INTRODUCTION — Tumor necrosis factor (TNF)-alpha inhibitors, including infliximab, adalimumab, and certolizumab pegol, are biologic agents used for treating patients with moderately to severely active Crohn disease.
Dosing, monitoring, and adverse effects of anti-TNF agents for the treatment of Crohn disease in adults will be reviewed here. The decision whether to use infliximab, adalimumab, or certolizumab pegol in patients requiring anti-TNF-alpha therapy is influenced by the indication, patient preference, patient medical history, and availability in individual countries. Overviews of the medical management of Crohn disease and use of thiopurines are discussed separately:
●(See "Overview of the medical management of mild (low risk) Crohn disease in adults".)
●(See "Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease".)
●(See "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease".)
●(See "Management of Crohn disease after surgical resection".)
TUMOR NECROSIS FACTOR INHIBITORS — Infliximab, adalimumab, and certolizumab pegol are monoclonal antibodies directed against tumor necrosis factor (TNF)-alpha. The basis for their use in Crohn disease is that tumor necrosis factor (TNF)-alpha has several biologic activities that may be directly related to the pathogenesis of inflammatory bowel disease and to the dysregulation of the immune system that occurs in patients with IBD. (See "Overview of biologic agents and kinase inhibitors in the rheumatic diseases", section on 'Anticytokine approaches'.)
●Infliximab – Infliximab is a chimeric monoclonal antibody comprised of 75 percent human and 25 percent murine sequences, which has a high specificity for and affinity to tumor necrosis factor (TNF)-alpha. Infliximab neutralizes the biologic activity of TNF-alpha by inhibiting binding to its receptors. In contrast to some other TNF inhibitors (eg, etanercept), infliximab can also induce apoptosis of activated lymphocytes in the gut mucosa [1-3].
●Adalimumab – Adalimumab is a recombinant fully human monoclonal antibody that binds to TNF-alpha, thereby interfering with binding to TNF-alpha receptor sites and subsequent cytokine-driven inflammatory processes. The humanized construction of adalimumab is presumed to lower the risk of forming anti-drug antibodies compared with infliximab. (See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases", section on 'Adalimumab-induced human anti-human antibodies'.)
●Certolizumab pegol – Certolizumab pegol is a humanized monoclonal antibody Fab fragment linked to polyethylene glycol that increases its plasma half-life and reduces the requirement for frequent dosing, possibly reducing immunogenicity as well. In vitro studies suggest that certolizumab pegol also has a higher binding affinity for TNF as compared with adalimumab or infliximab [4].
Certolizumab pegol does not have an Fc region; as a result, it does not activate the complement pathway, result in cell- or antibody-mediated cytotoxicity, or induce apoptosis [4]. However, the clinical significance of these differences is unclear.
PRETREATMENT SCREENING — Prior to starting an anti-TNF agent, we obtain the following screening tests in all patients:
●Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), and hepatitis B core antibody (HBcAb).
Patients with serologic evidence of hepatitis B virus (HBV) infection (HBsAg-positive or anti-HBc-positive) are at risk for HBV reactivation if they receive immunosuppressive therapy. Prevention, diagnosis, and treatment of HBV reactivation are discussed separately. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
●Interferon-gamma release assay such as QuantiFERON-TB Gold In-Tube assay (preferred) or tuberculin skin test.
If the screening test for latent tuberculosis is positive, a chest radiograph is obtained and the patient is referred to an infectious disease specialist for further evaluation.
•(See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".)
CONTRAINDICATIONS — The contraindications to the use of anti-TNF therapies include the following (see "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Use of TNF inhibitors'):
●Active, uncontrolled infection
●Latent (untreated) tuberculosis
●Demyelinating disease (eg, multiple sclerosis, optic neuritis)
●Heart failure (New York Heart Association class III/IV) (table 1)
●Active lymphoma
The safety of anti-TNF therapies and risk of recurrent malignancy in patients with a history of malignancy is less well established than in patients without such a history; the available data are discussed in detail separately. (See "Tumor necrosis factor-alpha inhibitors: Risk of malignancy".)
DOSING AND ADMINISTRATION
Overview — This section describes the induction and maintenance dosing for infliximab, adalimumab, and certolizumab pegol. In addition, options for dose escalation are included for patients with loss of response while on maintenance therapy. The approach to the patient who is not responding to induction anti-TNF therapy, including the use of adjuvant glucocorticoids or immunomodulators, is discussed separately. (See "Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease", section on 'Induction therapy'.)
Decisions regarding dose adjustments for patients on maintenance therapy who lose response can be guided by therapeutic drug monitoring (table 2). (See 'Monitoring' below and "Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults", section on 'Monitoring'.)
Infliximab — The induction dose of infliximab for treatment of patients with moderately to severely active Crohn disease, including fistulizing disease, is 5 mg/kg intravenously at zero-, two-, and six- weeks [5,6].
Patients who achieve an adequate response (based on clinical, endoscopic, and laboratory findings) to initial therapy will require repeat infusions of 5 mg/kg, usually every eight weeks, to maintain remission.
Patients who have a disease flare while on maintenance dosing can be managed by escalating the dose [7]. Additionally, individuals who achieve an incomplete response can be managed in a similar fashion. Dose escalation can be accomplished by either decreasing the dosing interval (eg, from eight weeks to six weeks) or by increasing the dose (eg, from 5 mg/kg to 10 mg/kg). The maximal dose of infliximab is 10 mg/kg every four weeks.
Adalimumab — Induction therapy with adalimumab is given subcutaneously with the following regimen:
●Week zero, initial dose – 160 mg once
●Week two – 80 mg once
●Week four and thereafter – 40 mg every other week (maintenance dose)
We suggest the same induction regimen for patients who are being switched to adalimumab from another anti-tumor necrosis factor (TNF) agent. Adalimumab is available in a single-use prefilled pen (Humira Pen) or in a single-use prefilled glass syringe.
For patients who have a disease flare while on maintenance dosing, the dosing interval can be shortened to every week [8]. A meta-analysis of 39 studies showed that the mean percentage of loss of response to adalimumab among primary responders was 18 percent and the annual risk was 20 percent per patient-year; the mean percentage of patients who required dose escalation (ie, shortening the dosing interval) among primary responders to adalimumab was 37 percent and the annual risk was 25 percent per patient-year [9].
In this pooled analysis of outcomes following dose escalation, response was achieved in 71 percent of patients, and remission was achieved in 40 percent of patients [9]. A large number of factors predicted loss of response or need for dose escalation in patients treated with adalimumab (male gender, high body mass index, current/former smoking, family history of inflammatory bowel disease, isolated colonic disease, extraintestinal manifestations, 80/40 mg induction therapy, longer disease duration, greater baseline Crohn Disease Activity Index, concomitant glucocorticoid use, absence of deep remission at week 12, low serum trough concentrations of adalimumab, previous infliximab non-response, and prior treatment with an anti-TNF-alpha agent) [9,10].
In addition to loss of response, some patients do not respond initially to anti-TNF induction therapy (primary nonresponse), and rates of primary nonresponse have ranged from 10 to 40 percent in clinical trials and observational studies [11]. In addition, studies have suggested that primary nonresponse has often been related to inadequate drug concentrations [12]. Thus, it seems most appropriate to escalate the dose of anti-TNF therapy during induction for patients who are not responding and utilize therapeutic drug monitoring. (See 'Therapeutic drug monitoring' below.)
Certolizumab pegol — The recommended dose of certolizumab pegol for induction of remission in Crohn disease is 400 mg subcutaneously at weeks zero, two, and four, and then every four weeks for maintenance therapy [13]. For patients who have loss of response while on maintenance dosing and who are candidates for dose escalation, options include shortening the interval between doses (eg, every two to three weeks) or giving a single re-induction dose (ie, 400 mg) between scheduled four-week doses [14,15].
MONITORING — In addition to clinical observation, monitoring the response to anti-TNF agents may include therapeutic drug monitoring (checking drug trough levels, anti-drug antibodies) and levels of biomarkers (C-reactive protein [CRP], fecal calprotectin). Time intervals for follow-up colonoscopy are discussed separately. (See "Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease".)
Therapeutic drug monitoring — Therapeutic drug monitoring involves measuring serum drug trough concentrations and antidrug antibodies to optimize the use of anti-TNF agents for patients with inflammatory bowel disease (IBD). For patients with clinical features of inflammation (eg, symptoms, laboratory studies, endoscopic appearance), therapeutic drug monitoring can help the clinician decide whether a dose increase is needed or if switching to a different drug is preferred. Approximately 40 percent of patients who initially achieve remission will develop secondary loss of response during the first year of therapy [5,16]. Potential causes of secondary loss of response include (table 2) [17]:
●Low drug levels (due to either immune or non-immune mediated clearance mechanisms)
●Mechanistic failure (eg, non-TNF-mediated cytokine pathways may be playing a greater role in pathogenesis of IBD)
Available drug assays report both drug concentration and anti-drug antibodies. The suggested target drug trough concentrations are generally based on cross-sectional studies of patients on maintenance therapy [17]:
●Infliximab: ≥5 microg/mL for luminal disease. Some but not all studies have reported that higher infliximab trough levels were associated with healing of perianal fistula related to Crohn disease [18-22], and a trough level of ≥10 microg/mL has been suggested for patients with fistulizing disease [19].
●Adalimumab: ≥7.5 microg/mL.
●Certolizumab pegol: ≥20 microg/mL.
Patients with active disease despite maintenance therapy — A guideline from the American Gastroenterological Association (AGA) suggests that adult patients with active inflammatory bowel disease who are being treated with an anti-TNF agent receive reactive therapeutic drug monitoring using drug trough levels and anti-drug antibodies [17]. The drug trough level should be drawn no more than 24 hours prior to the next scheduled dose of the drug. Measurement of drug levels and anti-drug antibodies with dose adjustments to reach a target drug trough concentration can result in fewer flares during the course of treatment and is more cost-effective compared with empiric dose escalation in patients with a loss of response (table 2) [23-25]. Because antibodies to anti-TNF agents can reduce drug blood levels, a subset of patients will lose their response and have recurrence of symptoms between treatment intervals.
Patients with sustained anti-drug antibodies — For patients with sustained, high levels of anti-drug antibodies, it is appropriate to discontinue the index agent and switch to another drug. If the patient has inadequate (ie, subtherapeutic) drug trough concentrations, switching to an alternative anti-TNF agent is suggested. If the patient has adequate (ie, therapeutic) drug trough concentrations, switching to another mechanism of treatment (eg, anti-integrin antibody [vedolizumab], anti-IL-12/23 antibody [ustekinumab], anti-IL-23 antibody [risankizumab]) is preferred [17,23].
While transient anti-drug antibodies can disappear spontaneously or can be overcome by dose optimization (particularly when drug concentrations are low), sustained, high anti-drug antibody levels may lead to permanent loss of response and necessitate discontinuation of the index drug. In contrast to target drug trough concentrations, the reporting of anti-drug antibodies has varied among commercial assays and has not been standardized [17]. (See 'Therapeutic drug monitoring' above.)
For patients with anti-drug antibodies who switch to a different biologic agent within the same class, the addition of an immunomodulator may be helpful. The use of immunomodulators (ie, azathioprine, 6-mercaptopurine or methotrexate) decreases the rate of formation of antibodies to anti-TNF agents and results in higher response and remission rates [26-28]. In a meta-analysis of 24 studies including over 4600 patients with inflammatory bowel disease, patients who were treated with combination therapy (ie, anti-TNF agent and immunomodulator) were less likely to develop antibodies against tumor necrosis factor antagonists (anti-TNFs) compared with patients treated with anti-TNF monotherapy (RR 0.49, 95% CI 0.41-0.59) [28] (see "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease").
Preliminary data suggested that patients who develop antibodies against one anti-TNF agent were more likely to develop antibodies against another anti-TNF agent, thus highlighting this concept [29].
One retrospective study analyzed 788 serum samples from 57 infliximab-treated patients with IBD in whom anti-infliximab antibodies had been detected at least once during follow-up [30]. In this study, patients with transient anti-infliximab antibodies had significantly lower median anti-infliximab antibodies levels than those with persistent antibodies (6 and 18 units/mL respectively). In patients with transient anti-infliximab antibodies, antibodies disappeared spontaneously or after infliximab dose optimization in 42 and 58 percent, respectively. A higher proportion of patients with persistent anti-infliximab antibodies discontinued treatment as compared with those with transient antibodies (74 versus 26 percent).
Patients in remission — While therapeutic drug monitoring is useful in the setting of active IBD (ie, reactive drug monitoring), we do not routinely use therapeutic drug monitoring for patients in clinical remission (ie, proactive drug monitoring) because data from randomized trials suggested that proactive monitoring did not improve outcomes. We reserve proactive monitoring for patients who are at higher risk of complications from a disease flare. In a meta-analysis of nine trials including 1405 patients with IBD who were in remission, there were no significant differences in rates of sustained remission, anti-drug antibodies, or serious adverse events between patients who had proactive drug monitoring compared with conventional management [31]. (See 'Therapeutic drug monitoring' above.)
Biomarkers of inflammation — In addition to therapeutic drug monitoring, obtaining biomarkers of inflammation including CRP and fecal calprotectin can help guide therapy to achieve endoscopic and clinical remission in patients with Crohn disease [32,33]. Although the AGA has published guidelines on therapeutic drug monitoring, biomarker monitoring is used at the discretion of the clinician.
Biomarkers of inflammation are typically obtained before initiating therapy, and as an example, CRP levels have been used to predict response to treatment [34,35]. In addition, elevated biomarkers can be followed after initiating biologic therapy to see if the biomarkers improve with treatment.
In a trial of 244 patients with Crohn disease, patients who were monitored by clinical symptoms and with biomarkers (ie, CRP and fecal calprotectin) and in whom biologic and/or immunomodulator therapy was started and escalated based on those results, were more likely to have mucosal healing at 48 weeks compared with patients who were monitored by clinical symptoms alone (46 versus 30 percent, adjusted risk difference 16 percent [95% CI 3.9-28.3]) [32].
●CRP – A high baseline CRP level that normalizes with treatment has been associated with a higher chance of having a response to infliximab [26,36]. In a study of 718 patients with Crohn disease who were receiving infliximab, patients with elevated CRP levels before treatment were more likely to respond to infliximab compared with patients with normal levels (91 versus 83 percent) [36]. Early normalization of the CRP level was associated with a sustained, long-term response and CRP levels remained significantly higher in patients who lost their response to infliximab than in patients who had a sustained response.
●Fecal calprotectin – Fecal calprotectin can be used to monitor response to anti-TNF therapy in patients with IBD, but because of limited sensitivity and specificity it should be used in conjunction with other laboratory tests and symptoms to arrive at clinical decisions [37]. Fecal calprotectin levels correlate with endoscopic disease activity and may differentiate between active and inactive IBD [38-41]. Calprotectin is a zinc and calcium binding protein that is derived mostly from neutrophils and monocytes, and fecal calprotectin levels are increased in patients with mucosal inflammation. (See "Approach to the adult with chronic diarrhea in resource-abundant settings", section on 'General laboratory tests'.)
ADVERSE EVENTS — The tumor necrosis factor (TNF)-alpha inhibitors have multiple potential adverse events that are listed below and discussed in more detail separately [42-45] (see "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects"):
●Infection (see "Tumor necrosis factor-alpha inhibitors and mycobacterial infections" and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections").
●Malignancy (see "Tumor necrosis factor-alpha inhibitors: Risk of malignancy").
●Induction of autoimmunity (see "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases").
●Demyelinating disease.
●Heart failure.
●Injection site reactions.
●Neutropenia.
●Infusion reactions (table 3 and algorithm 1).
●Cutaneous reactions, including psoriaform lesions (suggest referring the patients with skin lesions to dermatology for further evaluation).
Severe adverse reactions may result in discontinuation of anti-TNF therapy. In other cases, the reaction may be manageable, and stopping anti-TNF therapy may not be necessary.
Risks with combination therapy — The risk of lymphoma in patients on infliximab (or other anti-TNF agents) in combination with an immunomodulator (azathioprine or 6-mercaptopurine), along with an increased incidence of infections in patients on more than one immunosuppressive agent, has led to the use of anti-TNF monotherapy in some patients with IBD.
The magnitude of the risk of developing lymphoma is low when viewed in absolute terms (ie, less than one case per 1000 person years) [46]. In a large cohort study including over 189,000 patients with inflammatory bowel disease, the risk of lymphoma was increased in patients exposed to combination therapy (adjusted hazard ratio [aHR] 6.11, 95% CI 3.46-10.8), anti-TNF monotherapy (aHR 2.41, 95% CI 1.6-3.64), or thiopurine monotherapy (aHR 2.6, 95% CI 1.96-3.44) compared with patients who were not exposed to any of these drug regimens during a median follow-up of 6.7 years [46].
Long-term thiopurine use (more than two years) appears to be a common denominator in cases of hepatosplenic T-cell lymphomas, and this issue is addressed separately [47]. (See "Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease", section on 'Hepatosplenic T-cell lymphoma'.)
PREGNANCY — The use of anti-TNF agents during pregnancy and lactation is discussed elsewhere. (See "Fertility, pregnancy, and nursing in inflammatory bowel disease", section on 'Anti-tumor necrosis factor agents'.)
BIOSIMILARS FOR BIOLOGIC AGENTS — Copies of biologic agents, including several of the tumor necrosis factor inhibitors, have been marketed and are under development. A "biosimilar" is a copy which is similar but not identical to the original ("reference" or "legacy") product and is no longer under patent protection. Infliximab-dyyb is an example of a biosimilar. Biosimilars for biologic agents are discussed separately. (See "Overview of biologic agents and kinase inhibitors in the rheumatic diseases", section on 'Biosimilars for biologic agents'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Crohn disease in adults".)
The American Gastroenterological Association (AGA) guidelines on the use of anti-TNF agents for Crohn disease and on therapeutic drug monitoring can be accessed through the AGA website [17,48,49]. In addition, the American College of Gastroenterology (ACG) has issued practice guidelines that can be accessed through the ACG website [50].
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Crohn disease in adults (The Basics)")
●Beyond the Basics topics (see "Patient education: Crohn disease (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Anti-tumor necrosis factor (TNF) therapy – Tumor necrosis factor (TNF)-alpha inhibitors, including infliximab, adalimumab, and certolizumab pegol, are biologic agents used for treating patients with moderately to severely active Crohn disease. The decision whether to use infliximab, adalimumab, or certolizumab pegol in patients requiring anti-TNF therapy is influenced by the indication, patient preference, and availability in individual countries. (See 'Introduction' above and "Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease".)
Infliximab, adalimumab, and certolizumab pegol are all monoclonal antibodies directed against TNF-alpha. (See 'Tumor necrosis factor inhibitors' above.)
●Contraindications to use of anti-TNF agents – Contraindications to the use of anti-TNF therapies include the following (see 'Contraindications' above):
•Active infection
•Latent (untreated) tuberculosis
•Demyelinating disease (eg, multiple sclerosis, optic neuritis)
•Heart failure (NYHA class III/IV) (table 1)
•Active lymphoma
The safety of anti-TNF therapies and risk of recurrent malignancy in patients with a history of malignancy is discussed in detail separately. (See "Tumor necrosis factor-alpha inhibitors: Risk of malignancy".)
●Therapeutic drug monitoring – Therapeutic drug monitoring involves measuring serum drug trough concentrations and anti-drug antibodies to optimize the use of anti-TNF agents for patients with inflammatory bowel disease. Some patients who initially achieve remission will develop secondary loss of response during the first year of therapy. Reactive drug monitoring in this setting can help the clinician decide whether dose escalation is needed or if switching to a different drug is preferred.
For patients in clinical remission, we reserve therapeutic drug monitoring for patients at higher risk of complications from a disease flare, rather than performing it routinely in all patients. (See 'Therapeutic drug monitoring' above.)
●Adverse events – Potential adverse events associated with TNF-alpha inhibitors include (see 'Adverse events' above):
•Infection
•Malignancy
•Induction of autoimmunity
•Demyelinating disease
•Heart failure
•Injection site reactions
•Infusion reactions
•Neutropenia
•Cutaneous reactions, including psoriaform lesions
ACKNOWLEDGMENT — The UpToDate editorial staff thank Dr. Richard MacDermott for his contributions as author to prior versions of this topic review.
We are saddened by the death of Paul Rutgeerts, MD, who passed away in September 2020. UpToDate gratefully acknowledges Dr. Rutgeerts' work as our Section Editor for Gastroenterology.
