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TNF Inhibitors in RA: Efficacy & Risks

1. Methyltrexate acts by blocking T cell effects like reducing IFN gamma and augmenting apoptosis. It also reduces turnover of rapidly dividing cells, and its adverse effects stem from this property. 2. TNF is a pivotal cytokine in RA pathogenesis, so research focused on inhibiting its action. Inhibiting TNF didn't help treat septic shock in humans, possibly due to late administration in disease progression. 3. TNF inhibitor treatment reduced levels of IL6 and IL1 in serum, along with clinical improvements within days. Hematological markers like hemoglobin and CRP also fell with treatment.

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48 views3 pages

TNF Inhibitors in RA: Efficacy & Risks

1. Methyltrexate acts by blocking T cell effects like reducing IFN gamma and augmenting apoptosis. It also reduces turnover of rapidly dividing cells, and its adverse effects stem from this property. 2. TNF is a pivotal cytokine in RA pathogenesis, so research focused on inhibiting its action. Inhibiting TNF didn't help treat septic shock in humans, possibly due to late administration in disease progression. 3. TNF inhibitor treatment reduced levels of IL6 and IL1 in serum, along with clinical improvements within days. Hematological markers like hemoglobin and CRP also fell with treatment.

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meilunly
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We take content rights seriously. If you suspect this is your content, claim it here.
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Molecule to Malady Lecture 24

Human Clinical Trial Data


Methyltrexate (chimeric molecule) acts by blocking a number of T cell effects
reduce IFN gamma production, augmenting apoptosis. It reduces the turnover of
rapidly turnover of cells and its in this property in which its adverse effects
reside.
The TFN production is the pivotal cytokine of the pathogenesis of RA disease,
thus focus was on ways of inhibiting action of TFN.
Septic shock introduction of TNF inhibitor didnt aid in treatment of disease in
humans, but that could be due to the fact that its administered much later in
disease progression. May be an issue of timing rather than a mechanistic
problem
Serum levels of IL6 and IL1 fell with treatment of TNF inhibitors.
IL1A (details)
Reduction of these cytokine levels fall within hours with clinical improvements
usually occurs in days of treatments. Haematological indices haemoglobin
levels, CSR, CRP all fell following treatment.
Improvement of T regulatory cells function and response to antigens. Repeated
dosing showed attenuation of benefits over time.
Benefit of the two drugs together was better than the sum of the action of the
two drugs individually showed synergy.

TRIALS
All groups: each treated with varying drugs, showed significant placebo
responses

Primary Failure: Lack of response to TNFI

30% patients fail to achieve ACR 20 with initial treatment

Some patients improve when switched from one TNFI to another because
of lack of treatment effect.
This may be due to regression to the mean or varying mechanism (MAb
vs receptor). Pharmacokinetics, stability of TNF/TNFI complex or TNF-BPs
could also be contributing factors.

Generally, newer biologics targeting other molecules are more effective in


these patients

Secondary Failure: Acquired Therapeutic Resistance

Data from national biologics registers


Median drug survival time = 3 years

Cessation due to adverse effects is significantly shorter than lack of


efficacy

Median drug survival longest for the first anti-TNF agent, decreased with
subsequent anti-TNF agents

Overall, patients cease TNFI for adverse events (AEs) (50%) & inefficacy
(50%)

Biologically nave for both drugs exhibited a longer drug survival rate (both
Etanercept and Adalimumab). Many patients also developed Ab to these TNF
inhibitors but these Ab dont necessarily affect the efficacy of the drug. With
subsequent TNF inhibitors prescribed, the probability of eliciting a response was
lower, the duration of efficacy was also lower.

Safety biologic therapy in RA


RA patients have a definite increased risk for:
Infection:

Mycobacterium species and other intracellular (granulomatous) bacterial


infection reactivation (12- 20 fold): infliximab>etanercept
There is greatest risk of chronic infections by mycobacterium TB, it is
common in populations prescribed anti-TNF Ab or TNFI

Bacterial esp respiratory, urinary tract. (Overall slight)

Fungal (various) (Overall slight)

Viral reactivation esp Varicella Zoster Virus and HBV

Skin cancer:

Non-melanotic 1.5 fold


Melanotic 2.3 fold

AutoAb development (antinuclear, dsNDA)

Rashes (psoriasis however these drugs also tend to be used to treat


rashes)
Allergic reactions (hypersensitivity, blocking Ab despite molecules being
humanized, injection site reactions after subcutaneous administration)

Newer Biologics

Anakinra IL1 inhibitor

Tocilizumab IL6 inhibitor

Abatcept T cell co-stimulation (used in transplants)

Rituximab B cell depleting (immune modulating drug)

Details of the : ellular roles in RA synovium summary slide (learn


where each relevant drug acts)

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