Understanding Anti-TNF Therapy for Crohn's Disease: A Comprehensive Patient Guide

Table of Contents

• Introduction to Crohn's Disease and Anti-TNF Therapy
• What is TNF and How Does It Work?
• TNF's Role in Crohn's Disease Development
• How Anti-TNF Medications Work
• Types of Anti-TNF Treatments and Their Effectiveness
• Loss of Response to Anti-TNF Therapy
• Important Treatment Considerations
• Future Directions in Anti-TNF Treatment
• Key Takeaways for Patients
• Source Information

Introduction to Crohn's Disease and Anti-TNF Therapy

Crohn's disease is a chronic inflammatory condition that can affect any part of the gastrointestinal tract from the mouth to the anus. It belongs to a group of conditions called inflammatory bowel disease (IBD), which also includes ulcerative colitis. These conditions are characterized by chronic, uncontrolled inflammation that follows a pattern of flare-ups and remission periods.

The incidence of Crohn's disease is increasing worldwide, with the highest rates found in North America at 20.2 cases per 100,000 people each year. What makes Crohn's particularly challenging is that it often affects younger people, including children, and typically follows a relapsing and remitting course that progresses to complications requiring surgery in most patients if not properly managed.

The disease manifests in different forms classified by the Montreal Classification system: inflammatory, stricturing (narrowing), and fistulizing (abnormal connections between organs). Common symptoms include chronic diarrhea, abdominal pain, and weight loss, while perianal disease affects approximately one-third of patients with manifestations like fistulas, anal stenosis, skin tags, and ulceration.

Treatment goals focus on achieving both clinical remission (symptom control) and endoscopic remission (mucosal healing), preventing disease progression, minimizing surgical interventions, and optimizing quality of life. Traditional treatment follows a "step-up" approach starting with antibiotics, corticosteroids, and immunomodulators before advancing to biologic therapies like anti-TNF agents.

However, growing evidence supports a "top-down" approach using anti-TNF therapy earlier, especially in severe disease phenotypes. Anti-TNF therapy was first approved for Crohn's disease treatment in 1998 and has fundamentally changed treatment paradigms, leading to significantly improved response and remission rates for patients.

What is TNF and How Does It Work?

Tumor necrosis factor (TNF or TNF-α) is a powerful inflammatory protein that belongs to a large family of proteins involved in immune regulation. In its active form, TNF is a 17 kD protein that gets cleaved from its cell-surface-bound precursor by an enzyme called TACE (TNFα converting enzyme).

Both forms of TNF have biological activity. The soluble form acts at sites distant from where it's produced, while the membrane-bound form works through direct cell-to-cell contact, transmitting signals to target cells that express TNF receptors. This latter mechanism is known as "reverse signaling."

Various cells produce TNF, primarily monocytes, macrophages, and T lymphocytes, but also mast cells, granulocytes, fibroblasts, and other cell types. Numerous triggers can stimulate TNF release, including bacteria, viruses, immune complexes, super-antigens, tumor cells, radiation, and stress.

TNF exerts its effects through two distinct receptors: TNF receptor 1 (found on all nucleated cells) and TNF receptor 2 (primarily on endothelial and hematopoietic cells). These interactions produce strongly pro-inflammatory effects through multiple mechanisms:

• Increased production of other proinflammatory cytokines including interleukin (IL)-1β and IL-6
• Expression of adhesion molecules that help inflammatory cells stick to blood vessel walls
• Proliferation of fibroblasts and procoagulant factors
• Initiation of acute-phase responses
• Inhibition of apoptosis (programmed cell death) of inflammatory cells

This cytokine plays crucial roles in key inflammatory processes including activation of coagulation and fibrinolytic responses, promoting neutrophil-endothelial adhesion necessary for recruiting inflammatory cells to sites of inflammation, and promoting granulomatous inflammation through recruitment of T lymphocytes, monocytes and macrophages.

TNF's Role in Crohn's Disease Development

The exact cause of Crohn's disease isn't fully understood, but researchers believe it involves a complex interaction between environmental triggers, gut bacteria imbalance (dysbiosis), abnormal immune responses, and genetic susceptibility. The disease process involves mucosal injury and inflammation where the protective intestinal barrier becomes compromised, allowing gut bacteria to trigger an excessive inflammatory immune response.

Crohn's disease is characterized by a T-cell mediated immune response with transmural inflammation (affecting all layers of the intestinal wall) as its hallmark. This inflammation is driven by increased levels of proinflammatory cytokines, particularly interferon gamma, interleukin 12, and TNF.

Studies have found increased TNF secretion from mononuclear cells in the intestinal mucosa of Crohn's patients, with TNF-positive cells located deeper in the intestinal wall layers compared to healthy individuals. Researchers have also demonstrated elevated TNF levels in the stool of patients with active Crohn's disease compared to those with inactive disease or healthy controls, though serum concentrations have been less distinctive.

TNF appears early in the inflammatory process underlying Crohn's disease and laboratory studies have shown its involvement in several pathological processes seen in the condition, including neutrophil accumulation, granuloma formation, and increased epithelial permeability that compromises the intestinal barrier function.

How Anti-TNF Medications Work

Initial antibody neutralization studies in animal models first suggested TNF's significant role in Crohn's pathogenesis, leading to the first administration of an anti-TNF-α antibody (cA2, which later became infliximab) in a Crohn's patient, followed by the first case series. These promising results spurred multicenter studies that led to FDA approval of anti-TNF agents for Crohn's treatment in 1998.

Anti-TNF antibodies work through multiple mechanisms of action that include:

• Neutralization of TNF-α by binding both soluble and transmembrane forms
• Reverse signaling that triggers cell activation, cytokine suppression or apoptosis
• Induction of apoptosis (programmed cell death) of activated lamina propria T lymphocytes
• Antibody-dependent cell mediated cytotoxicity and complement-dependent cytotoxicity (for drugs with Fc region like infliximab and adalimumab)

These medications work by depleting TNF-α overexpression by binding to both soluble and membrane-bound TNF-α, preventing them from interacting with their receptors and blocking proinflammatory signals. They also distribute efficiently into inflamed tissue where they're most needed.

The reverse signaling phenomenon is particularly interesting—when anti-TNF drugs bind to the cell-surface-bound precursor to TNF, they act as ligands that trigger cell activation, cytokine suppression, or apoptosis of the cell bearing the precursor. This may work by exhausting common signaling products during simultaneous activation of endotoxin/lipopolysaccharide signaling pathways.

By inducing apoptosis of activated T lymphocytes in the intestinal lining, anti-TNF therapies counter a proposed pathological mechanism in Crohn's where mucosal T cell proliferation exceeds T cell apoptosis. Medications containing an Fc region (infliximab and adalimumab but not certolizumab) can also induce antibody-dependent cell mediated cytotoxicity and complement-dependent cytotoxicity.

Types of Anti-TNF Treatments and Their Effectiveness

Three main anti-TNF medications are currently available for Crohn's disease treatment, each with distinct characteristics, dosing regimens, and evidence supporting their use.

Infliximab (Remicade)

Infliximab was the first biological response modifier used in inflammatory bowel disease treatment. It's a genetically engineered chimeric (mouse/human) immunoglobulin (Ig) G1 antibody against human tumor necrosis factor. This medication can fix complement and lyse cells expressing membrane-bound TNF-alpha while inducing downregulation of inflammatory mechanisms throughout the entire mucosal layer.

Administered intravenously, infliximab typically follows a maintenance schedule of every eight weeks after an initial three-dose induction regimen (weeks 0, 2, and 6). Two landmark randomized controlled trials—the ACCENT I and II studies (A Crohn's disease Clinical study Evaluating infliximab in a New long-term Treatment regimen)—evaluated infliximab's efficacy in both luminal and fistulizing Crohn's phenotypes.

In luminal disease, these trials demonstrated increased likelihood for both short and longer term remission, as well as discontinuation of corticosteroids that would otherwise have been required to control the immune response. Subsequent studies confirmed that infliximab treatment produces not only clinical improvement but also significant endoscopic improvement, with histological examination showing complete reduction of inflammatory infiltrate only in infliximab-treated patients.

For perianal fistulizing disease (including rectovaginal and perianal fistulas), outcomes included closure of draining fistulas. In the first placebo-controlled trial of 94 patients (mostly with perianal fistulae), closure of ≥50% of fistulas occurred in 68% of patients receiving infliximab compared with 26% on placebo (p = 0.002). Complete closure of all fistulas draining at baseline occurred in 55% of the 63 patients receiving infliximab at 0, 2, and 6 weeks compared with 13% on placebo (p = 0.001). Maintenance therapy resulted in approximately one-third of patients remaining in remission at one year.

Adalimumab (Humira)

Adalimumab is a fully human antibody that also fixes complement and lyses cells expressing TNF-α. It's administered subcutaneously via auto-injector pen every two weeks. Key studies demonstrating adalimumab's effectiveness include the CLASSIC-I trial (Clinical Assessment of adalimumab Safety and efficacy Studied as Induction therapy in Crohn's disease), which showed efficacy in inducing clinical response and remission for moderate to severe Crohn's.

A subsequent phase 3 study (CLASSIC II) demonstrated maintenance of remission in those with moderate to severe Crohn's. The CHARM trial (Crohn's trial of the fully Human Antibody Adalimumab for Remission Maintenance) also demonstrated safety and efficacy of adalimumab for maintaining clinical remission following successful induction therapy and in healing draining perianal fistulas.

The GAIN (Gauging Adalimumab efficacy in Infliximab Nonresponders) trial assessed adalimumab efficacy in patients who had lost response or developed intolerance (secondary failure) to infliximab therapy. Researchers reported significantly higher induction of clinical remission at week 4 in the adalimumab-treated group versus the placebo-treated group.

A meta-analysis including the CLASSIC-I, GAIN and CHARM studies, representing over 700 participants with moderate to severe Crohn's, revealed lower likelihood of failure to induce remission on adalimumab versus placebo at weeks four and twelve [Relative risk (RR) 0.85, 95% confidence interval (CI) 0.79–0.91]. These studies used the Crohn's Disease Activity Index (CDAI) scoring system, with a decrease of 100 points signifying response and a decrease of 150 points signifying remission.

A subsequent study using the more objective outcome measure of mucosal healing (the EXTEND trial) found that patients with moderate to severely active Crohn's who continued receiving adalimumab were more likely to achieve mucosal healing.

Certolizumab (Cimzia)

Certolizumab pegol is a chimeric humanized antibody fragment against both soluble (secreted) TNF and transmembrane TNF, attached to polyethylene glycol (PEG) in a process called "pegylation." It differs from infliximab and adalimumab by lacking the crystallisable fragment (Fc) region of typical antibodies. Consequently, it doesn't induce apoptosis as one of its mechanisms, doesn't activate the complement pathway, and doesn't result in cell or antibody mediated cytotoxicity.

However, it's thought to have higher binding affinity for TNF than adalimumab or infliximab. Administered subcutaneously, certolizumab has a longer half-life (due to the PEG addition), with maintenance dosing every four weeks instead of every two weeks like adalimumab.

The PRECISE (Pegylated antibody fragment evaluation in Crohn's disease safety and efficacy) 1 and 2 studies evaluated induction and maintenance of remission with certolizumab in patients with moderate to severe Crohn's. The PRECiSE 1 study found no significant difference in remission at six weeks between certolizumab and placebo groups, but response rates were significantly improved with certolizumab versus placebo (35% vs. 27%, p = 0.02).

The PRECiSE 2 trial reported significantly higher response rate (62% vs. 34%, p < 0.001) and remission rate (48% vs. 29%, p < 0.001) with maintenance certolizumab following positive response to induction therapy at 26 weeks, compared to placebo. Certolizumab has also been evaluated using health-related quality of life as an outcome measure via the Inflammatory Bowel Disease Questionnaire (IBDQ), with significantly improved quality of life at all time points assessed compared with placebo.

The PRECiSE 3 trial assessed long-term outcomes in patients successfully maintained on certolizumab at 26 weeks and reported remission rates of 63% at 80 weeks, though this wasn't statistically significantly different from those in whom the drug was stopped at 26 weeks (placebo). A meta-analysis of four trials assessing certolizumab in over 800 patients found no statistically significant difference between certolizumab and placebo in inducing remission of active luminal Crohn's (RR = 0.95; 95% CI 0.90–1.01).

Maintenance therapy with certolizumab has demonstrated efficacy in perianal fistula closure. In a subgroup analysis of the PRECiSE 2 trial, 58 patients with draining fistulas who responded to induction with certolizumab were randomized to certolizumab or placebo every four weeks. Rates of clinical remission (100% closure of fistulas at baseline) at week 26 were significantly higher in patients treated with certolizumab compared with placebo (36% versus 17%, p = 0.038).

Comparison Between Anti-TNF Therapies

No trials have directly compared all three anti-TNF therapies, but evidence suggests no significant efficacy differences between infliximab and adalimumab. Both are thought superior to certolizumab in inducing remission. A pooled analysis of ten trials including over 2700 Crohn's patients found that those treated with any of the three anti-TNF agents were less likely to fail to achieve remission compared with placebo (RR 0.87, 95% 0.80–0.94).

Biosimilars: The Future of Anti-TNF Therapy

The proven efficacy of anti-TNF medications has led to biosimilars—synthesized versions of existing biological drugs with no perceived difference in safety or efficacy—as patents of older anti-TNF agents have expired or near expiration. Several have been approved for Crohn's treatment in the USA and Europe (with 19 products authorized by the end of 2015), expected to gain substantial market share of biological therapy due to lower costs that reduce healthcare spending and improve patient access.

Biosimilar development requires selecting an appropriate reference biologic agent, understanding its key molecular attributes, developing a manufacturing process to match these attributes, and thorough preclinical and clinical evaluation including pharmacokinetic/pharmacodynamic studies and randomized controlled trials.

Preliminary data from real-life cohort studies across different countries support the bioequivalence of infliximab biosimilars in IBD, rheumatology, and dermatology. One study found a significant decrease in clinical activity index and C-reactive protein (CRP) in the whole study population (including Crohn's and ulcerative colitis patients), with only four allergic reactions in subjects previously exposed to infliximab.

The large prospective NOR-SWITCH study in Norway reported that switching to a biosimilar infliximab was noninferior to continued treatment with the reference product in terms of efficacy, safety, and immunogenicity, though the trial wasn't powered to demonstrate noninferiority in individual disease states including Crohn's and ulcerative colitis.

However, contrasting data from an Irish cohort comparing patients treated with infliximab originator versus biosimilars showed increased surgery rates, less steroid-free remission, and less normalization of inflammatory marker CRP. Further observational studies and efficient pharmacovigilance programs are warranted to address implications of these new drugs and whether existing drug monitoring techniques for efficacy and safety apply equally.

Loss of Response to Anti-TNF Therapy

Despite the paradigm shift in Crohn's treatment over the past two decades with anti-TNF agents, some patients experience diminished response over time. This loss of response represents a significant clinical challenge that requires careful management strategies including dose optimization, switching to another anti-TNF agent, or transitioning to a different class of biologic medication.

Important Treatment Considerations

When considering anti-TNF therapy, several important factors must be weighed including immunogenicity (development of antibodies against the medication), safety profile, and optimal treatment duration. Patients and physicians must work together to assess individual risk factors, disease severity, and treatment goals when selecting the most appropriate therapeutic approach.

Regular monitoring through blood tests, clinical assessment, and sometimes endoscopic evaluation helps ensure treatment remains effective and safe over time. Therapeutic drug monitoring—measuring drug levels and antibodies—can help optimize dosing and identify reasons for treatment failure.

Future Directions in Anti-TNF Treatment

Research continues to refine anti-TNF therapy approaches, including head-to-head trials to assess optimal treatment pathways, better outcome measures for fistula management, and standardized use guidelines for biosimilars. Close cooperation between regulatory authorities, scientific societies, and the pharmaceutical industry will help improve knowledge and clinical practice guidelines.

Emerging biomarkers may help predict which patients will respond best to specific anti-TNF agents, allowing for more personalized treatment approaches. Additionally, combination therapies and sequencing strategies involving anti-TNF medications alongside other biologic classes represent an active area of investigation.

Key Takeaways for Patients

Anti-TNF therapy has transformed Crohn's disease management over the past twenty years, offering patients significantly improved chances of achieving and maintaining remission. The three available medications—infliximab, adalimumab, and certolizumab—each have distinct characteristics but share the common mechanism of targeting tumor necrosis factor, a key driver of intestinal inflammation in Crohn's.

These treatments have demonstrated effectiveness in multiple large clinical trials for both luminal and fistulizing disease, with proven ability to induce clinical response, promote mucosal healing, close fistulas, reduce corticosteroid dependence, and improve quality of life. While considerations around immunogenicity, safety, and treatment duration remain important, anti-TNF agents represent a cornerstone of modern Crohn's disease management.

The emergence of biosimilar versions promises to increase accessibility and reduce costs while maintaining efficacy. Patients should work closely with their gastroenterologists to determine if anti-TNF therapy is appropriate for their specific situation and which agent might offer the best balance of efficacy, safety, and convenience for their individual needs.

Source Information

Original Article Title: Anti-TNF Therapy in Crohn's Disease
Authors: Samuel O. Adegbola, Kapil Sahnan, Janindra Warusavitarne, Ailsa Hart, Philip Tozer
Publication: International Journal of Molecular Sciences, 2018
Note: This patient-friendly article is based on peer-reviewed research from the original publication.