TNF-α Drugs to Maintain Corticosteroid- or Anti–TNF-α—Induced Remission in Patients With CD (Strong Recommendation, High-Quality Evidence)
  • We Make No Recommendation for or Against the Combination of an Anti–TNF-α Drug and a Thiopurine Versus an Anti–TNF-α Drug Alone to Maintain Remission Induced by a Combination of These Drugs in Patients With CD (No Recommendation, Low-Quality Evidence)

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Adult versus Pediatric Data: Autoimmune Hepatitis

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Recent data in adults indicate that budesonide may be more effective than prednisone for treating autoimmune hepatitis (AIH) (Gastroenterol 2010; 139: 1198-206).  Is this true in pediatrics? A small study and an associated editorial indicate that budesonide may be inferior (J Pediatr 2013; 163: 1347-53 & editorial 1246).

The study consisted of 46 pediatric patients with AIH (35 females) who were enrolled in a prospective double-blind, randomized, active-controlled trial with budesonide at a dose of 3 mg TID or prednisone (starting at 40 mg and tapered to 10 mg); all patients received concomitant treatment with azathioprine (1-2 mg/kg/day).  After the initial 6 months, a further 6-month open-label treatment with budesonide (n=42) followed.  Approximately 70% of the patients had type 1 AIH.

Results:

  • Normalization of aminotransferases occurred in only 16% of budesonide group and 15% of prednisone group after 6 months.
  • At 12 months, 46% of those on budesonide had biochemical remission

The editorial explains why these results are unlikely to affect current management and provides succinct summary of AIH management.

Key points:

  • “The juvenile form of AIH is particularly aggressive…between 40% and 80% of children are reported to have cirrhosis at diagnosis”
  • Standard treatment for juvenile AIH: Prednisone 2 mg/kg/day (max 60 mg) which is tapered over 4-8 weeks with the decline of aminotransferase levels to a maintenance dose of 2.5-5 mg/day.  80% of the improvement (in ALT values) occurs within the first two months.  Typically, azathioprine is added after some improvement in aminotransferases.  In the absence of toxicity, the dose is increased to 2-2.5 mg/kg/day.
  • Remission is defined as complete normalization of aminotransferases along with normalization of serum immunoglobulin G levles, negative or very low autoantibody titer, and histologic resolution of inflammation.
  • Histologic remission lags biochemical response, “though 95% of patients have a marked histologic improvement after a mean duration of 4 years of effective therapy.”
  • Budesonide is not used in the presence of cirrhosis
  • Problems with current study are detailed in the editorial.  The design likely contributed to remission rates which were significantly lower than reported with standard prednisone/azathioprine.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and specific medical management interventions should be confirmed by prescribing physician.  Application of the information in a particular situation remains the professional responsibility of the practitioner.

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.”

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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.

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More data on DILI

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Using a population-based cohort, the authors of a recent study from Iceland performed a prospective study, collecting data on 96 individuals with drug-induced liver injury (DILI) from 2010-2011 (Gastroenterol 2013; 144: 1419-25 & editorial 1335-36).  This study benefitted from a centralized medical care system with about 250,000 adults.  Patients with acetaminophen toxicity were excluded.

Results:

  1. DILI occurred in 19 cases per 100,000 persons per year.  This is higher than previous DILI estimates in other populations and may be due to identifying more subclinical cases.
  2. DILI increased markedly with age from 9 per 100,000 among 15-29 year olds to 41 per 100,000 among those >70; however, this paralleled the increase use of medications.
  3. Eight drugs were implicated in more than 1 case with subsequent risk estimates:
  • Augmentin 1 per 2350 users
  • Azathioprine 1 per 133  (mostly anicteric cases)
  • Infliximab 1 per 148
  • Nitrofurantoin 1 per 1369
  • Isotretinoin 1 per 732
  • Atorvastatin 1 per 3693
  • Diclofenac 1 per 9148
  • Doxycycline 1 per 16,339

Some commonly implicated drugs did not show up on the list: fluoroquinolones, macrolide antibiotics, minocycline, valproic acid, and cancer chemotherapeutic agents (except one case due to imatinib).  The editorialist notes that these agents are not commonly used in Iceland.  Also, 16% of cases were due to herbals and dietary supplements.

Consequences of DILI: 27% developed jaundice, 12% required hospitalization, and 1 patient died.  The median time for liver tests to normalize in those that recovered was 64 days.

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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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Data on Allopurinol

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Given the limited number of therapeutic options for inflammatory bowel disease (IBD), it is important to optimize each individual treatment.  Allopurinol can increase the effectiveness of thiopurines and if used properly can be safe (Inflamm Bowel Dis 2013; 19: 363-69).

The referenced study took place between 2004-2011 and examined 77 patients who failed monotherapy with a thiopurine due to “skewed” metabolism.  The average age of study participant was 38 years (28-45).  23% had previous surgery. Cotreatment with an anti-TNF occurred in 7 patients and with an 5-ASA i 17 patients.

Results:

  • Median 6-thioguanine (6-TGN) levels increased from 145 to 271 pmol/8 x10-to-the-8th. 6-methyl mercaptopurine (6-MMP) concentrations decreased from 10,110 to 265 pmol/8 x10-to-the-8th.
  • Leukopenia occurred in 16%, necessitating dose reductions.
  • Liver tests normalized in 81% with the addition of allopurinol
  • The median azathioprine dose while on combination therapy was 0.64 mg/kg/day and the median 6-mercaptopurine dose was 0.39 mg/kg/day.  While on mono therapy, median values were 2.05 mg/kg/day and 1.23 mg/kg/day respectively.
  • 21% had to discontinue combination therapy.
  • Combination therapy was continued at 6, 12, 24, and 60 months in 87%, 85%, 76%, and 65%.

Take-home Message:

Allopurinol can salvage failed thiopurine monotherapy, but only in a minority of these patients.  Allopurinol should be considered for patients unable to achieve therapeutic 6-TGN levels who have liver toxicity/elevated 6-MMP levels.  Careful attention to dose reduction of the thiopurine is essential to avoid life-threatening bone marrow suppression.

Related blog entry:

Thiopurine Metabolite Testing -NASPGHAN … – gutsandgrowth

Additional references:

  • -Aliment Pharmacol Ther 2010; 31: 640-47. use of allopurinol.
  • -Gastro & Hep 2008; 4: 505. use of allopurinol. Consider if pts unable to enter steroid-free remission AND on adequate AZA/6MP dose. ONLY in those who preferentially metabolize towards 6-MMP (~15% of population); thus subtherapeutic 6-TG levels and increased 6-MMP (>5700). Need adequate WBC >4.5 at start since this will decrease. Check labs every week x 4 at start, then qoweek x 4, then per routine.
  • -IBD 2008; 14: 1678. Experience with allopurinol in children -dose 100mg of allopurinol if >30kg and 50mg if < 30kg. AZA dose decreased to 25% of previous dose. n=13.
  • -Clin Gastro & Hep 2007; 5: 170 (editorial) & 209.  Use of allopurinol (100mg/day) in 20 adults.  Dose of 6-MP reduced 25-50% concomitantly.  Improved disease control w/o hepatotoxicity.  Important to follow counts closely for first 2 months.

Azathioprine metabolite measurement for Autoimmune Hepatitis

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While obtaining azathioprine (AZA) metabolite levels in inflammatory bowel disease has proven clinical utility, there is less data with regard to autoimmune hepatitis (AIH).  Now a study of 70 adults with AIH reports that therapeutic levels of 6-thioguanine (TGN) (>220 pmol/8 x 10 to the 8th) are associated with remission (Hepatology 2012; 56: 1401-8).

Patients in this study had an average age of 61 years; the average participant had a diagnosis of AIH for 8 years at the start of the study. For induction of remission, patients had received a combination of prednisolone along with AZA.  AZA was started at 1 mg/kg/day and gradually increased to 2 mg/kg/day.  All patients had a complete response to steroids prior to AZA dose escalation.

Outcome from this study was characterized by ability to maintain remission with ALT <33 IU/L and/or relapse which was indicated by ALT >2 x ULN (upper limit of normal) or liver histology showing active disease.

Serial measurements of red blood cell TGN and methylmercaptopurine nucleotides (MeMPNs) were obtained over two years.

Results:

  • 53 patients maintained remission and 17 did not.
  • Those in remission tended to be receiving lower doses of AZA (1.7 vs 2 mg/kg/day) but had higher average TGN levels (237 vs 177 pmol/8 x 10 to the 8th)
  • TGN levels >220 pmol/8 x 10 to the 8th best predicted remission
  • There was no measurable difference in thiopurine methyltransferase (TPMT) activity between the two groups (remission vs relapse).
  • Two patients developed cholestasis and this was associated with high MeMPN levels.

The authors note that several previous studies did not demonstrate a relationship between TGN levels and efficacy.  This is likely related to patient selection (all in remission at start in current study), repeated TGN levels, and the definition of remission.

Conclusion: Obtaining metabolites in adherent patients may be beneficial in patients with active disease to assist with dose modification and in individuals with potential AZA toxicity.

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