TNF inhibitors Chapter 25

shevyatiwari's version from 2016-09-19 05:11

Section 1

Question Answer
Psoriatic skin has increased TNF-a compared to non lesional skinT
TNFa does not correlate with disease severityF
Etanercept is fully humanT
Etanercept is dimericT. Dimeric fully human fusion protein. Produced in Chinese hamster ovary cells. Consists of 2 ligand-binding domains of the p75 TNF receptor fused with Fc portion of human IgG1.
Etanercept binds only to soluble TNFaF. Binds to soluble AND membrane bound, preventing TNFa from binding to any cell surface receptors
Etanercepts binds to TNFb/LTaT
Etanercept can bind to three TNF molecules at onceF. 2
Etanercept binds to TNFa with lesser affinity than TNFa binds to natural TNFRF. 100 fold greater affinity
Etanercept binds to TNFa and remains until it is degradedF. Binds for 2-3 hours. Releases TNF- alpha quickly 90% released after 2-3 hours
Etanercept reduces LTa by 50%F, 80%
Etanercept reduces TNFa by 50%T
Etanercept is IgMF, IgG
Etanercept has a T1/2 of 7 daysF. 4.8 days
Etanercept peak levels are in 24 hoursF. 2 days - 48 hours
Etanercept BA is approx 50% F 58%
Etanercept is metabolised in the liverF. Proteolysed
Etanercept is excreted predominantly in the urineF. Fragments in to Equal bile, urine
Liver failure is a relative C/I for EtanerceptF
Etanercept is composed of p50 TNFR fused to Fc portion of IgG1F. p75
Etanercept is FDA approved for psoriasisT
Etanercept can be safely used with anankiraF. Absolute C/I. Anakinra IL-1 receptor antagonist is a contraindication to ALL biologics therapy as increased risk of serious infection
Active infection is a relative C/I to EtanerceptF. Absolute
Chronic/localised infections including TB are absolute C/I to EtanerceptT
Family history of demyelinating disease incl MS is a relative C/I to EtanerceptT
Etanercept is Cat CF. Cat B
Etanercept is excreted in breast milkT
15% of patients on Etanercept develop authoantibodiesF. 2% rare. Not neutralising therefore not anti-drug antibodies
The most common adverse event in Etanercept incl injection site reactionsT. 14%
Injection site reactions usually appear on the first day of treatmentF. On second injection, and can be seen on other injected sites too.Delayed type hypersensitivity . Continue sue and reactions settle at 4 weeks
Injection site reactions are a type 3 immunological reaction F, 4
Etanercept influences dosing of warfarinF. All TNF inhibitors metabolism via proteolysis therefore do NOT interfere with metabolism or excretion of most drugs .
Etanercept has no interaction with digoxinT
Live vaccines are relative C/I to EtanerceptF. If required, discontinue for 10 days prior and 10 days after
Etanercept can be stored in the patient's freezerF
Etanercept lasts for up to 14/7 in the patient's fridgeT
Before administration, Etanercept should be brought to room temperature over 15 minutesT, to avoid injection site pain

Section 2

Question Answer
Infliximab/Remicade is 100% BAT
Infliximab is chimeric (25% mouse, 75% human) gig monoclonal antibodyT
Like Etanercept, Inflixmab binds to TNFa and TNFbF. Only TNFa
Infliximab neutralises soluble TNFaT Neutralises soluble TNF alpha and blocks membrane bound TNF alpha
Infliximab blocks membrane bound TNFaT
Concentrations in serum are not a good marker of dose givenF. Serum concentration directly related to dose and does NOT correlate with age
The T1/2 of infliximab is approx 4.8 daysF. 7 days (5mg/kg dose ) and 9 days for 10mg/kg dose
Infliximab is metabolised by the liverF. Proteolysed
Renal/hepatic impairment is a C/I to inflixmabF.
Infliximab is still safe in an individual with murine protein hypersensitivityF. Absolute C/I
Infliximab is safe to use in CCF as long as doses are <5mg/kgT
Infliximab is not found in breastmilkT. Differs from Etanercept and Aadlimumab - v. low levels
Infliximab is cat DF. B. All TNF inhibitors are B . Rituximab is C - for cancer
Infliximab is C/I with ananikraT. There are no other significant drug interactions
Infliximab - absolute C/I include active, chronic or localised infectionT
A family history of demyelinating disease is a relative C/I to InfliximabT
CCF is a relative C/I to Infliximab when used in doses >5mg/kgT. But OK to use at 5mg/kg with CCF
Infusion reactions count up to 3 hours post transfusionT
Approx 2% of Inflixmab patients experience injection reactionsF. 20% infusion reactions - most common. Most mild <1% serious
25% of patients on inflixmab develop anti drug antibodiesF. 25% with no autoantibodies will have an infusion reaction
Those who develop anti-drug ab's on inflixmab are more likely to have infusion reactions, clear inflixmab faster and have reduced efficacyT
Infliximab anti drug ab's are associated with increased severity of infusion reactionsF. Antidrug antibodies assoc with increase drug clearance rate, decreased efficacy and increased incidence but NOT severity of infusion reactions
Infliximab and concurrent use of corticosteroids/Mtx may reduce the incidence of anti drug ab'sT
Hepatotoxicity is a rare S/E of InfliximabT
Infliximab is highly protein boundF
Infliximab similar to Etanercept is given S/CF. Infliximab given as an infusion

Section 3

Question Answer
Adalimumab/Humira is a fully human IgG1 to TNFaT
Adalimumab lyses cells that express TNFa on their surfaceT, same as inflixmab
BA of Adalimumab is 64%T
T1/2 of Adalimumab is 14 daysT
Adalimumab reaches peak levels in 2 daysF. 5.5 days - 131 hours (longest to reach peak.) Etanercept 2 days , infliximab =immediately
Adalimumab is given mg/kgF. Adlimumab is given as 80mg week 0, 40mg week 1, then 40mg subcut alternative weeks (No dose week 2). Infliximab is given at mg/kg
Adalimumab is simlar to inflixmab/etanercept in its metabolism and excretionT. Metabolism= proteolysis . Excretion = fragments in bile and urine
Absolute C/I are exactly the same as Inflixmab and EtanerceptT. ABSOLUTE C/I - known hypersensitivity to agent (or murine proteins if inflixi) , concurrent administration with Anakinra - IL1 receptor antagonist - as increased risk of serious infection, avoid with active infections, chronic or localised infections inc. TB. Relative C/I Family history of demyelinating disease inc. MS - for all TNF -alpha inhibitors
Relative C/I are exactly the same as Inflixmab and EtanerceptF. Same as etanercept. Infliximab has relative C/I for CCF - . Ok if 5mg/kg dose but not OK for 10mg/kg
Adalimumab is cat AF. Cat B. All TFN -alpha inhibitors and IL 12/23 inhibitors = cat B. Rituximab = cat C
Adalimumab is excreted in breast milkT. V. low levels - similar to Etanercept. Infilixmab differs - NONE in breast milk
15% of those on Adalimumab develop injection site reactionsF. 6% in table 3.2%in text. Most common adverse effect- erythema a, swelling and itching
Anti-drug antibodies are seen in 2% of those on AdalimumabF. 5%.
Those with anti drug ab's to Adalimumab were more likely to have adverse eventsF. No relation. Anti-drug antibodies in 5% - with low titres .no effect on efficacy
Methotrexate can be used to reduce the formation of anti drug ab's in AdalimumabF. Reduces clearance of Adalimumab by 44%, doesn't reduce efficacy
Live vaccines are C/I in Adaimumab T
Adalimumab is administered in infusions like infliximabF. S/C

Section 4

Question Answer
TNF inhibitor therapy -> increase risk of malignancy, esp lymphoma and in combination with Mtx or aztT
There is no increase in risk of NMSC in those taking biologics F
Children on TFN inhibitors have increased risk of malignancy in combination with other immunosuppressionT
It is reasonable to stop biologics if there is an active infectionT
Etanercept, Infliximab and Adalimumab are equally causative in TB reactivationF. Inflixmab and adalimumab higher
Invasive fungal infections are seen most commonly with AdalimumabF. INfliximab > etanercept > adalimumab
Most people who develop invasive fungal infection were not on any other immunosuppressionF
Hep B can be reactivated in TNF inhibitorsT
There is a small risk of demyelinating disease with TNF inhibitiorsT
CCF patients should use TNF inhibitors with cautionT
ANA and dsDNA are associated with all three TNF inhibitorsT
ANA is more likely to be induced than dsDNAT
Adalimumab has the highest association for ANA and dsDNA developmentF. Infliximab
Most drug induced lupus will resolve on cessation of therapyT
Sporadic haematological toxicity including pancytopenias are possible with TNF inhibitorsT
FBP, UEC, LFT, quantiferon should be checked at baseline then weekly for 1 month, then 3 monthly while on therapyF. At baseline, then in 2-3 months, or in infliximab at time of infusion. Consider 6-12 monthly for adalimumab and etanercept

Recent badges