What is the role of the Diamond trial in guiding the use of azathioprine with Tumor Necrosis Factor-alpha (TNF-alpha) antagonists like adalimumab (Humira) in inflammatory bowel disease treatment?

The DIAMOND Trial and Adalimumab-Azathioprine Combination Therapy in IBD

The DIAMOND trial showed no significant benefit of adding azathioprine to adalimumab for clinical remission in Crohn's disease, though it demonstrated improved endoscopic remission at 26 weeks but not at 1 year. 1 Despite this negative primary endpoint, current guidelines conditionally suggest combination therapy based on pharmacokinetic benefits and extrapolation from infliximab data.

Key Findings from the DIAMOND Trial

The DIAMOND study was an open-label randomized controlled trial comparing adalimumab plus azathioprine versus adalimumab monotherapy in biologic-naïve and immunomodulator-naïve adults with Crohn's disease over 52 weeks. 1

Primary Outcome (Clinical Remission):

• No difference in clinical remission at 26 weeks: 68.1% (combination) vs 71.8% (monotherapy), p=0.63 1
• No difference in maintenance of remission at 52 weeks: RR 1.13 (95% CI 0.72-1.78) 1

Secondary Outcomes:

• Endoscopic remission at 26 weeks was significantly higher with combination therapy: 84.2% vs 63.2%, p=0.02 1
• This endoscopic benefit was not sustained at 1 year 1
• Trends toward higher adalimumab trough levels and fewer anti-adalimumab antibodies in the combination group (not statistically significant) 1

Safety Concerns:

• Withdrawals specifically for side effects were significantly more frequent in the combination group 1
• High rates of drug discontinuations due to treatment intolerance 1

Current Guideline Recommendations Despite DIAMOND Results

For Adults with Crohn's Disease

The 2021 AGA guidelines conditionally suggest using adalimumab in combination with thiopurines over adalimumab monotherapy for induction and maintenance of remission, despite very low certainty evidence. 1 This recommendation is based on:

• Indirect evidence from pharmacokinetic benefits (reduced immunogenicity, higher trough levels) 1
• Extrapolation from proven benefits of infliximab-azathioprine combination therapy 1
• Real-world observational data showing combination therapy reduces immunogenicity (HR 0.34,95% CI 0.21-0.56, p=0.0001) 1

For Pediatric Patients

The 2019 Canadian pediatric guidelines suggest AGAINST using adalimumab in combination with a thiopurine in males due to the risk of hepatosplenic T-cell lymphoma (HSTCL) without proven clinical benefit. 1

• HSTCL risk is highest in males aged <35 years receiving combination thiopurine and anti-TNF therapy 1
• No consensus recommendation was made for females 1

Clinical Decision Algorithm

When starting adalimumab in Crohn's disease:

1. For adult males <35 years: Consider methotrexate instead of azathioprine if combination therapy is desired, due to HSTCL risk 1

2. For adult patients with high immunogenicity risk factors:

   • Consider combination therapy if patient has HLA-DQA1*05 genotype (associated with higher antibody formation) 1
   • Consider combination in patients with unfavorable pharmacokinetics (severe disease, high inflammatory burden, low albumin, higher BMI) 1

3. For patients who previously lost response to infliximab with antibodies:

   • Strongly consider adding azathioprine to adalimumab - observational data shows 77-78% success with combination vs 22% with monotherapy (p<0.001) 1

4. For biologic-naïve patients prioritizing mucosal healing:

   • Combination therapy may be reasonable given the 26-week endoscopic benefit in DIAMOND 1
   • However, counsel patients that this benefit was not sustained at 1 year 1

5. For patients prioritizing safety/tolerability:

   • Adalimumab monotherapy is reasonable given no proven clinical remission benefit and higher withdrawal rates with combination 1

Important Caveats and Pitfalls

The evidence quality is very low due to the DIAMOND trial being unblinded, having high discontinuation rates, and showing only indirect/surrogate benefits. 1

The 2025 British Society of Gastroenterology guidelines note that adalimumab with purine analogues "is probably better than placebo" based on network meta-analysis, but acknowledge the lack of direct RCT data beyond DIAMOND. 1

Real-world Canadian data from 11,244 IBD patients showed combination therapy decreased treatment failure for both Crohn's disease (aHR 0.77,95% CI 0.66-0.90) and ulcerative colitis (aHR 0.72,95% CI 0.62-0.84), and was equally effective for adalimumab and infliximab in Crohn's disease. 2

Lower doses of azathioprine (<2 mg/kg/day) may be sufficient in combination therapy - multiple studies found no differences in anti-TNF trough levels, antibody formation, or inflammatory biomarkers between standard (≥2 mg/kg/day) and reduced doses, potentially minimizing side effects. 3, 4