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. 2019 Aug 6;8(8):CD010233.
doi: 10.1002/14651858.CD010233.pub3.

Azathioprine and 6-mercaptopurine for maintenance of surgically-induced remission in Crohn's disease

Teuta Gjuladin-Hellon  1 , Zipporah Iheozor-Ejiofor, Morris Gordon, Anthony K Akobeng
Affiliations

Azathioprine and 6-mercaptopurine for maintenance of surgically-induced remission in Crohn's disease

Teuta Gjuladin-Hellon et al. Cochrane Database Syst Rev. .

Abstract

Background: Crohn's disease (CD) is a chronic relapsing inflammatory condition and maintenance of remission is a major issue as many patients fail to achieve remission with medical management and require surgical interventions. Purine analogues such as azathioprine (AZA) and 6-mercaptopurine (6-MP) have been used to maintain surgically-induced remission in CD, but the effectiveness, tolerability and safety of these agents remains controversial.

Objectives: To assess the efficacy and safety of purine analogues (AZA and 6-MP) for maintenance of surgically-induced remission in CD.

Search methods: We searched PubMed, MEDLINE, Embase, CENTRAL, and the Cochrane IBD Group Specialized Register from inception to 26 July 2018 (and from inception to 31 July 2019). In addition, we searched reference lists of all included studies and relevant reviews, conference proceedings and trials registers.

Selection criteria: Randomised controlled trials (RCTs) with a duration of at least three months that enrolled adults and children with surgically-induced remission of CD and compared AZA or 6-MP to no treatment, placebo or any other active intervention were considered for inclusion.

Data collection and analysis: Two authors independently assessed trial eligibility, extracted data, assessed the risk of bias and assessed the certainty of the evidence using GRADE. The primary outcome was clinical relapse. Secondary outcomes included endoscopic relapse, radiologic and surgical relapse, adverse events (AEs), serious adverse events (SAEs), withdrawal due to AEs and health-related quality of life.

Main results: Ten RCTs with a total of 928 participants were included. Study participants were adults recruited from university clinics and gastroenterology hospitals who received interventions post-surgery for a duration between 12 to 36 months. Most study participants were recruited less than three months after surgery in all except one study where participants were recruited between 6 to 24 months post-surgery. One study was rated as low risk of bias, six studies were rated high risk of bias and three were rated unclear risk of bias.There was moderate certainty evidence that purine analogues are more efficient for preventing clinical relapse than placebo. At 12 to 36 months, 51% (109/215) of AZA/6-MP participants relapsed compared to 64% (124/193) of placebo participants (RR 0.79; 95% CI 0.67 to 0.92; 408 participants; 3 studies; I² = 0%; moderate certainty evidence). The certainty of the evidence regarding the efficacy of AZA or 6-MP for maintaining postoperative clinical remission compared to 5-ASA compounds was low. At 12 to 24 months , 64% (113/177) of purine analogue participants relapsed compared to 59% (101/170) of 5-ASA participants (RR 1.05; 95% CI 0.89 to 1.24; 347 participants; 4 studies; I² = 8%; low certainty evidence). The certainty of evidence that purine analogues are inferior for preventing postsurgical clinical relapse compared to tumour necrosis factor alpha agents (anti-TNF-α) was very low. At 12 to 24 months, 43% (29/67) of AZA participants relapsed compared to 14% (10/72) of anti-TNF-α participants (RR 2.89; 95% CI 1.50 to 5.57; 139 participants; 3 studies; I² = 0%; very low certainty evidence).The effect of purine analogues compounds on AEs compared to placebo or any active treatment was uncertain, as the quality of evidence ranged from very low to low. After 12 to 24 months, 14% (12/87) of purine analogue participants experienced an AE compared to 10% (8/81) of placebo participants (RR 1.36; 95% CI 0.57 to 3.27; 168 participants; 2 studies; I² = 0%; low certainty evidence). The effect of purine analogues on AEs compared to 5-ASA agents was uncertain. After 12 to 24 months, 41% (73/176) of purine analogue participants had an AE compared to 47% (81/171) of 5-ASA participants (RR 0.89; 95% CI 0.74 to 1.07; 346 participants; 4 studies; I² = 15%; low certainty evidence). The effect of purine analogues on AEs in comparison to anti TNF-α agents was uncertain. At 12 to 24 months, 57% (32/56) of AZA participants had an AE compared to 51% (31/61) of anti-TNF-α participants (RR 1.13; 95% CI 0.83 to 1.53; 117 participants; 2 studies; I² = 0%; low certainty evidence). Purine analogue participants were more like than 5-ASA participants to have a SAE (RR 3.39, 95% CI 1.26 to 9.13, 311 participants; 3 studies; I² = 9%; very low certainty evidence), or to withdraw due to an AE (RR 2.21, 95% CI 1.28 to 3.81; 425 participants; 5 studies; I² = 0%; low certainty evidence). Commonly reported AEs across all studies included leucopenia, arthralgia, abdominal pain or severe epigastric intolerance, elevated liver enzymes, nausea and vomiting, pancreatitis, anaemia, nasopharyngitis and flatulence.

Authors' conclusions: Moderate certainty evidence suggests that AZA and 6-MP may be superior to placebo for maintenance of surgically-induced remission in participants with CD. There was no clear difference in the number of clinical relapses when purine analogues were compared with 5-ASA agents, however this is based on low certainty evidence. There was very low certainty evidence that AZA and 6-MP are more likely to result in more serious adverse events (SAEs) and withdrawals due to an AE (low certainty) when compared to 5-ASA agents. Very low certainty evidence suggests that purine analogues may be inferior to anti-TNF-α agents, however, no firm conclusions can be drawn. Further research investigating the efficacy and safety of AZA and 6-MP in comparison to other active medications in surgically-induced remission of CD is warranted.

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Conflict of interest statement

Teuta Gjuladin‐Hellon: None known.

Zipporah Iheozor‐Ejiofor: None known.

Morris Gordon: Received travel fees to attend international scientific and training meeting such as DDW, Advances in IBD, ESPGHAN, BSPGHAN and Cochrane focused international events from companies including: Abbott, Nutricia, Biogaia, Ferring, Allergan, and Tillots.

Anthony K Akobeng: None known.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
1.1
1.1. Analysis
Comparison 1 Azathioprine or 6‐mercaptopurine versus placebo, Outcome 1 Clinical relapse at 12 to 36 months (subgroup by drug type).
1.2
1.2. Analysis
Comparison 1 Azathioprine or 6‐mercaptopurine versus placebo, Outcome 2 Clinical relapse (subgroup by length of follow‐up).
1.3
1.3. Analysis
Comparison 1 Azathioprine or 6‐mercaptopurine versus placebo, Outcome 3 Endoscopic relapse at 12 to 36 months (subgroup by drug type).
1.4
1.4. Analysis
Comparison 1 Azathioprine or 6‐mercaptopurine versus placebo, Outcome 4 Endoscopic relapse (subgroup by length of follow‐up).
1.5
1.5. Analysis
Comparison 1 Azathioprine or 6‐mercaptopurine versus placebo, Outcome 5 Adverse events at 12 to 24 months (subgroup by drug type).
1.6
1.6. Analysis
Comparison 1 Azathioprine or 6‐mercaptopurine versus placebo, Outcome 6 Adverse events (subgroup by length of follow‐up).
1.7
1.7. Analysis
Comparison 1 Azathioprine or 6‐mercaptopurine versus placebo, Outcome 7 Serious adverse events at 24 to 36 months.
1.8
1.8. Analysis
Comparison 1 Azathioprine or 6‐mercaptopurine versus placebo, Outcome 8 Withdrawal due to adverse events at 12 to 36 months (subgroup by drug type).
1.9
1.9. Analysis
Comparison 1 Azathioprine or 6‐mercaptopurine versus placebo, Outcome 9 Withdrawal due to adverse events (subgroup by length of follow‐up).
2.1
2.1. Analysis
Comparison 2 Azathioprine or 6‐mercaptopurine versus 5‐aminosalicylic acid, Outcome 1 Clinical relapse at 12 to 24 months (subgroup by drug type).
2.2
2.2. Analysis
Comparison 2 Azathioprine or 6‐mercaptopurine versus 5‐aminosalicylic acid, Outcome 2 Clinical relapse (subgroup by length of follow‐up).
2.3
2.3. Analysis
Comparison 2 Azathioprine or 6‐mercaptopurine versus 5‐aminosalicylic acid, Outcome 3 Endoscopic relapse at 24 months.
2.4
2.4. Analysis
Comparison 2 Azathioprine or 6‐mercaptopurine versus 5‐aminosalicylic acid, Outcome 4 Radiologic relapse at 24 months.
2.5
2.5. Analysis
Comparison 2 Azathioprine or 6‐mercaptopurine versus 5‐aminosalicylic acid, Outcome 5 Surgical relapse at 24 months.
2.6
2.6. Analysis
Comparison 2 Azathioprine or 6‐mercaptopurine versus 5‐aminosalicylic acid, Outcome 6 Adverse events at 12 to 24 months (subgroup by drug type).
2.7
2.7. Analysis
Comparison 2 Azathioprine or 6‐mercaptopurine versus 5‐aminosalicylic acid, Outcome 7 Adverse events (subgroup by length of follow‐up).
2.8
2.8. Analysis
Comparison 2 Azathioprine or 6‐mercaptopurine versus 5‐aminosalicylic acid, Outcome 8 Serious adverse events at 12 to 24 months (subgroup by drug type).
2.9
2.9. Analysis
Comparison 2 Azathioprine or 6‐mercaptopurine versus 5‐aminosalicylic acid, Outcome 9 Serious adverse events (subgroup by length of follow‐up).
2.10
2.10. Analysis
Comparison 2 Azathioprine or 6‐mercaptopurine versus 5‐aminosalicylic acid, Outcome 10 Withdrawal due to adverse events at 12 to 24 months (subgroup by drug type).
2.11
2.11. Analysis
Comparison 2 Azathioprine or 6‐mercaptopurine versus 5‐aminosalicylic acid, Outcome 11 Withdrawal due to adverse events (subgroup by length of follow‐up).
2.12
2.12. Analysis
Comparison 2 Azathioprine or 6‐mercaptopurine versus 5‐aminosalicylic acid, Outcome 12 HRQoL ‐ IBDQ > 170 at 24 months.
2.13
2.13. Analysis
Comparison 2 Azathioprine or 6‐mercaptopurine versus 5‐aminosalicylic acid, Outcome 13 HRQoL ‐ IBDQ at 12 months.
3.1
3.1. Analysis
Comparison 3 Azathioprine or 6‐mercaptopurine versus anti TNF‐α, Outcome 1 Clinical relapse at 12 to 24 months.
3.2
3.2. Analysis
Comparison 3 Azathioprine or 6‐mercaptopurine versus anti TNF‐α, Outcome 2 Clinical relapse (subgroup by length of follow‐up).
3.3
3.3. Analysis
Comparison 3 Azathioprine or 6‐mercaptopurine versus anti TNF‐α, Outcome 3 Endoscopic relapse at 12 to 24 months (subgroup by drug type).
3.4
3.4. Analysis
Comparison 3 Azathioprine or 6‐mercaptopurine versus anti TNF‐α, Outcome 4 Endoscopic relapse (subgroup by length of follow‐up).
3.5
3.5. Analysis
Comparison 3 Azathioprine or 6‐mercaptopurine versus anti TNF‐α, Outcome 5 Radiologic relapse at 12 to 24 months.
3.6
3.6. Analysis
Comparison 3 Azathioprine or 6‐mercaptopurine versus anti TNF‐α, Outcome 6 Histologic relapse at 12 months.
3.7
3.7. Analysis
Comparison 3 Azathioprine or 6‐mercaptopurine versus anti TNF‐α, Outcome 7 Adverse events at 12 to 24 months.
3.8
3.8. Analysis
Comparison 3 Azathioprine or 6‐mercaptopurine versus anti TNF‐α, Outcome 8 Adverse events (subgroup by length of follow‐up).
3.9
3.9. Analysis
Comparison 3 Azathioprine or 6‐mercaptopurine versus anti TNF‐α, Outcome 9 Serious adverse events at 12 months.
3.10
3.10. Analysis
Comparison 3 Azathioprine or 6‐mercaptopurine versus anti TNF‐α, Outcome 10 Withdrawal due to adverse events at 12 to 24 months.
3.11
3.11. Analysis
Comparison 3 Azathioprine or 6‐mercaptopurine versus anti TNF‐α, Outcome 11 Withdrawal due to adverse events (subgroup by length of follow‐up).
3.12
3.12. Analysis
Comparison 3 Azathioprine or 6‐mercaptopurine versus anti TNF‐α, Outcome 12 HRQoL ‐ IBDQ > 170 at 24 months.
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Update of

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References to studies excluded from this review

Ferrante 2015 {published data only}
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References to ongoing studies

NCT03185611 {published data only}
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References to other published versions of this review

Gordon 2014
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