Biologic Therapy in Crohn’s Disease: An Overview of Current Approaches and Emerging Treatments
Crohn’s disease, a chronic inflammatory bowel disease, requires advanced therapeutic strategies to manage and mitigate its symptoms effectively. Among the most promising treatments in recent decades have been biologic therapies, particularly anti-TNF (tumor necrosis factor) agents, which have significantly advanced the management of this challenging condition.
Anti-TNF Agents: A Cornerstone in Crohn’s Disease Management
Anti-TNF therapy has been foundational in inducing and maintaining remission in Crohn’s disease. Key agents such as infliximab and adalimumab are globally recognized for their efficacy. Infliximab is particularly notable, being the only therapy with a randomized controlled trial demonstrating its effectiveness in treating perianal disease. Adalimumab also proved its worth in the CHARM trial, showing efficacy in fistula healing as a secondary endpoint.
These agents not only address intestinal symptoms but are also effective against extraintestinal manifestations, including conditions like pyoderma, uveitis, psoriasis, and axial spondyloarthropathy. They have been found beneficial in specific clinical situations such as treating stricture disease, offering postoperative prophylaxis, and being safe during pregnancy.
The use of biosimilars, approved since 2013 in Europe and 2016 in the USA, represents a significant advancement, providing similar efficacy and safety at a reduced cost, thus increasing accessibility worldwide.
However, it’s essential to recognize that not all patients respond to anti-TNF therapy; approximately 15-20% do not see an improvement, and about 30% may lose responsiveness over time. Concerns also exist about potential side effects, including serious infections and skin reactions, which necessitate careful consideration, especially when combined with immunomodulators in older populations due to heightened infection and lymphoma risks.
Beyond Anti-TNF: Exploring Alternative Biologic Therapies
As the landscape of Crohn’s disease treatment evolves, newer biologic agents such as vedolizumab and ustekinumab have emerged, targeting different inflammatory pathways. These agents offer a favorable safety profile and reduced immunogenicity, eliminating the need for combination therapy with immunomodulators.
Vedolizumab, an anti-α4β7 integrin monoclonal antibody with gut selectivity, is administered intravenously and is particularly suitable for treating Crohn’s disease without extraintestinal manifestations.
Ustekinumab, targeting IL-12 and IL-23, is beneficial for its dual approval for treating plaque psoriasis and psoriatic arthritis, marking it as a versatile therapeutic option.
The Rise of JAK Inhibitors
The development of Janus kinase (JAK) inhibitors like upadacitinib and filgotininib has introduced another dimension to Crohn’s disease management. These agents are selective for JAK-1 and have shown promise in phase 3 trials, successfully inducing and maintaining remission in moderate to severe cases. The U-EXCEL, U-EXCEED, and U-ENDURE studies highlighted their efficacy in achieving clinical and endoscopic remission. JAK inhibitors are particularly useful due to their rapid onset of action and potential to address multiple extraintestinal symptoms. However, their use requires caution, particularly in older patients or those at increased risk for thromboembolic events and major cardiovascular conditions.
Strategic Positioning and the Future of Crohn’s Disease Treatment
The introduction of new therapies and the results from comparative trials such as the SEAVUE study, which compared ustekinumab and adalimumab, provide insights into how these treatments can be best utilized. Positioning these therapies effectively in clinical practice involves considering disease activity, safety profiles, and patient-specific factors like comorbidities and personal preferences.
The future of Crohn’s disease treatment appears promising, with ongoing research into molecular markers that could guide therapy selection, known as precision medicine. This approach aims to tailor treatments based on individual characteristics, potentially improving outcomes and minimizing adverse effects.
Dosing
1. Infliximab
Infliximab is administered intravenously, typically at a hospital or infusion center. The standard dosing regimen for Crohn’s disease includes:
- An induction phase with doses at weeks 0, 2, and 6.
- A maintenance phase with doses every 8 weeks thereafter.
The usual dose is 5 mg/kg, but dosing can be adjusted based on clinical response, up to 10 mg/kg or dosing intervals shortened to every 4 weeks in cases of partial response or loss of response.
2. Adalimumab
Adalimumab is administered via subcutaneous injection, which patients can perform at home after proper training. The dosing for Crohn’s disease involves:
- An initial induction dose of 160 mg (given as four 40 mg injections in one day or split between two consecutive days).
- A second dose of 80 mg two weeks after the initial dose.
- A maintenance dose of 40 mg every other week starting two weeks after the second dose. Adjustments may be made based on response and disease severity.
3. Certolizumab Pegol
Although certolizumab pegol is less widely used than infliximab and adalimumab, it is also administered via subcutaneous injection. The dosing schedule includes:
- An initial dose of 400 mg (given as two 200 mg injections) at weeks 0, 2, and 4 for induction.
- A maintenance dose of 400 mg every four weeks thereafter.
4. Vedolizumab
Vedolizumab is given intravenously and specifically targets the gut, which minimizes systemic immunosuppression. The dosing schedule is:
- An induction phase with doses at weeks 0, 2, and 6.
- A maintenance phase with a dose every 8 weeks.
Each dose is typically 300 mg.
5. Ustekinumab
Ustekinumab is administered initially via intravenous infusion, followed by subcutaneous injections for maintenance. The dosing involves:
- An initial weight-based intravenous dose (approximately 6 mg/kg).
- Subcutaneous maintenance injections of 90 mg every 8 weeks starting 8 weeks after the initial dose.
6. Upadacitinib and Filgotinib (JAK inhibitors)
These newer agents are oral medications, which offer a significant convenience advantage over injectables and infusions.
The typical dosing for upadacitinib in Crohn’s disease, as per phase 3 trial data, is:
- An induction dose of 45 mg once daily.
- A maintenance dose of 30 mg once daily after successful induction.
Filgotinib dosing in its trials has been:
- A dose of 200 mg once daily during induction and maintenance phases.
Conclusion
For individuals struggling with moderate-to-severe Crohn’s disease, the evolving landscape of biologic therapies offers hope and improved quality of life. As recommended by Dr. Christos Zavos, a board-certified gastroenterologist and hepatologist, patients should explore these advanced treatment options. For further guidance and personalized treatment planning, patients are encouraged to reach out directly to Dr. Zavos through his website peptiko.gr, by phone at (+30)-6976596988 or (+30)-2311283833, or via email at czavos@ymail.com.
Biologic therapies continue to transform the therapeutic landscape for Crohn’s disease, offering effective management strategies and paving the way for even more innovative treatments in the future.
Reference
- Dolinger M, Torres J, Vermeire S. Crohn’s disease. Lancet 2024;403:1177-1191.