Infliximab …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 04.18.2021
Released 05.26.2009
Expires For CME 04.18.2024

Infliximab

Author: K K Jain MD†

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Infliximab

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Introduction

Historical note and terminology

Infliximab is a monoclonal antibody for the treatment of autoimmune diseases. Originally a mouse antibody, it was later developed into a human (humanized) antibody. Because it is a combination of mouse and human antibody, it is called a chimeric monoclonal antibody. The chimeric antibody was designed to reduce immunogenicity and improve pharmacokinetics in humans (19). Infliximab has been approved by the United States Food and Drug Administration for the treatment of psoriasis, Crohn disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, sarcoidosis, and ulcerative colitis.

Pharmacology

Infliximab, administered by intravenous injection, binds specifically to human tumor necrosis factor alpha and neutralizes its biological activity. Tumor necrosis factor alpha is a proinflammatory cytokine produced by many cell types (blood monocytes, macrophages, mast cells, and endothelial cells) that play a key role in the pathogenesis of multiple autoimmune disorders.

Pharmacodynamics. Elevated concentrations of tumor necrosis factor alpha have been found in involved tissues and body fluids of patients with autoimmune diseases. Treatment with infliximab reduces infiltration of inflammatory cells into inflamed areas. Most of the clinical pharmacology has been studied in Crohn disease, rheumatoid arthritis, and spondyloarthritis as it is widely used as a treatment for these diseases. However, several forms of vasculitis appear responsive to tumor necrosis factor antagonists, which include Behçet disease, Churg-Strauss vasculitis, polyarteritis nodosa, and giant cell arteritis among others. Wegener granulomatosis and sarcoidosis have been shown to improve with infliximab.

Biological activities attributed to tumor necrosis factor alpha include: induction of proinflammatory cytokines, such as interleukins 1 and 6; enhancement of leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes; activation of neutrophil and eosinophil functional activity; and induction of acute phase reactants and other liver proteins. The relationship of these biological response markers to the mechanisms by which infliximab exerts its clinical effects is unknown.

Antidepressant response to infliximab in patients with increased baseline inflammation, as reflected by a plasma C-reactive protein concentration, involves inhibition of genes related to innate immune activation with alterations in glucose and lipid metabolism (22).

Pharmacokinetics. In adults, single intravenous infusions of infliximab 3 mg/kg to 20 mg/kg show a linear relationship between the dose administered and the maximum serum concentration. The volume of distribution at steady state is independent of dose and indicates that infliximab is distributed primarily within the vascular compartment. The median terminal half-life of infliximab is 7.7 to 9.5 days.

Following an initial dose of infliximab, repeated infusions at 2 and 6 weeks result in predictable concentration-time profiles following each treatment. No systemic accumulation of infliximab occurs on continued repeated treatment with 3 mg/kg or 10 mg/kg at 4- or 8-week intervals. Development of antibodies to infliximab increases infliximab clearance. At 8 weeks after a maintenance dose of 3 to 10 mg/kg of infliximab, median infliximab serum concentrations range from approximately 0.5 to 6 mcg/mL.

Clinical trials

Clinical trials have been conducted for all the approved conditions, which are mainly systemic disorders but may have neurologic complications. Only a few clinical trials of neurologic disorders treated with infliximab have been published.

A randomized controlled trial evaluated the long-term efficacy of infliximab in patients with acute or subacute sciatica secondary to herniated disc (20). One-year follow-up showed that 67% of patients in the infliximab group reported no pain compared with 63% in the control group. Although the long-term results of this randomized trial do not support the use of infliximab compared with placebo for lumbar radicular pain in patients with disc herniation-induced sciatica, further study appears to be warranted in a subgroup of patients with L4-L5 or L3-L4 herniations.

In a multicenter, open-label, investigator-driven study, the European Ankylosing Spondylitis Infliximab Cohort (EASIC), most patients were successfully treated with infliximab for 5 years whereas discontinuation and reintroduction of therapy was less satisfactory due to the frequent occurrence of hypersensitivity reactions (14). A multicenter, prospective, open-label, single-arm phase 3 study of infliximab therapy for intestinal, neurologic, and vascular involvement in Behcet disease reported improvement of clinical symptoms in all the systems involved (16). Safety and pharmacokinetics of infliximab in Behcet disease was comparable with that in patients with rheumatoid arthritis or Crohn disease. A retrospective multicenter study of patients diagnosed as suffering from CNS sarcoidosis, including some previously refractory to other immunosuppressive treatments, showed favorable responses to treatment with infliximab as assessed by imaging as well as clinical examination (12). In a retrospective study, the infliximab biosimilar was as effective and safe for treating neurosarcoidosis as the original preparation (26).

Indications

Indications are listed below according to the disease.

Rheumatoid arthritis. Infliximab, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis. The results of a prospective nonrandomized study showed that the use of accelerated infliximab infusion in rheumatic patients is safe, with high satisfaction among patients and health care providers (09).

Crohn disease. Infliximab is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult and pediatric patients with moderately to severely active Crohn disease who have had an inadequate response to conventional therapy.

Ankylosing spondylitis. Infliximab is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.

Psoriatic arthritis. Infliximab is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis.

Plaque psoriasis. Infliximab is indicated for the treatment of adult patients with chronic severe plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. Infliximab should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.

Ulcerative colitis. Infliximab is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use.

Off-label uses

(1) Infliximab is used for the treatment of Behçet disease based on the rationale that it blocks TNF-alpha involved in the pathogenesis of the disease. A case of life-threatening vasculo-Behçet disease was reported with remission for 3 years with use of infliximab and recurrence after withdrawal, but with response on reintroduction of the drug (21). Neuro-Behçet disease has been treated with infliximab, and it effectively prevents further relapses and stabilizes the symptoms of patients who are being treated with single or multiple immunosuppressant drugs (32).

(2) Sciatica due to intervertebral disc herniation.

(3) Cogan syndrome.

(4) Treatment of central nervous system involvement associated with primary Sjögren syndrome. Clinical trials have not shown efficacy of infliximab in Sjögren syndrome (25).

(5) For sarcoidosis of the nervous system that is refractory to treatment using steroids combined with various immunosuppressive drugs (27). A retrospective long-term study on patients with severe and resistant sarcoidosis involving the central nervous system showed remission in 11 out of 12 cases following treatment with infliximab (06). Infectious complications were frequent and occurred mainly in male patients with longer duration of steroids and immunosuppressant use prior to infliximab. Paradoxically, several case reports in the literature describe the development of sarcoidosis as an adverse effect of treatment with infliximab (08).

(6) A randomized, controlled trial has shown that infliximab does not have generalized efficacy in treatment-resistant depression but may improve depressive symptoms in patients with high baseline inflammatory biomarkers (24).

(7) Infliximab combined with methylprednisolone has been shown to be effective for recovery following acute spinal cord injury in experimental animals (07).

(8) Autoimmune sensorineural hearing loss associated with rheumatoid arthritis (11).

(9) In an open study, injection of infliximab into sacroiliac joints of patients with non-radiographic axial spondyloarthritis who had failed to respond to non-steroidal anti-inflammatory drugs resulted in significant decrease in back pain as well as stiffness, lowering of C-reactive protein levels, and improvement of MRI parameters of disease activity (31).

(10) Treatment of aseptic neutrophilic myositis, an inflammatory skin condition with rare infiltration into the muscle (13).

(11) A systematic review of controlled trials showed that infliximab is ineffective in reducing depressive symptoms according to the Hamilton Scale for Depression if the patients already have increased inflammatory genes, including tumor necrosis factor and C-reactive protein (03).

(12) Recent large retrospective studies from the United States and France established that infliximab appears to be efficacious for neurologic manifestations of sarcoidosis when other treatments are inadequate (23).

Adverse effects

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tumor necrosis factor alpha-blocking agents. The most commonly reported opportunistic infections were tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis. Patients have frequently presented with disseminated rather than localized disease and are often taking concomitant immunosuppressants such as methotrexate or corticosteroids with infliximab. Treatment with infliximab should not be initiated in patients with an active infection, including clinically important localized infections. The risks and benefits of treatment should be considered prior to initiating therapy in patients:

	• with chronic or recurrent infection.
	• who have been exposed to tuberculosis.
	• who have resided or traveled in areas of endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis.
	• with underlying conditions that may predispose them to infection.

Neurologic complications. Infliximab and other agents that inhibit tumor necrosis factor alpha have been associated with various neurologic complications, which include seizures and new onset or exacerbation of clinical symptoms or radiographic evidence of central nervous system demyelinating disorders (including multiple sclerosis and CNS manifestations of systemic vasculitis) and peripheral demyelinating disorders (including Guillain-Barré syndrome). In a case report, infliximab treatment was associated with CNS inflammatory demyelinating activity that was histopathologically indistinguishable from multiple sclerosis (17). Aseptic meningitis is an uncommon side effect of infliximab with 5 case reports in the literature (29).

One case report and review of literature shows 15 patients in whom the symptoms of optic neuritis developed following tumor necrosis factor alpha antagonist therapy: 9 patients experienced complete resolution and 2 patients had partial resolution whereas 4 patients continued to have symptoms (30). The possibility of anterior optic neuropathy, in addition to retrobulbar optic neuritis, should be considered in patients who experience sudden-onset visual loss while being treated with infliximab (05). Patients being treated with a tumor necrosis factor alpha antagonist should be closely monitored for the development of ophthalmologic or neurologic signs and symptoms; if optic neuritis is diagnosed, medication should be discontinued, and steroid treatment should be started.

A patient with severe rheumatoid arthritis who was successfully treated with infliximab suffered diverse neurologic complications: brachial plexitis, asymptomatic thoracic myelitis with extensive lesions in MRI study, and herpes zoster lumbar plexitis (01). In rare cases, multifocal motor neuropathy with conduction block has been reported as an adverse effect of infliximab (04). In a patient with ankylosing spondylitis treated with infliximab, multifocal demyelinating axonal neuropathy has been reported as an adverse effect, which resolved after treatment with intravenous immunoglobulin (02). A patient with Crohn disease developed parkinsonism after starting treatment with infliximab and gradual but continual improvement of the resting tremor occurred after withdrawal of infliximab (15).

A review of adverse effects of infliximab indicates that demyelinating disorders might persist despite discontinuation of treatment, suggesting that the drug could trigger the demyelinating process, which further evolves independently (28). Prescribers should exercise caution in considering the use of infliximab in patients with preexisting or recent onset of demyelinating or seizure disorders. Discontinuation of infliximab should be considered in patients who develop significant central nervous system adverse reactions.

References

01: Arias M, Arias-Rivas S, Dapena D, Mera A. Brachial plexitis and myelitis and herpes-zoster lumbar plexus disorder in patient treated with infliximab. Neurologia 2005;20(7):374-6. PMID 16163582
02: Bandelow N, Wiederkehr M, Hasler P. Mononeuritis multiplex under the TNF-alpha inhibitor infliximab. Praxis 2011;100(4):241-3. PMID 21328239
03: Bavaresco DV, Uggioni MLR, Ferraz SD, et al. Efficacy of infliximab in treatment-resistant depression: a systematic review and meta-analysis. Pharmacol Biochem Behav 2020;188:172838. PMID 31837338
04: Bayrak AO, Ulusoy H, Bolat N, Doğan B, Ozbenli T. Multifocal motor neuropathy associated with infliximab: a case report and a literature review. Neurologist 2017;22(4):144-6. PMID 28644258
05: Chan JW, Castellanos A. Infliximab and anterior optic neuropathy: case report and review of the literature. Graefes Arch Clin Exp Ophthalmol 2010;248(2):283-7. PMID 19916016
06: Chapelon-Abric C, Saadoun D, Biard L, et al. Long-term outcome of infliximab in severe chronic and refractory systemic sarcoidosis: a report of 16 cases. Clin Exp Rheumatol 2015;33(4):509-15. PMID 26120779
07: Chengke L, Weiwei L, Xiyang W, et al. Effect of infliximab combined with methylprednisolone on expressions of NF-κB, TRADD, and FADD in rat acute spinal cord injury. Spine (Phila Pa 1976) 2013;38(14):E861-9. PMID 23574812
08: Clementine RR, Lyman J, Zakem J, et al. Tumor necrosis factor-alpha antagonist-induced sarcoidosis. J Clin Rheumatol 2010;16(6):274-9. PMID 20808167
09: de Carvalho JF, Dos Santos MNP, de Oliveira JMV, Lanty Silva ANS, de Araujo RPC, Cardozo JB. Evaluation of the safety and satisfaction of rheumatic patients with accelerated infliximab infusion. Adv Rheumatol 2018;58(1):22. PMID 30657070
10: Djokanovic N, Klieger-Grossmann C, Pupco A, Koren G. Safety of infliximab use during pregnancy. Reprod Toxicol 2011;32(1):93-7. PMID 21621603
11: Gazeau P, Saraux A, Devauchelle-Pensec V, Cornec D. Long-term efficacy of infliximab in autoimmune sensorineural hearing loss associated with rheumatoid arthritis. Rheumatology (Oxford) 2014;53(9):1715-6. PMID 24625506
12: Gelfand JM, Bradshaw MJ, Stern BJ, et al. Infliximab for the treatment of CNS sarcoidosis: a multi-institutional series. Neurology 2017;89(20):2092-100. PMID 29030454
13: Guillaume-Jugnot P, Guégan S, Léonard-Louis S, Barete S, Benveniste O, Allenbach Y. Infliximab as effective treatment for aseptic neutrophilic myositis. Neurology 2019;93(23):1009-11. PMID 31662493
14: Heldmann F, Brandt J, van der Horst-Bruinsma IE, et al. The European ankylosing spondylitis infliximab cohort (EASIC): a European multicentre study of long term outcomes in patients with ankylosing spondylitis treated with infliximab. Clin Exp Rheumatol 2011;29(4):672-80. PMID 21906431
15: Henriksen JN, Eriksson BO. Parkinsonism as a side effect of infliximab. BMJ Case Rep 2016;2016. PMID 27151053
16: Hibi T, Hirohata S, Kikuchi H, et al. Infliximab therapy for intestinal, neurological, and vascular involvement in Behcet disease: efficacy, safety, and pharmacokinetics in a multicenter, prospective, open-label, single-arm phase 3 study. Medicine (Baltimore) 2016;95(24):e3863.** PMID 27310969
17: Kalinowska-Lyszczarz A, Fereidan-Esfahani M, Guo Y, Lucchinetti CF, Tobin WO. Pathological findings in central nervous system demyelination associated with infliximab. Mult Scler 2020;26(9):1124-9.** PMID 31845616
18: Kane S, Ford J, Cohen R, Wagner C. Absence of infliximab in infants and breast milk from nursing mothers receiving therapy for Crohn's disease before and after delivery. J Clin Gastroenterol 2009;43(7):613-6. PMID 19142167
19: Knight DM, Trinh H, Le J, et al. Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol Immunol 1993;30(16):1443-53. PMID 8232330
20: Korhonen T, Karppinen J, Paimela L, et al. The treatment of disc-herniation-induced sciatica with infliximab: one-year follow-up results of FIRST II, a randomized controlled trial. Spine 2006;31:2759-66. PMID 17108825
21: Magro-Checa C, Salvatierra J, Rosales-Alexander JL, Orgaz-Molina J, Raya-Álvarez E. Life-threatening vasculo-Behçet following discontinuation of infliximab after three years of complete remission. Clin Exp Rheumatol 2013;31(3 Suppl 77):96-8. PMID 23739315
22: Mehta D, Raison CL, Woolwine BJ, et al. Transcriptional signatures related to glucose and lipid metabolism predict treatment response to the tumor necrosis factor antagonist infliximab in patients with treatment-resistant depression. Brain Behav Immun 2013;31:205-15. PMID 23624296
23: Pawate S. Sarcoidosis and the nervous system. Continuum (Minneap Minn) 2020;26(3):695-715. PMID 32487903
24: Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 2013;70(1):31-41. PMID 22945416
25: Ramos-Casals M, Tzioufas AG, Stone JH, Sisó A, Bosch X. Treatment of primary Sjögren syndrome: a systematic review. JAMA 2010;304(4):452-60. PMID 20664046
26: Riller Q, Cotteret C, Junot H, et al. Infliximab biosimilar for treating neurosarcoidosis: tolerance and efficacy in a retrospective study including switch from the originator and initiation of treatment. J Neurol 2019;266(5):1073-8. PMID 30739183
27: Santos E, Shaunak S, Renowden S, Scolding NJ. Treatment of refractory neurosarcoidosis with Infliximab. J Neurol Neurosurg Psychiatry 2010;81(3):241-6. PMID 18977810
28: Seror R, Richez C, Sordet C, et al. Pattern of demyelination occurring during anti-TNF-α therapy: a French national survey. Rheumatology (Oxford) 2013;52(5):868-74. PMID 23287362
29: Shah R, Shah M, Bansal N, Manocha D. Infliximab-induced aseptic meningitis. Am J Emerg Med 2014;32(12):1560.e3-4. PMID 24993681
30: Simsek I, Erdem H, Pay S, Sobaci G, Dinc A. Optic neuritis occurring with anti-tumour necrosis factor alpha therapy. Ann Rheum Dis 2007;66(9):1255-8. PMID 17456525
31: Soliman E, El-Tantawi G, Matrawy K, Aldawoudy A, Naguib A. Local infliximab injection of sacroiliac joints in non-radiographic axial spondyloarthritis: Impact on clinical and magnetic resonance imaging parameters of disease activity. Mod Rheumatol 2015;25(3):421-6. PMID 25401227
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Infliximab

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Affective disorders in neurologic disease
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Churg-Strauss syndrome
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Infliximab

Infliximab …

Infliximab

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

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Questions or Comment?

Also in This Category

Anti-IgLON5 disease

Anti-LGI1 encephalitis

Progressive encephalomyelitis with rigidity and myoclonus and glycine receptor antibodies

Drug-induced myasthenic syndromes

Giant cell arteritis

Acupuncture

Chronic inflammatory demyelinating polyradiculoneuropathy

Autoimmune autonomic neuropathy

Infliximab

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Anti-IgLON5 disease

Anti-LGI1 encephalitis

Progressive encephalomyelitis with rigidity and myoclonus and glycine receptor antibodies

Drug-induced myasthenic syndromes

Giant cell arteritis

Acupuncture

Chronic inflammatory demyelinating polyradiculoneuropathy

Autoimmune autonomic neuropathy

This is an article preview.
Start a Free Account
to access the full version.