Infliximab (IFX) is a biologic agent that specifically targets an immune mediator, tumor necrosis factor alpha (TNFa), involved in a pathological process. Anti TNFa agents have enjoyed use as therapeutic modalities since 1998; however, their first use in dermatology dates back to 2002 when they first saw use in the treatment of psoriasis. The first anti-TNF therapy was discovered by Knight et al. in the form of a chimeric monoclonal antibody, now known as infliximab, comprising a 25-30% murine fusion or antigen-binding variable segment and a 70-75% human IgG antibody constant segment.. The first trial of IFX was carried out in 1994 on patients with rheumatoid arthritis in whom IFX resulted in marked clinical improvement compared with placebo.
Crohn disease – Moderately to severely active Crohn disease is an indication for induction and maintenance of clinical remission
An inadequate response to conventional therapy holds as an indication for starting infliximab in such cases.
Pediatric cases aged six years or older with moderate-to-severe disease that fails to respond to conventional therapy are indications for infliximab.
Ulcerative colitis – Infliximab is prescribed for inducing and maintaining clinical remission and for eliminating corticosteroid therapy in those showing inadequate response.
Pediatric cases 6 years and older are suitable for this mode of treatment.
Rheumatoid arthritis - Patients undergoing infliximab therapy for moderate-to-severe disease have reported inhibition of progressing joint damage and improved physical strength.
Psoriasis – The following types of psoriasis benefit from infliximab therapy:
Infliximab, being a TNFa inhibitor, acts by blocking TNFa, which is a proinflammatory pleiotropic cytokine particularly involved in defense mechanisms. Nevertheless, the role of TNFa differs respectively to its concentration as low levels confer a protective effect while high amounts display a pathogenic role. TNFa exists in two forms; soluble and transmembrane, that is both biologically active via TNF receptors (TNFR) Type 1 and Type 2.
The protective role in infection is the most important effect of TNFa. Interestingly, TNFa is involved in attaining resistance to infectious agents, as well as having a pathogenic role in septic shock. TNFa produces anti-inflammatory effects by signaling via TNFR Type 2. The explanation has been that TNFa promotes resistance by activation of polymorphonuclear leucocytes and platelets, while enhancing the cytotoxic action of macrophages and natural killer cells, and thereby stimulation of the immune system. In particular, studying the concept on patients with meningococcal disease showed high levels of TNFa in the serum that coincided with its cytotoxic effect.
Another role of TNFa is resistance to tumors and occurs due to the cytotoxic effect of TNFa leading to cell lysis or apoptosis. Fiers studied the effect of TNFa on tumors in animal models and found that TNFa acts directly on the tumor cells, particularly in the presence of interferon. Additionally, TNFa has been determined to exert proinflammatory effects on the vascular endothelium that results in hemorrhagic necrosis.
In particular, the biological effects are beneficial in a variety of host responses. However, TNFa has been found to exert pathogenic roles in certain instances.
The role of TNFa in inflammatory diseases was identified in 1988 with the finding of increased TNFa expression in synovial fluid of patients with rheumatoid arthritis making it the prototypic disease of TNFa. This finding obtained confirmation with the discovery of increased TNFR expression in active diseases. Furthermore, the quantities of shed receptors correlate with the disease activity. The evidence suggests that TNFa acts as a regulator of proinflammatory cytokines and therefore, has a central role in inflammatory processes.
Another disease linked with TNFa is psoriasis. Studies have shown increased expression of TNFa in psoriatic skin lesions. The study confirmed this by investigating the peripheral blood mononuclear cells for the presence of TNFa mRNA expression and revealed increased expression in psoriatic patients when compared to healthy controls.
Infliximab acts by binding to both soluble and membrane-bound forms of TNF, the binding with TNFa is found to be stable with high affinity, thereby neutralizing its action; In addition, it causes apoptosis of cells that release TNFa, alters the cytokine secretion and up regulates p38 MAP kinase which takes part in the downward signaling of TNFa. Binding triggers intracellular signaling, complement-mediated cell lysis and decrease of cytokine production.
The effect of intracellular signaling launches a variety of responses including reduction of cytokines, an increase in vascular permeability, a decrease in adhesion molecule expression, and inactivation of cell lines. Another response is the delayed recruitment of immune cells to sites of inflammation, however, this excludes the regulatory T-cells that play a beneficial role in immune responses and leads to its increased expression.
Prior to infliximab infusion, pretreatment with loratadine or cetirizine (0.5 mg/kg; max 25 mg), hydrocortisone (4 mg/kg; max 200 mg) and paracetamol (15 mg/kg; max 1 gm) 30 – 60 minutes before infusion is necessary for combating infusion reactions that may occur.
Infliximab is prepared as an intravenous infusion the dosage of which can vary from 3 to 10 mg/kg, most commonly being 5 mg/kg. Infliximab has a half-life of 7-12 days as it has a low rate of elimination. Therefore, dosing schedule repeats at weeks 2, 6 and every eight weeks thereafter.
The pharmaceutical product contains 100 mg lyophilized drug powder in 20 ml vial. Each vial is reconstituted with 10 ml sterile distilled water using a 21-gauge needle following which gentle stirring is performed to dissolve the powder. The vial is kept aside for 5 mins, and the solution dissolved in 250 ml of 0.9% sodium chloride intravenous solution.
Infusion of this agent should begin within 3 hours of dilution and over a period or 2-3 hours during which period the recording of vitals including temperature, pulse, blood pressure, and respiratory rate is required until 1-hour post infusion.
FDA-approved indications with dosages:
The absolute contraindications for the use of biologics are:
Other contraindications include:
Overuse of infliximab results in long-term inhibition of TNFa and thereby enhances the risk of infections, which furthermore poses deleterious effects for pregnancy and lactation by impairing newborn’s defense mechanisms.
Since TNFa is involved in embryogenesis and organogenesis, a deleterious effect on embryo and fetal development is postulated.
Another toxic effect of infliximab is the carcinogenic potential resulting from reports of malignancies in children, adolescents, and young adults receiving infliximab over a median value of 30 sessions. This hypothesis comes from the finding that TNFa causes tumoral hemorrhagic necrosis and therefore used as a treatment for selective tumors.
The primary drawback with biologic therapy is the necessity for life-long or long-term treatment, the failure of which can lead to incomplete resolution or recurrences. Combination with other agents such as methotrexate can enhance the efficacy and response.
Live vaccines and contact with infectious agents should be avoided during infliximab therapy due to the markedly depressed immunity that can result in disseminated infections. History of latent or active tuberculosis with no confirmation of complete therapy or recent travel to a country with a high incidence of tuberculosis may warrant a course of empiric anti-tubercular therapy. Avoidance of concomitant therapy with anakinra and abatacept is important due to the increased risk of severe infections.
|||Cordoro KM,Feldman SR, TNF-alpha inhibitors in dermatology. Skin therapy letter. 2007 Sep [PubMed PMID: 17940711]|
|||Knight DM,Trinh H,Le J,Siegel S,Shealy D,McDonough M,Scallon B,Moore MA,Vilcek J,Daddona P, Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Molecular immunology. 1993 Nov [PubMed PMID: 8232330]|
|||Maini RN,Breedveld FC,Kalden JR,Smolen JS,Davis D,Macfarlane JD,Antoni C,Leeb B,Elliott MJ,Woody JN,Schaible TF,Feldmann M, Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis and rheumatism. 1998 Sep [PubMed PMID: 9751087]|
|||Steeland S,Libert C,Vandenbroucke RE, A New Venue of TNF Targeting. International journal of molecular sciences. 2018 May 11 [PubMed PMID: 29751683]|
|||Sfikakis PP, The first decade of biologic TNF antagonists in clinical practice: lessons learned, unresolved issues and future directions. Current directions in autoimmunity. 2010 [PubMed PMID: 20173395]|
|||Tracey D,Klareskog L,Sasso EH,Salfeld JG,Tak PP, Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacology [PubMed PMID: 18155297]|
|||Schottelius AJ,Moldawer LL,Dinarello CA,Asadullah K,Sterry W,Edwards CK 3rd, Biology of tumor necrosis factor-alpha- implications for psoriasis. Experimental dermatology. 2004 Apr [PubMed PMID: 15086336]|
|||Wong M,Ziring D,Korin Y,Desai S,Kim S,Lin J,Gjertson D,Braun J,Reed E,Singh RR, TNFalpha blockade in human diseases: mechanisms and future directions. Clinical immunology (Orlando, Fla.). 2008 Feb [PubMed PMID: 17916444]|
|||Esposito E,Cuzzocrea S, TNF-alpha as a therapeutic target in inflammatory diseases, ischemia-reperfusion injury and trauma. Current medicinal chemistry. 2009 [PubMed PMID: 19689289]|
|||Waage A,Halstensen A,Espevik T, Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet (London, England). 1987 Feb 14 [PubMed PMID: 2880163]|
|||Fiers W, Tumor necrosis factor. Characterization at the molecular, cellular and in vivo level. FEBS letters. 1991 Jul 22 [PubMed PMID: 1649771]|
|||Feldmann M, Development of anti-TNF therapy for rheumatoid arthritis. Nature reviews. Immunology. 2002 May [PubMed PMID: 12033742]|
|||Uyemura K,Yamamura M,Fivenson DF,Modlin RL,Nickoloff BJ, The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response. The Journal of investigative dermatology. 1993 Nov [PubMed PMID: 7693825]|
|||Mitoma H,Horiuchi T,Tsukamoto H,Ueda N, Molecular mechanisms of action of anti-TNF-α agents - Comparison among therapeutic TNF-α antagonists. Cytokine. 2018 Jan [PubMed PMID: 27567553]|
|||Charles P,Elliott MJ,Davis D,Potter A,Kalden JR,Antoni C,Breedveld FC,Smolen JS,Eberl G,deWoody K,Feldmann M,Maini RN, Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis. Journal of immunology (Baltimore, Md. : 1950). 1999 Aug 1 [PubMed PMID: 10415055]|
|||Danese S,Sans M,Scaldaferri F,Sgambato A,Rutella S,Cittadini A,Piqué JM,Panes J,Katz JA,Gasbarrini A,Fiocchi C, TNF-alpha blockade down-regulates the CD40/CD40L pathway in the mucosal microcirculation: a novel anti-inflammatory mechanism of infliximab in Crohn's disease. Journal of immunology (Baltimore, Md. : 1950). 2006 Feb 15 [PubMed PMID: 16456024]|
|||Ritchlin CT,Haas-Smith SA,Li P,Hicks DG,Schwarz EM, Mechanisms of TNF-alpha- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. The Journal of clinical investigation. 2003 Mar [PubMed PMID: 12639988]|
|||Souto-Carneiro MM,Mahadevan V,Takada K,Fritsch-Stork R,Nanki T,Brown M,Fleisher TA,Wilson M,Goldbach-Mansky R,Lipsky PE, Alterations in peripheral blood memory B cells in patients with active rheumatoid arthritis are dependent on the action of tumour necrosis factor. Arthritis research [PubMed PMID: 19500335]|
|||Leipe J,Skapenko A,Lipsky PE,Schulze-Koops H, Regulatory T cells in rheumatoid arthritis. Arthritis research [PubMed PMID: 15899057]|
|||Bayry J,Lacroix-Desmazes S,Dasgupta S,Kazatchkine MD,Kaveri SV, Efficacy of regulatory T-cell immunotherapy: are inflammatory cytokines key determinants? Nature reviews. Immunology. 2008 Jan [PubMed PMID: 18049489]|
|||Wasserman MJ,Weber DA,Guthrie JA,Bykerk VP,Lee P,Keystone EC, Infusion-related reactions to infliximab in patients with rheumatoid arthritis in a clinical practice setting: relationship to dose, antihistamine pretreatment, and infusion number. The Journal of rheumatology. 2004 Oct [PubMed PMID: 15468353]|
|||Rajagopalan M,Mital A, Biologics use in Indian psoriasis patients. Indian dermatology online journal. 2016 Nov-Dec [PubMed PMID: 27990383]|
|||Hanauer SB,Feagan BG,Lichtenstein GR,Mayer LF,Schreiber S,Colombel JF,Rachmilewitz D,Wolf DC,Olson A,Bao W,Rutgeerts P, Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet (London, England). 2002 May 4 [PubMed PMID: 12047962]|
|||Monaco C,Nanchahal J,Taylor P,Feldmann M, Anti-TNF therapy: past, present and future. International immunology. 2015 Jan [PubMed PMID: 25411043]|
|||Aygun D,Sahin S,Adrovic A,Barut K,Cokugras H,Camcıoglu Y,Kasapcopur O, The frequency of infections in patients with juvenile idiopathic arthritis on biologic agents: 1-year prospective study. Clinical rheumatology. 2018 Nov 17 [PubMed PMID: 30448935]|
|||Kerbleski JF,Gottlieb AB, Dermatological complications and safety of anti-TNF treatments. Gut. 2009 Aug [PubMed PMID: 19592682]|
|||Archer R,Hock E,Hamilton J,Stevens J,Essat M,Poku E,Clowes M,Pandor A,Stevenson M, Assessing prognosis and prediction of treatment response in early rheumatoid arthritis: systematic reviews. Health technology assessment (Winchester, England). 2018 Nov [PubMed PMID: 30501821]|
|||Svenson M,Geborek P,Saxne T,Bendtzen K, Monitoring patients treated with anti-TNF-alpha biopharmaceuticals: assessing serum infliximab and anti-infliximab antibodies. Rheumatology (Oxford, England). 2007 Dec [PubMed PMID: 18032541]|
|||Khanna D,McMahon M,Furst DE, Safety of tumour necrosis factor-alpha antagonists. Drug safety. 2004 [PubMed PMID: 15061685]|
|||Barland C,Kerdel FA, Addition of low-dose methotrexate to infliximab in the treatment of a patient with severe, recalcitrant pustular psoriasis. Archives of dermatology. 2003 Jul [PubMed PMID: 12873907]|
|||Heller MM,Wu JJ,Murase JE, Fatal case of disseminated BCG infection after vaccination of an infant with in utero exposure to infliximab. Journal of the American Academy of Dermatology. 2011 Oct [PubMed PMID: 21920245]|
|||Salliot C,Dougados M,Gossec L, Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumatoid arthritis: meta-analyses of randomised placebo-controlled trials. Annals of the rheumatic diseases. 2009 Jan [PubMed PMID: 18203761]|