Infliximab

Infliximab is a chimeric monoclonal antibody that specifically binds to tumor necrosis factor alpha (TNFα), a pro-inflammatory cytokine central to the pathogenesis of various autoimmune and inflammatory diseases.^[1] Developed as a biologic therapy, it neutralizes the biological activity of both soluble and transmembrane forms of TNFα, thereby inhibiting its interaction with cell surface receptors, reducing the production of other inflammatory mediators such as interleukin-1 (IL-1) and IL-6, and limiting leukocyte migration to sites of inflammation.^[1] Structurally, infliximab is an IgG1κ immunoglobulin composed of human constant regions and murine variable regions, with an approximate molecular weight of 149.1 kilodaltons, produced via recombinant DNA technology in a murine myeloma cell line.^[1] Marketed primarily under the brand name Remicade, it is administered intravenously and has a median terminal half-life of 7.7 to 9.5 days, with pharmacokinetics showing dose-proportional serum concentrations.^[1] First approved by the U.S. Food and Drug Administration (FDA) in 1998 for the treatment of moderately to severely active Crohn's disease in adults, infliximab's indications have expanded to include pediatric Crohn's disease (ages 6 and older), ulcerative colitis (adults and children 6 and older), rheumatoid arthritis (in combination with methotrexate), ankylosing spondylitis, psoriatic arthritis, and chronic severe plaque psoriasis.^[1] In these conditions, it reduces signs and symptoms, induces and maintains remission, promotes mucosal healing, inhibits structural damage, and improves physical function, particularly in patients unresponsive to conventional therapies.^[1] Several biosimilars have since been approved, offering equivalent efficacy and safety profiles.^[2]

Pharmacology

Mechanism of action

Infliximab is a chimeric monoclonal antibody composed of 75% human immunoglobulin G1 (IgG1) constant regions and 25% murine variable regions, engineered to specifically target tumor necrosis factor-alpha (TNF-α), a key proinflammatory cytokine in autoimmune and inflammatory diseases.^[3] This structure allows infliximab to exhibit high affinity binding to TNF-α while minimizing immunogenicity compared to fully murine antibodies.^[4] Unlike other cytokines, infliximab does not cross-react with TNF-β (lymphotoxin-α), ensuring its selectivity for TNF-α-mediated pathways.^[3] The primary mechanism involves infliximab binding to both soluble and membrane-bound forms of TNF-α, forming stable immune complexes that prevent TNF-α from interacting with its cell surface receptors, TNFR1 (p55) and TNFR2 (p75).^[4] This blockade inhibits the initiation of intracellular signaling cascades, such as those involving nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase (JNK), which would otherwise promote transcription of proinflammatory genes.^[5] By neutralizing TNF-α, infliximab disrupts the amplification of inflammatory responses in tissues affected by TNF-mediated diseases.^[3] Downstream effects of this binding include the inhibition of secondary cytokine production, such as interleukin-1 (IL-1) and IL-6, as well as reduced expression of adhesion molecules (e.g., vascular cell adhesion molecule-1 [VCAM-1] and intercellular adhesion molecule-1 [ICAM-1]) on endothelial cells, thereby decreasing inflammatory cell migration and infiltration into affected sites.^[4] Additionally, infliximab induces apoptosis in TNF-α-producing cells, including activated T lymphocytes and monocytes, through mechanisms such as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and reverse signaling via transmembrane TNF-α.^[5] These actions collectively attenuate the chronic inflammation driven by TNF-α in autoimmune conditions.^[3]

Pharmacokinetics

Infliximab is primarily administered via intravenous infusion due to its large molecular size of approximately 149 kDa, which prevents oral absorption and bioavailability; however, as of 2023, subcutaneous formulations have been approved for maintenance therapy in certain indications such as Crohn's disease and ulcerative colitis.^[6]^[7] The following pharmacokinetic parameters apply to intravenous administration.^[6] Following intravenous administration, infliximab exhibits near-complete bioavailability of approximately 100%, with a linear relationship between dose and maximum serum concentration.^[8] The volume of distribution is limited to the vascular and interstitial spaces, approximately 3-6 L at steady state, reflecting its confinement primarily to the intravascular compartment.^[6]^[9] The terminal half-life of infliximab ranges from 7.7 to 9.5 days, with clearance occurring primarily through catabolism to peptides and amino acids via the reticuloendothelial system, without significant hepatic metabolism or renal excretion of the intact drug.^[6]^[8]^[9] Pharmacokinetic parameters are influenced by patient factors, including higher clearance observed in individuals with elevated disease activity (as indicated by markers such as C-reactive protein or fecal calprotectin), development of antibodies to infliximab, and increased body weight.^[6]^[10] Concomitant use of immunosuppressants like methotrexate can reduce antibody formation and thereby lower clearance.^[9] Subcutaneous infliximab formulations exhibit different pharmacokinetics, including higher serum trough levels and potentially altered clearance compared to intravenous administration.^[7] Dosing is typically weight-based, such as 5 mg/kg for most indications, to account for these pharmacokinetic variations and achieve therapeutic serum concentrations.^[6]

Medical uses

Crohn's disease

Infliximab received FDA approval in 1998 as the first biologic therapy for the treatment of moderately to severely active Crohn's disease in adults who had an inadequate response to conventional therapies.^[6] The standard induction regimen consists of intravenous infusions of 5 mg/kg at weeks 0, 2, and 6, followed by maintenance dosing of 5 mg/kg every 8 weeks to sustain remission.^[6] This dosing schedule was established based on pivotal clinical trials demonstrating its ability to induce rapid clinical response and maintain long-term benefits in both inflammatory and fistulizing subtypes of the disease. In patients with inflammatory Crohn's disease, infliximab induces clinical response in 60-70% of cases by week 4, defined as a significant reduction in the Crohn's Disease Activity Index score.^[11] Maintenance therapy further supports remission, with rates of 39-45% at week 30 and sustained benefits up to week 54 in responders to the initial dose, as shown in the ACCENT I trial.^[12] Endoscopic evaluation in an ACCENT I substudy revealed mucosal healing in approximately 30% of patients at week 10, increasing to higher rates with scheduled maintenance compared to episodic treatment.^[13] For fistulizing Crohn's disease, infliximab reduces the number of draining fistulas by more than 50% in about 60% of patients during induction, with 68% achieving this outcome at week 4 in the pivotal trial; maintenance therapy sustains closure in 36% at week 54, per the ACCENT II trial.^[14]^[15] Infliximab is also approved for pediatric patients aged 6 years and older with moderately to severely active Crohn's disease unresponsive to conventional treatment, using the same 5 mg/kg induction and maintenance regimen.^[6] The REACH trial demonstrated clinical response in 88% and remission in 59% of children at week 10 post-induction, with 56% maintaining remission at week 54 on every-8-week dosing.^[6] Combination therapy with immunomodulators such as azathioprine enhances efficacy, achieving corticosteroid-free remission in 57% of patients at week 26 in the SONIC trial, compared to 44% with infliximab monotherapy and 30% with azathioprine alone; it also promotes mucosal healing in 44% versus 30% and 17%, respectively.^[16] Loss of response to infliximab occurs in up to 40% of patients over time, primarily due to immunogenicity leading to antidrug antibody formation, which clears the drug faster and reduces its duration of effect.^[17] Monitoring involves measuring serum infliximab trough levels and antidrug antibodies, with optimization strategies like dose escalation or interval shortening recapturing response in many cases; concurrent immunomodulators reduce immunogenicity risk by up to 3-fold.^[17]^[16]

Ulcerative colitis

Infliximab received FDA approval in 2006 for the treatment of adults with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy.^[18] The recommended dosing regimen mirrors that used for Crohn's disease, consisting of an intravenous induction phase of 5 mg/kg at weeks 0, 2, and 6, followed by maintenance infusions of 5 mg/kg every 8 weeks thereafter.^[6] This schedule aims to induce and sustain clinical remission while minimizing immunogenicity risks associated with intermittent dosing. The efficacy of infliximab in ulcerative colitis was established through the pivotal ACT 1 and ACT 2 randomized, double-blind, placebo-controlled trials, which enrolled patients with moderate-to-severe disease. In both trials, approximately 65-69% of patients receiving 5 mg/kg infliximab achieved clinical response at week 8, compared to 29-37% on placebo (P<0.001).^[19] For maintenance, clinical remission rates at week 30 reached 26-34% in the infliximab groups versus 11-16% with placebo (P<0.01), demonstrating sustained benefits.^[19] Additionally, infliximab promoted endoscopic remission, with mucosal healing observed in about 60% of treated patients at week 8 versus 30-34% on placebo, highlighting its role in repairing colonic mucosa beyond symptom control.^[19] Infliximab has also shown benefits in reducing the need for colectomy, a critical outcome in ulcerative colitis management. Pooled analysis from the ACT trials indicated that patients treated with infliximab had a colectomy rate of approximately 10% at 54 weeks, compared to 15% in the placebo group, representing up to a 50% relative risk reduction in high-risk subgroups.^[20] In pediatric patients aged 6 years and older, infliximab gained FDA approval in 2011 based on a phase 3 trial demonstrating clinical response in 73% of children with moderately to severely active ulcerative colitis after induction, supporting its use for remission induction and maintenance in this population.^[6] As rescue therapy for acute severe ulcerative colitis refractory to intravenous corticosteroids, infliximab provides a viable alternative to immediate surgery. Real-world studies report that about two-thirds of patients avoid colectomy within 3 months of infliximab administration, with short-term clinical response rates exceeding 60%, though long-term outcomes depend on factors like disease severity and drug levels.^[21]^[22]

Rheumatoid arthritis

Infliximab was approved by the U.S. Food and Drug Administration in 1999 for the treatment of moderately to severely active rheumatoid arthritis in adults with an inadequate response to methotrexate, in combination with methotrexate to reduce signs and symptoms, inhibit progression of structural damage, and improve physical function.^[23] The standard dosing regimen involves an initial dose of 3 mg/kg administered intravenously over at least 2 hours, followed by doses at 2 and 6 weeks, and then every 8 weeks thereafter, always in conjunction with methotrexate to optimize efficacy and minimize immunogenicity.^[6] The efficacy of infliximab in rheumatoid arthritis was demonstrated in the Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) study, a multicenter, randomized, double-blind, placebo-controlled trial involving 428 patients with active disease despite methotrexate therapy. In this trial, patients receiving infliximab at 3 mg/kg every 8 weeks plus methotrexate achieved American College of Rheumatology 20% (ACR20) response rates of 50% at 30 weeks and approximately 59% at 54 weeks, compared to 20% and 17% with placebo plus methotrexate, respectively, indicating substantial clinical improvement in signs and symptoms such as joint swelling and tenderness.^[24] Additionally, over 102 weeks, infliximab plus methotrexate significantly reduced radiographic progression of joint damage, with a mean change in modified Sharp score of 0.0 units versus 3.7 units in the placebo group, highlighting its role in preserving joint integrity and slowing erosive disease.^[25] Concurrent methotrexate is essential for infliximab therapy in rheumatoid arthritis, as it enhances clinical response, prolongs drug persistence, and reduces the formation of anti-infliximab antibodies, which can neutralize the drug and lead to loss of efficacy. Studies show that methotrexate co-administration lowers immunogenicity rates to below 10% in combination regimens, compared to over 50% with infliximab monotherapy, thereby supporting sustained therapeutic levels.^[26] Infliximab is not recommended as monotherapy for rheumatoid arthritis due to these heightened immunogenicity risks and inferior long-term outcomes, including faster disease progression and reduced durability of response.^[27] In patients with early rheumatoid arthritis (disease duration less than 3 years), infliximab combined with methotrexate has shown superior outcomes compared to methotrexate alone, including greater inhibition of radiographic joint damage, improved functional status as measured by the Health Assessment Questionnaire, and higher rates of remission induction over 1-2 years. Systematic reviews of randomized trials confirm that this early intervention strategy yields better long-term structural and clinical benefits, with sustained low disease activity in over 60% of responders at 7-year follow-up.^[28]

Ankylosing spondylitis

Infliximab was approved by the U.S. Food and Drug Administration in 2004 for reducing signs and symptoms in adults with active ankylosing spondylitis. The recommended dosing regimen is 5 mg/kg administered intravenously at weeks 0, 2, and 6, followed by maintenance infusions every 6 weeks thereafter. This approval was supported by clinical trials demonstrating significant improvements in disease activity and inflammation in patients with axial involvement refractory to nonsteroidal anti-inflammatory drugs. The pivotal Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy (ASSERT), a randomized, placebo-controlled trial involving 279 patients, showed that infliximab at 5 mg/kg led to an ASAS20 response in 61.2% of participants at week 24, compared to 19.2% in the placebo group, indicating at least 20% improvement in key disease domains such as pain, function, and inflammation. Additionally, magnetic resonance imaging assessments in a subset of ASSERT participants revealed a major reduction in spinal inflammation, with significant decreases in T1-weighted gadolinium enhancement scores after 24 weeks of treatment, underscoring infliximab's impact on active axial disease. These findings highlight its role in alleviating spinal symptoms and enthesitis, core features of ankylosing spondylitis. Infliximab also provides benefits for peripheral joint involvement, with improvements in swollen and tender joint counts observed in up to 70% of patients with concomitant peripheral arthritis in clinical studies. For extra-articular manifestations, it reduces the incidence and severity of anterior uveitis, a common complication, by suppressing underlying inflammatory pathways, as evidenced by lower flare rates in treated cohorts compared to historical controls. Long-term observational data indicate sustained clinical efficacy, with approximately 50% of patients maintaining treatment for over 5 years and achieving partial remission or low disease activity in nearly 90% of those continuing therapy. Regular monitoring of spinal radiographic progression is recommended, as infliximab has been associated with slower advancement of structural damage, such as syndesmophyte formation, over 2 years compared to untreated progression rates, though complete halt of fusion is not achieved.

Psoriatic arthritis

Infliximab received FDA approval in May 2005 for the treatment of adults with active psoriatic arthritis, including those with inadequate response to disease-modifying antirheumatic drugs (DMARDs). The standard regimen involves an initial dose of 5 mg/kg administered intravenously at weeks 0, 2, and 6, followed by maintenance doses every 8 weeks. This therapy targets tumor necrosis factor-alpha (TNF-α), a key cytokine in psoriatic arthritis pathogenesis, and can be used with or without methotrexate on the background of conventional DMARD failure. Clinical efficacy was established through the Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT) studies. In the phase 3 IMPACT 1 trial, involving 104 patients with active psoriatic arthritis, 65% of those receiving infliximab 5 mg/kg achieved an American College of Rheumatology 20% improvement (ACR20) response at week 16, compared to 10% on placebo; higher responses included 46% ACR50 and 29% ACR70. For skin manifestations, 68% of patients with ≥3% body surface area involvement reached a 75% improvement in the Psoriasis Area and Severity Index (PASI 75). The IMPACT 2 trial, a larger phase 3 study with 200 patients, reported 58% ACR20 at week 14 (versus 11% placebo) and 64% PASI 75, with sustained responses through 54 weeks in 59-61% for ACR20. These trials demonstrated radiographic benefits, with infliximab inhibiting structural damage progression in peripheral joints. Infliximab offers dual therapeutic effects on joint and skin symptoms in psoriatic arthritis, reducing psoriatic plaques via TNF-α neutralization while alleviating entheseal inflammation at tendon and ligament insertions. In IMPACT 1, enthesitis resolved in 72% of infliximab-treated patients at week 14, compared to 24% on placebo. Similarly, dactylitis—a hallmark of sausage-like digit swelling—improved significantly, with resolution in 82% of affected infliximab recipients versus 23% placebo in IMPACT 1. For nail involvement, which affects up to 80% of psoriatic arthritis patients and correlates with disease severity, infliximab yields substantial reductions; a 1-year observational study reported mean nail psoriasis severity index scores dropping from 44.6 to 8.3, with 64% achieving clear or almost clear nails. These outcomes highlight infliximab's role in addressing the multifaceted manifestations of psoriatic arthritis beyond traditional joint-focused metrics.

Plaque psoriasis

Infliximab received FDA approval in September 2006 for the treatment of adult patients with chronic severe (moderate-to-severe) plaque psoriasis.^[18] It is indicated for patients who have failed to respond or have contraindications to other systemic therapies.^[29] The recommended dosing regimen for plaque psoriasis consists of an induction phase with 5 mg/kg administered intravenously at weeks 0, 2, and 6, followed by a maintenance phase of 5 mg/kg every 8 weeks thereafter.^[29] This schedule aims to achieve and sustain skin clearance in eligible patients.^[30] Efficacy data from the phase III EXPRESS trial demonstrated that 80% of patients receiving infliximab 5 mg/kg achieved a Psoriasis Area and Severity Index (PASI) 75 response (at least 75% improvement in PASI score) at week 10, compared to 3% with placebo.^[31] Continuous maintenance therapy preserved responses, with 61% maintaining PASI 75 at week 50.^[31] The treatment exhibits a rapid onset, with significant PASI improvements observed as early as week 2.^[32] Long-term remission of skin lesions has been reported with ongoing infusions, supporting its role in achieving sustained clearance.^[33] Infliximab is particularly utilized in patients with moderate-to-severe plaque psoriasis who are unresponsive to topical therapies or phototherapy.^[34] It has shown substantial improvements in quality of life, as measured by the Dermatology Life Quality Index (DLQI), with mean scores decreasing from baseline levels around 11-12 to near 1 by week 10 in trial participants.^[35] These enhancements reflect reduced disease burden and better patient well-being.^[31]

Other indications

Infliximab has been utilized off-label for the management of hidradenitis suppurativa, particularly in moderate-to-severe cases refractory to conventional therapies, with guidelines recommending its use alongside adalimumab as a TNF inhibitor option.^[36] Clinical studies have demonstrated response rates, such as a 60% improvement in Hurley Stage I/II lesions with infliximab compared to placebo, though it lacks formal FDA or EMA approval for this indication as of 2025.^[37] In Behçet's disease-associated uveitis, infliximab serves as an effective off-label therapy for refractory posterior uveitis, achieving remission or significant improvement in approximately 80-90% of cases in multicenter studies, often allowing steroid tapering.^[38] Similarly, for refractory sarcoidosis, particularly involving cutaneous, neurologic, or pulmonary manifestations, infliximab has shown efficacy in real-world analyses, with response rates up to 70% in extrapulmonary disease when added to corticosteroids.^[39] Off-label application in pyoderma gangrenosum yields superior healing compared to placebo, with a randomized trial reporting 46% complete response at 5 mg/kg dosing over 8 weeks.^[40] Investigational uses include pediatric noninfectious uveitis, where infliximab demonstrates sustained efficacy in adalimumab-refractory cases, achieving quiescence in over 70% of patients with long-term follow-up and a favorable safety profile.^[41] For steroid-refractory acute graft-versus-host disease post-hematopoietic stem cell transplantation, studies indicate modest response rates around 50%, though with heightened infection risks necessitating careful monitoring.^[42] In refractory cases outside FDA-approved settings, infliximab is considered for rare inflammatory conditions based on case series evidence, emphasizing individualized dosing (typically 5-10 mg/kg) and multidisciplinary oversight to balance benefits against immunosuppression risks.^[43]

Contraindications

Absolute contraindications

Infliximab is absolutely contraindicated in patients with active severe infections, such as sepsis or untreated tuberculosis, due to the drug's immunosuppressive effects that can exacerbate or disseminate these conditions, leading to life-threatening outcomes.^[3]^[44] Similarly, the presence of undrained abscesses represents an absolute contraindication, as initiating therapy could worsen localized or systemic infection risks.^[3] A history of severe hypersensitivity reactions to infliximab, its inactive ingredients, or other murine proteins is an absolute contraindication, as re-exposure may provoke anaphylaxis, hypotension, or serum sickness-like reactions.^[44]^[3] Infliximab at doses greater than 5 mg/kg is contraindicated in patients with moderate to severe heart failure (New York Heart Association class III/IV), based on clinical trials demonstrating increased mortality and hospitalization rates in this population.^[44]^[3]

Relative precautions

Infliximab should be used with caution or avoided in patients with active or a history of demyelinating disorders, such as multiple sclerosis, as tumor necrosis factor inhibitors like infliximab may exacerbate neurological symptoms or precipitate new demyelination events.^[3]^[45]^[6] Regarding pregnancy, available data from clinical trials, postmarketing surveillance, and animal studies do not suggest an increased risk of adverse developmental outcomes with infliximab use; however, as an IgG1 monoclonal antibody, it crosses the placenta, with higher transfer in the second and third trimesters, potentially leading to immunosuppression in the newborn. Use during pregnancy when the benefits outweigh the risks, considering maternal disease control. Exposed infants should not receive live vaccines for at least 6 months after birth.^[3]^[6] Prior to initiating infliximab therapy, patients should be evaluated for latent tuberculosis infection using tuberculin skin testing (PPD) or interferon-gamma release assays (IGRA), with treatment for latent infection—typically with isoniazid—initiated prior to or concomitantly with infliximab if positive, to mitigate reactivation risk.^[6] Periodic re-evaluation for tuberculosis is recommended during therapy, particularly in high-risk populations.^[29] In patients with a history of malignancy, infliximab initiation should be delayed until remission has been achieved for at least several months to years, depending on the cancer type, followed by close monitoring for recurrence due to potential immunosuppression-related risks.^[29] Therapy continuation requires careful risk-benefit assessment if malignancy develops during treatment.^[29] For chronic infections such as hepatitis B virus (HBV) carriage, screening is essential before starting infliximab; chronic carriers should receive antiviral prophylaxis (e.g., lamivudine or entecavir) to prevent reactivation, with monitoring of liver function throughout therapy.^[46] Similar precautions apply to other chronic infections, balancing therapeutic benefits against infection exacerbation potential.^[3] Elderly patients over 65 years old warrant heightened caution due to elevated infection rates and overall frailty; dose adjustments or closer surveillance may be needed, as adverse event risks, including serious infections, increase with age.^[3] Comprehensive geriatric assessment can guide individualized therapy decisions.^[47] Regarding surgical procedures, infliximab dosing should be withheld perioperatively—typically 4-8 weeks pre- and post-surgery—to minimize wound healing complications and postoperative infection risks, resuming only after recovery.^[48] Timing should be coordinated with the surgical team based on disease control needs.^[49]

Adverse effects

Infliximab, a monoclonal antibody used in the treatment of various inflammatory conditions, can elicit infusion-related reactions, which are primarily immune-mediated hypersensitivity responses occurring during or shortly after intravenous administration. These reactions are categorized as acute (occurring within 2 hours of infusion) or delayed (manifesting 3 to 12 days post-infusion).^[1] Acute infusion reactions affect approximately 20% of infliximab-treated patients across clinical trials, compared to 10% in placebo groups, with nonspecific symptoms like fever or chills reported in about 3% of all infusions, cardiopulmonary reactions in 1%, and pruritus or urticaria in less than 1%. Common manifestations include hypotension, dyspnea, flushing, rash, headache, and, in severe cases, anaphylaxis. Premedication with antihistamines, acetaminophen, and/or corticosteroids prior to infusion has been shown to reduce the incidence and severity of these acute reactions.^[1]^[50] Delayed infusion reactions occur in 1% to 3% of patients, typically presenting as arthralgia, fever, pruritus, urticaria, or serum sickness-like symptoms such as myalgias and polyarthralgias. These reactions are often self-limited but may require symptomatic treatment with antihistamines, acetaminophen, or corticosteroids in more severe instances.^[50]^[1] Key risk factors for both acute and delayed reactions include the presence of antibodies to infliximab (ATI), which increase the likelihood of acute reactions twofold and serious events sixfold, as well as discontinuous or episodic therapy with prolonged drug-free intervals that promote ATI development. Reactions are more common during initial infusions and in patients receiving infliximab monotherapy without concomitant immunosuppressants.^[50]^[1] Management of acute reactions involves slowing or temporarily halting the infusion for mild to moderate symptoms, with immediate discontinuation and administration of epinephrine, antihistamines, or corticosteroids for severe cases like anaphylaxis; desensitization protocols may be employed for patients requiring continued therapy. For delayed reactions, prompt recognition and supportive care are essential, often resolving without long-term sequelae. The incidence of infusion reactions decreases with scheduled maintenance therapy beyond the initial doses, remaining stable over time.^[50]^[1]

Infections

Infliximab, a tumor necrosis factor-alpha (TNF-α) inhibitor, increases the risk of infections by suppressing the immune response that controls microbial pathogens.^[1] In clinical trials across rheumatoid arthritis, Crohn's disease, and other indications, infections occurred in approximately 36% of infliximab-treated patients compared to 25% of placebo-treated patients, with an average follow-up of 51 weeks. Serious infections, defined as those requiring hospitalization or intravenous antibiotics (such as pneumonia or sepsis), were reported in 5.3% of patients receiving infliximab every 8 weeks with methotrexate, versus 3.4% in the placebo group.^[1]^[1] Common infections include upper respiratory tract infections (e.g., sinusitis and pharyngitis) and urinary tract infections, which are among the most frequently observed adverse events in treated patients. Opportunistic infections are also elevated, particularly reactivation of latent tuberculosis (TB), with clinical trials documenting 14 cases (including 4 fatal) among infliximab users, most occurring within the first 2 months of therapy; the incidence rate has been estimated at 54 per 100,000 patients. In endemic regions such as the Ohio and Mississippi River valleys, invasive fungal infections like histoplasmosis pose a heightened risk, with cases of disseminated disease reported in post-marketing surveillance.^[1]^[1]^[51]^[1] Post-marketing surveillance and clinical trials have identified an increased risk of pneumonia associated with infliximab use compared to placebo (e.g., 1.7% vs. 0.3% in rheumatoid arthritis trials). The risk of serious infections rises further with concomitant immunosuppressants, such as methotrexate or corticosteroids, where rates can reach 5.3% at higher doses (10 mg/kg) versus 1.7% at lower doses (3 mg/kg).^[1]^[1] To mitigate these risks, patients should receive non-live vaccinations (e.g., pneumococcal and influenza) prior to initiating therapy, and prophylaxis against opportunistic infections is recommended for high-risk individuals, such as those in TB-endemic areas following latent TB screening.^[1]^[1]

Malignancy risks

Infliximab, a tumor necrosis factor inhibitor, has been associated with an increased risk of certain malignancies due to its immunosuppressive effects, though the extent to which this is attributable to the drug versus the underlying autoimmune conditions remains debated.^[52] In patients with rheumatoid arthritis (RA), the standardized incidence ratio (SIR) for lymphoma ranges from 3 to 6 compared to the general population, with some studies reporting SIR values of 2.6 to 5.26 specifically for infliximab or other TNF inhibitors.^[53]^[54] This elevated risk may partly stem from the underlying disease activity or concomitant therapies, as RA itself confers a twofold increase in lymphoma incidence.^[55] Non-melanoma skin cancer (NMSC) risk is also heightened, with relative risks of 1.5 to 2-fold in RA patients treated with TNF inhibitors like infliximab, particularly for basal cell and squamous cell carcinomas.^[56] In inflammatory bowel disease (IBD) cohorts, biologics including infliximab show a modest association with NMSC (odds ratio 1.14), though thiopurines contribute more substantially.^[57] Patients are advised to practice sun protection measures, such as using sunscreen and avoiding excessive sun exposure, to mitigate this risk.^[57] In hepatitis B virus (HBV) carriers, infliximab can induce viral reactivation, potentially leading to hepatocellular carcinoma, necessitating pre-treatment screening and antiviral prophylaxis in at-risk individuals.^[58] Long-term data from IBD studies indicate no overall increase in solid tumors with infliximab use, though pediatric patients face heightened concerns, including rare but aggressive hepatosplenic T-cell lymphoma when combined with thiopurines.^[59]^[1] Monitoring includes periodic dermatologic examinations, ideally annually for high-risk patients, and infliximab should be avoided in those with a history of recent malignancy.^[1]^[60]

Other adverse effects

Infliximab therapy has been associated with hepatotoxicity, manifesting primarily as elevations in serum alanine aminotransferase (ALT) levels in approximately 3% to 5% of patients during clinical trials, typically occurring within the first few months of treatment and often resolving without intervention.^[58] These elevations are generally mild and transient but can occasionally exceed three times the upper limit of normal, prompting monitoring recommendations.^[6] More rarely, infliximab can induce autoimmune hepatitis, characterized by significant hepatocellular injury, positive autoantibodies such as antinuclear antibodies, and histological features of interface hepatitis on liver biopsy, with cases reported after prolonged exposure and resolution upon drug discontinuation and corticosteroid use.^[58] Lupus-like syndrome has been reported in association with infliximab treatment, presenting with symptoms such as arthralgia, myalgia, rash, serositis, and positive autoantibodies (antinuclear antibody [ANA] and anti-double-stranded DNA [anti-dsDNA]); it typically resolves upon discontinuation of therapy.^[1] Hematologic adverse effects of infliximab include thrombocytopenia, occurring in 0.1% to 1% of patients, which may present with bruising, bleeding, or petechiae and requires hematologic evaluation.^[6] Aplastic anemia is an even rarer complication, with incidence less than 1%, reported in postmarketing surveillance and linked to bone marrow suppression, sometimes fatal if not addressed promptly through drug withdrawal and supportive care.^[6] In patients with preexisting moderate to severe heart failure (New York Heart Association class III or IV), infliximab can exacerbate symptoms, with clinical trials showing an increased incidence of hospitalization and mortality (approximately 1% to 2% higher risk at higher doses), leading to contraindication of doses exceeding 5 mg/kg in this population.^[6] Neurologic adverse effects encompass reports of demyelinating disorders, such as optic neuritis and multiple sclerosis-like syndromes, which are rare but documented in postmarketing data, often resolving after infliximab cessation, though permanent sequelae may occur.^[6] Progressive multifocal leukoencephalopathy (PML), a severe opportunistic infection involving JC virus reactivation, has also been infrequently associated with infliximab use, particularly in immunocompromised individuals, with an estimated incidence below 0.1% based on case reports.^[6] Paradoxical reactions, including new-onset psoriasis, affect 1% to 2% of infliximab-treated patients, typically emerging after several months of therapy and presenting as psoriasiform lesions that may necessitate switching to alternative biologics for resolution.^[61] A February 2025 FDA label update added warnings for the onset of new immune-related disorders, including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. These events are thought to arise from dysregulation of immune pathways beyond TNF-alpha inhibition, with higher rates observed in inflammatory bowel disease cohorts.

Drug interactions

Immunosuppressants and biologics

Infliximab, a monoclonal antibody targeting tumor necrosis factor-alpha (TNF-α), is frequently used in combination with other immunosuppressive agents to manage autoimmune and inflammatory conditions, but these pairings can influence its immunogenicity, efficacy, and safety profile. Concomitant therapy often reduces the formation of antibodies to infliximab (ATI), thereby enhancing drug persistence and clinical response, particularly in rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). However, such combinations generally heighten the risk of serious infections due to additive immunosuppression, necessitating careful patient monitoring and risk-benefit assessment.^[6]^[62] Methotrexate (MTX) and azathioprine (AZA) are commonly co-administered with infliximab to mitigate ATI development and improve therapeutic outcomes. In RA, infliximab combined with MTX has demonstrated superior efficacy compared to monotherapy, with clinical response rates (e.g., ACR20) ranging from 42% to 66% versus 17% to 21% for placebo plus MTX, attributed to MTX's role in suppressing ATI and elevating infliximab serum concentrations.^[6] Similarly, in IBD, AZA or 6-mercaptopurine alongside infliximab reduces ATI incidence and preserves pharmacokinetics, with no significant difference in effectiveness between MTX and AZA/6-MP for this purpose. Despite these benefits, the combination elevates infection risk, including opportunistic infections, and carries a specific warning for hepatosplenic T-cell lymphoma in young males with IBD.^[6]^[62]^[63] Concurrent use of infliximab with other TNF inhibitors, such as etanercept or adalimumab, is not recommended due to the lack of additional clinical benefit and heightened immunosuppression leading to increased serious infection rates. Guidelines emphasize avoiding such overlaps, as they provide no synergistic efficacy while amplifying risks like bacterial sepsis or fungal infections without improving disease control.^[6]^[64] The combination of infliximab with abatacept or anakinra is contraindicated owing to substantially elevated risks of serious infections. Clinical studies of TNF blockers with abatacept showed higher infection rates without added therapeutic value, prompting recommendations against their use together. Likewise, trials pairing TNF inhibitors like etanercept with anakinra reported increased serious infections and neutropenia, with greater mortality in combination arms compared to TNF monotherapy; this extends to infliximab based on class effects.^[6]^[46]^[65] Corticosteroids, often used alongside infliximab, exhibit dose-dependent synergy in elevating infection susceptibility, as both agents independently impair immune responses. While premedication with intravenous corticosteroids can reduce ATI formation and infusion reaction incidence, chronic co-administration may complicate detection of early infection signs due to symptom suppression.^[6]^[66]^[67] When combining infliximab with immunosuppressants, therapeutic drug monitoring of trough levels and ATI is essential to optimize dosing and detect immunogenicity early. ATI positivity correlates with undetectable trough levels (<0.1 mcg/mL) and loss of response, occurring in up to 10% of RA and Crohn's disease patients on monotherapy but less frequently with concomitant MTX or AZA; proactive monitoring guides adjustments to maintain therapeutic ranges and minimize risks.^[6]^[68]^[69]

Live vaccines and other agents

Patients receiving infliximab should avoid live vaccines, such as measles-mumps-rubella (MMR), varicella, and yellow fever, during active therapy due to the risk of disseminated infection from vaccine-strain viruses in immunocompromised individuals.^[6] Live vaccines are recommended to be administered at least four weeks prior to initiating infliximab to allow for adequate immune response development.^[70] Following discontinuation of infliximab, live vaccination should be deferred for at least three months to minimize infection risk, though longer intervals may be considered based on individual immune recovery.^[71] In contrast, inactivated vaccines, including pneumococcal and inactivated influenza vaccines, are considered safe and are routinely recommended for patients on infliximab to maintain protection against preventable infections.^[72] Vaccination schedules should be updated prior to starting therapy whenever possible, as infliximab may attenuate immune responses to subsequent immunizations.^[73] Regarding other agents, no direct pharmacokinetic interactions have been established between infliximab and warfarin, but monitoring of warfarin's therapeutic effect (e.g., INR levels) is advised due to its narrow therapeutic index and the potential for altered response in immunosuppressed patients.^[6] Similarly, for nonsteroidal anti-inflammatory drugs (NSAIDs), no specific interactions with infliximab are reported, though caution is warranted with concurrent use; immunosuppression may exacerbate NSAID-related risks such as gastrointestinal bleeding, necessitating close monitoring in at-risk patients.^[6] Infliximab may influence theophylline clearance, potentially leading to altered serum levels; therefore, therapeutic drug monitoring of theophylline is recommended when coadministered.^[6] No direct interactions exist between infliximab and alcohol, but moderation is advised given infliximab's association with hepatotoxicity and the additive liver burden from excessive alcohol consumption.^[58]

History

Development

Infliximab, originally designated as the chimeric monoclonal antibody cA2, was discovered and developed by Centocor (now part of Janssen Biotech) in 1991 as a targeted therapy against tumor necrosis factor-alpha (TNF-α), a key cytokine implicated in inflammatory diseases.^[74] The antibody was engineered with murine variable regions fused to human IgG1 constant regions to neutralize human TNF-α with high affinity, binding to specific epitopes such as amino acids 59-80 and 87-108, thereby blocking its pro-inflammatory effects like cytotoxicity and induction of interleukin-6 secretion.^[74] This development built on foundational research by Marc Feldmann and Ravinder N. Maini at the Kennedy Institute of Rheumatology, who in the 1980s identified TNF-α's central role in rheumatoid arthritis (RA) pathogenesis through in vitro studies showing its regulation of other cytokines like IL-1 in synovial tissues.^[75] Their work demonstrated that anti-TNF antibodies could inhibit synovial cell IL-1 production in RA models, paving the way for clinical translation.^[76] Preclinical studies validated cA2's efficacy in animal models of inflammatory conditions, including colitis and arthritis. In murine models of dextran sulfate sodium (DSS)-induced colitis, local or systemic administration of infliximab reduced clinical symptoms, colonic inflammation, and immune cell infiltration, independent of direct TNF-α neutralization in some cases, suggesting additional mechanisms like enhanced apoptosis of inflammatory cells.^[77] Similarly, in human TNF-α transgenic mouse models of arthritis, infliximab protected against joint damage by modulating immunological responses, comparable to other TNF inhibitors, and confirmed its ability to suppress TNF-driven synovitis as shown in earlier dissociated synovial cell assays.^[77] These findings, including reduced cellular influx and adhesion molecule expression in inflamed tissues, supported advancement to human trials.^[78] The pivotal clinical trial demonstrating infliximab's efficacy was a 1997 multicenter, double-blind, placebo-controlled study in 108 patients with moderate-to-severe, refractory Crohn's disease, published by Targan et al.^[11] Patients received a single intravenous infusion of cA2 at doses of 5, 10, or 20 mg/kg or placebo; at week 4, the primary endpoint of clinical response (≥70-point reduction in Crohn's Disease Activity Index) was achieved in 65% of cA2-treated patients overall (81% at 5 mg/kg, 50% at 10 mg/kg, 64% at 20 mg/kg) compared to 17% with placebo (P<0.001), with remission rates of 33% versus 4% (P=0.005).^[11] This trial, conducted in collaboration with investigators like Sander van Deventer, provided proof-of-concept for TNF blockade in Crohn's disease and led to accelerated FDA approval in 1998.^[79] Feldmann and Maini's parallel RA trials in 1992, using cA2 supplied by Centocor, further corroborated the approach, showing rapid symptom relief in patients unresponsive to conventional therapies.^[75]

Regulatory approvals

Infliximab, marketed as Remicade, received its initial approval from the U.S. Food and Drug Administration (FDA) on August 24, 1998, for the treatment of moderately to severely active Crohn's disease in adults who had not responded to conventional therapies.^[80] The European Medicines Agency (EMA) followed with approval on August 13, 1999, for the same indication in adult patients with severe, active Crohn's disease unresponsive to treatment with a corticosteroid or an immunosuppressant, and for fistulizing, active Crohn's disease.^[81] Subsequent expansions broadened infliximab's indications. The FDA approved its use in combination with methotrexate for reducing signs and symptoms in moderate to severe rheumatoid arthritis on November 10, 1999.^[80] In 2002, the FDA extended approval to active ankylosing spondylitis for reducing signs and symptoms in adults.^[3] Further approvals came in 2005 for psoriatic arthritis in adults, either alone or with methotrexate, to reduce signs and symptoms, inhibit structural damage, and improve physical function.^[3] In 2006, the FDA approved infliximab for moderately to severely active ulcerative colitis in adults and chronic severe plaque psoriasis in adults who are candidates for systemic therapy.^[3] The EMA aligned with many of these expansions, approving rheumatoid arthritis in 2000, ankylosing spondylitis and psoriatic arthritis in 2002, ulcerative colitis in 2005, and plaque psoriasis in 2007.^[79] Pediatric indications were added in 2011 by the FDA for reducing signs and symptoms and inducing and maintaining clinical remission in patients aged 6 years and older with moderately to severely active Crohn's disease or ulcerative colitis who had inadequate response to conventional therapy.^[6] Biosimilars have expanded access to infliximab. The FDA approved the first, Inflectra (infliximab-dyyb), on April 5, 2016, for all indications of the reference product, including Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis.^[82] Renflexis (infliximab-abda) followed on April 21, 2017, with the same indications.^[83] Additional approvals include Avsola (infliximab-axxq) in 2019 and Zymfentra (infliximab-dyyb), the first subcutaneous formulation, in October 2023 for maintenance treatment of Crohn's disease and ulcerative colitis.^[84] The EMA approved its first infliximab biosimilar, Inflectra, in 2013 for similar indications.^[85] By 2025, multiple biosimilars were available, enhancing treatment options across regions.^[86] In 2025, the FDA revised the labeling for Remicade and its biosimilars to include warnings on the risk of new-onset autoimmune diseases based on postmarketing reports.^[87] These updates emphasize ongoing monitoring for patients on infliximab therapy.^[1]

Society and culture

Brand names and marketing

Infliximab is primarily marketed under the brand name Remicade by Janssen Biotech, Inc., a subsidiary of Johnson & Johnson, following its initial U.S. Food and Drug Administration approval on August 24, 1998, for the treatment of Crohn's disease.^[79] Remicade was positioned as the first-in-class tumor necrosis factor (TNF) inhibitor, establishing a new standard for biologic therapy in autoimmune conditions including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, and inflammatory bowel disease (IBD).^[79] Janssen's marketing emphasized its pioneering role in targeting TNF-alpha to reduce inflammation, supported by extensive clinical data demonstrating long-term remission and symptom control in patients unresponsive to conventional treatments.^[79] In the United States, where direct-to-consumer advertising (DTCA) is permitted, Janssen utilized targeted campaigns to increase IBD awareness and educate patients on biologic options like Remicade, including television and print ads highlighting real-patient stories of improved quality of life.^[88] These efforts contributed to Remicade's strong market penetration, with DTCA spending on the drug reaching approximately $191,000 in 2017 before tapering amid biosimilar emergence.^[88] Prior to biosimilar competition, Remicade achieved peak global annual sales of $8.355 billion in 2015, reflecting its dominance in the immunology sector through co-marketing agreements, such as with Merck outside the U.S.^[89] Janssen extended Remicade's market exclusivity in the European Union through pediatric studies, securing a six-month pediatric extension that delayed biosimilar launches until February 2015 following the core patent expiry.^[90] This was part of broader patent battles, including U.S. litigation in 2016 where a federal court invalidated a key formulation patent, paving the way for biosimilar entry despite Janssen's ongoing defenses of intellectual property rights.^[91] In the current landscape of biosimilar competition, Janssen maintains focus on the originator Remicade, promoting its proven track record in over 170 sponsored clinical trials and emphasizing physician preference for the reference product in infusion settings.^[92]

Biosimilars

The first infliximab biosimilar approved was Inflectra (infliximab-dyyb, developed by Celltrion and marketed by Hospira/Pfizer), which received European Medicines Agency (EMA) authorization on September 10, 2013, and U.S. Food and Drug Administration (FDA) approval on April 5, 2016.^[85]^[93] This approval was based on analytical, nonclinical, and clinical data demonstrating similarity to the reference product Remicade (infliximab) in terms of quality, safety, and efficacy across indications such as rheumatoid arthritis, Crohn's disease, and ulcerative colitis. Subsequent approvals followed, expanding options for clinicians and patients. Renflexis (infliximab-abda, Samsung Bioepis/Merck), approved by the EMA as Flixabi on May 26, 2016, and by the FDA on April 21, 2017, showed comparable pharmacokinetics and immunogenicity in phase 3 trials.^[94]^[95] Avsola (infliximab-axxq, Amgen) gained FDA approval on December 6, 2019, supported by a randomized trial in rheumatoid arthritis patients demonstrating equivalent clinical response rates.^[96] Ixifi (infliximab-qbtx, Pfizer), approved by the FDA on December 13, 2017, was based on totality-of-evidence data but has not been commercialized in the U.S. market.^[97] As of November 2025, no additional intravenous infliximab biosimilars have been approved by the FDA or EMA beyond these, though subcutaneous formulations like Zymfentra (infliximab-dyyb) were approved in 2023 for maintenance therapy.^[2]

Biosimilar	Developer/Marketer	EMA Approval	FDA Approval	Key Evidence
Inflectra (infliximab-dyyb)	Celltrion/Pfizer	September 10, 2013	April 5, 2016	Phase 3 trial in ankylosing spondylitis (n=250); equivalence in ASAS20 response (73.6% vs. 69.0%).
Flixabi/Renflexis (infliximab-abda)	Samsung Bioepis/Merck	May 26, 2016	April 21, 2017	Phase 3 trial in rheumatoid arthritis (n=302); similar ACR20 response (77.0% vs. 75.6%).
Avsola (infliximab-axxq)	Amgen	N/A (FDA only)	December 6, 2019	Phase 3 trial in rheumatoid arthritis (n=558); equivalence in ACR20 (84.7% vs. 84.6%).^[96]
Ixifi (infliximab-qbtx)	Pfizer	N/A (FDA only)	December 13, 2017	Analytical similarity; no dedicated switching study required.

None of these infliximab biosimilars have received FDA interchangeability designation as of 2025, which would allow pharmacy-level substitution without prescriber intervention; approvals remain as biosimilars demonstrating no clinically meaningful differences from Remicade.^[2] Clinical studies, including the NOR-SWITCH trial (n=482), have confirmed similar efficacy and safety profiles upon switching from originator infliximab to biosimilars like CT-P13 (Inflectra), with disease worsening rates of 26% in both switch and continuation arms across indications.^[98] Real-world data indicate that 70-80% of patients maintain clinical remission or response after switching, with no significant increases in immunogenicity or adverse events.^[99] By mid-2025, infliximab biosimilars have captured approximately 50% of the U.S. market share by volume, up from 3% shortly after initial launches, driven by payer preferences and competitive pricing.^[100] This uptake has contributed to overall cost reductions of 30-50% compared to the originator, yielding estimated U.S. healthcare savings of $260-842 million through 2023, with continued growth expected.^[101]

Availability and affordability

In the United States, the list price for a 100 mg vial of the originator infliximab product Remicade was approximately $1,229 as of April 2025, though actual costs to patients or payers can vary based on discounts, rebates, and pharmacy contracts.^[102] Annual therapy costs for infliximab typically range from $20,000 to over $50,000 per patient, depending on the indication, dosing regimen (e.g., higher for inflammatory bowel disease like Crohn's or ulcerative colitis compared to rheumatoid arthritis), and frequency of infusions, with some estimates reaching $50,000 to $150,000 for intensive IBD treatment without assistance.^[103]^[104] The introduction of biosimilars has significantly improved affordability in the US, with prices for 100 mg vials of products like Inflectra dropping to around $997 by April 2025, representing a reduction of about 19% compared to Remicade and leading to overall market savings estimated at $260 million to $842 million through increased utilization.^[102]^[105] Access remains challenged by variable insurance coverage, where commercial plans often cover infliximab but with high deductibles or prior authorization requirements, while Medicare Part B reimburses infusions at 80% after deductible; patient assistance programs such as Janssen CarePath and the J&J withMe Savings Program help eligible commercially insured patients pay as little as $5 per infusion, up to $20,000 annually, and provide free medication for uninsured or low-income individuals meeting income criteria.^[106]^[107] Globally, infliximab is available in over 100 countries, including widespread approvals in Europe, Asia, and the Americas, but pricing disparities exacerbate economic barriers. In markets like India and China, where biosimilars and generics are produced, costs are substantially lower—often 20-30% of US prices—with annual therapy in India estimated at $4,800 to $6,000 for IBD, compared to tens of thousands in high-income settings.^[108] Equity concerns are pronounced in low- and middle-income regions, where high out-of-pocket expenses limit access despite infliximab's inclusion on the World Health Organization's Model List of Essential Medicines (23rd edition, 2023), particularly for inflammatory bowel disease indications, highlighting the need for expanded biosimilar uptake to reduce the treatment burden.^[109]^[110]