Efficacy and Safety of Simultaneous Treatment With Two Biologic Medications in Refractory Crohn's Disease

Edward Yang; Nicola Panaccione; Natalie Whitmire; Parambir S. Dulai; Niels Vande Casteele; Siddharth Singh; Brigid S. Boland; Angelina Collins; William J. Sandborn; Remo Panaccione; Robert Battat


Aliment Pharmacol Ther. 2020;51(11):1031-1038. 

In This Article

Abstract and Introduction


Background: Biologic therapies in patients with Crohn's disease often yield low clinical and endoscopic remission rates. After multiple failed therapies, combining two biologic therapies is possibly the sole medical alternative to recurrent surgery. However, data on this approach are limited.

Aims: To assess the efficacy and safety of concomitant use of two biologic therapies in the largest cohort to date of refractory Crohn's disease patients.

Methods: Data were extracted from Crohn's disease patients started on dual biologic therapy at two referral centres. Biologics utilised include infliximab, adalimumab, vedolizumab, ustekinumab, certolizumab and golimumab. The primary outcome was endoscopic improvement (>50% reduction in Simplified Endoscopic Score-Crohn's disease [SES-CD] or explicitly stated). Endoscopic remission (SES-CD < 3 or stated), clinical response (Crohn's disease–patient-reported outcome-2 score [PRO2] reduced by 8), clinical remission (PRO2 < 8), and C-reactive protein (CRP) were also assessed.

Results: A total of 22 patients with 24 therapeutic trials of dual biologic therapy were identified. The majority of patients had prior surgical resections (91%), stricturing (59%) or penetrating (36%) phenotype, and perianal fistulas (50%). Median number of prior failed biologics was 4. Endoscopic improvement occurred in 43% of trials and 26% achieved endoscopic remission. Fifty per cent had clinical response and 41% achieved clinical remission. There were significant post-treatment reductions in median SES-CD (14.0 [12.0–17.5] to 6.0 [2.5–8.0], P = 0.0005], PRO-2 (24.1 [20.3–27.0] to 13.4 [4.6–21.8], P = 0.002] and CRP (17.0 [11.0–24.0] to 9.0 [4.0–14.0], P = 0.02). Presence of perianal fistulas decreased from 50% to 33%. Adverse events occurred in 13% of trials.

Conclusion: Dual biologic therapy was associated with clinical, biomarker and endoscopic improvements in selected patients with refractory Crohn's disease who failed multiple biologics. Further studies are needed to validate this approach.


Crohn's disease is a progressive immune-mediated disorder that can involve the entire gastrointestinal tract and presents with an inflammatory, stricturing, or penetrating phenotype.[1] Complications of Crohn's disease—including strictures, fistulas and abscesses—occur in 50% of patients.[2] Additionally, 50% of patients require surgery within 10 years of diagnosis.[3,4] Biologic medications have significantly advanced the management of inflammatory bowel disease and have become the cornerstone in the management of moderate-to-severe Crohn's disease.[1] Effective biologic agents for treating Crohn's disease include tumour necrosis factor-α (TNF)-antagonists (infliximab, adalimumab and certolizumab pegol), and more recently, antibodies inhibiting the p40 subunit of interleukins (IL)-12 and −23 (ustekinumab) and α4β7 integrins on leukocytes (vedolizumab).[5] Randomised controlled trials demonstrate that combination therapy with infliximab and azathioprine is more effective than either treatment alone.[6] However, few patients achieve prolonged clinical remission and significant risk for subsequent surgical resections exists despite biologic therapies.[1] In refractory Crohn's disease patients who have failed multiple biologics, therapeutic options are limited. Inability to achieve clinical remission or response deceases quality of life, and recurrent bowel resections can lead to complications such as short bowel syndrome with dependence on parenteral support, bile acid diarrhoea and nutritional deficiencies.[1,7,8] Thus, just as combination therapy with a biologic and immunomodulator is more effective than either alone,[6] the concomitant use of dual biologics that target different inflammatory pathways is a potential therapeutic approach in patients with severe and treatment refractory disease.[9] In all Crohn's disease patients, the simultaneous use of two biologic therapies can potentially lead to improved clinical and endoscopic outcomes.

Biologic agents are effective in treating immune-mediated diseases, but concerns remain regarding adverse events, including infection and malignancy. Data from the TREAT registry demonstrated that while infliximab was associated with an increase in serious infections, stronger associations were shown with corticosteroids, Crohn's disease severity and narcotic use.[10] Large nationwide cohort studies have demonstrated that both thiopurine and TNF-antagonist monotherapy was associated with an increased risk of lymphoma, and combination therapy further increased this risk.[11] While thiopurines are associated with infection and malignancy, their combination with TNF-antagonists is commonplace. Conversely, newer approved biologic agents for Crohn's disease such as vedolizumab and ustekinumab have not yet demonstrated these risks. Vedolizumab targets the α4β7 integrin receptor to block lymphocyte homing to the intestinal mucosa, and has demonstrated a favourable safety profile in clinical trial[12] and real-world[13] settings. Ustekinumab inhibits the common p40 subunit of IL-12 and −23 and is safe and effective in Crohn's disease. Additionally, randomised controlled trials as well as real world data demonstrate a favourable safety profile across multiple diseases.[14,15]

Previous randomised controlled trial data analysing the combination of natalizumab and infliximab in patients with refractory Crohn's disease did not demonstrate increased adverse events over infliximab monotherapy.[16] Although the trial was not designed to analyse efficacy and endoscopic endpoints were not assessed, a trend existed towards symptom-based clinical improvement. Currently, natalizumab is rarely used due to the risk of progressive multifocal leukoencephalopathy and availability of safer and more selectively targeted anti-integrin therapies such as vedolizumab.[1] Additional data on dual therapy with conventional biologics remain limited to case reports and series.[17–20] Thus, a major knowledge gap exists on the safety and efficacy of combining contemporary biologic therapies in Crohn's disease.

Despite the safety of newer biologics, simultaneous treatment with two (dual) biologic medications (DBT) is rarely utilised. It remains unknown if concomitant use of these newer biologics with one another or with a TNF-antagonist would increase the overall risk for infectious complications compared with current standard of care. We hypothesise that vedolizumab may be an optimal therapeutic anchor to dual biologic therapy due to its favourable safety profile, which is attributed to its gut-specific mechanism. For similar safety considerations, ustekinumab may be a reasonable alternative anchor.[12,13,21,22] We report the largest cohort to date on the preliminary evidence of efficacy and tolerability of DBT in a high-risk group of patients with refractory Crohn's disease.