Biologic DMARDs
Dr Gichuhi 1
Review of drug classification
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DMARDs
Conventional synthetic DMARDS
Are small molecules
Biologic DMARDS
Large molecules, usually proteins
Often produced by recombinant DNA technology
Targeted synthetic DMARDS
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Conventional Synthetic
DMARDs (csDMARDS)
Methotrexate
Azathioprine
Chloroquine
Hydroxychloroquine
Cyclophosphamide
Cyclosporine
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csDMARDS
Leflunomide
Mycophenolate mofetil
Sulfasalazine
Minocycline
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csDMARDs
Older agents
Gold salts
Penicillamine
No longer recommended because
Significant toxicities
Questionable efficacy
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Targeted synthetic DMARDS
(tsDMARDS)
Tofacitinib
Baricitinib
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Biologic DMARDs
Mainly antibodies or binding proteins
T-cell-modulating agent
Abatacept
B-cell cytotoxic agent
Rituximab
anti-IL-6 receptor antibody
Tocilizumab
Sarilumab
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bDMARDS
TNF-α-blocking agents
bDMARDs are further divided
into
Etanercept -biological original (or legacy)
products (boDMARDs)
Infliximab -biosimilar DMARDs
(bsDMARDs)
Adalimumab
BIOSIMILARS
Golimumab
-Designed to be generic
Certolizumab versions of the original biologic
molecule
IL-1 receptor antagonist -Maybe less costly hence more
patients can access them
Anakinra -These drugs appear to have
the same efficacy and toxicity
Rilonacept (not used in RA)
as the legacy compounds and
also the same degree of
immunogenicity
Canakinumab (not used in RA) 9
Drugs
NSAIDS
Usually acetylsalicylic acid
Other NSAIDS are not more effective
Other NSAIDS have less GIT effects esp COXIBS
Provide symptomatic relief (antiinflammatory)
However joint deformity progresses
Glucocorticoids
Prednisone
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Drugs
DMARDS or SARDS (S=Slow)
Have minimal direct analgesic or anti-
inflammatory effects so NSAID is needed
Effects take weeks – months to appear
Retard the development of bone erosions
and facilitate their healing
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TNF- α blocking drugs
Adalimumab
Infliximab
Etanercept
Golimumab
Certolizumab
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TNF-α is a cytokine in the inflammatory
process
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TNF- α blocking drugs
All are IgG anti-TNF monoclonal antibodies
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TNF- α
They have long half lives
Administered weekly, every 2, 4 or 8
weeks
Frequency varies with each agent
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Adalimumab
Mechanism of Action
It is a fully human IgG1 anti-TNF
monoclonal antibody
It complexes with soluble TNF-α and
prevents its interaction cell surface
receptors
This results in down-regulation of
macrophage and T-cell function
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Adalimumab
P’kinetics
SC
t½ = 10-20 days
Methotrexate (MTX) clearance
MTX production of antibodies against
this compound
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Adalimumab
Indications:
Rheumatoid arthritis (RA), Ankylosing
spondylitis (AS), Psoriatic arthritis (PsA)
Juvenile idiopathic arthritis (JIA), plaque
psoriasis
Crohn’s disease, and ulcerative colitis
Behçet’s disease, sarcoidosis
Noninfectious uveitis
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Adalimumab
NB: other bDMARDs also have a similar
list of inflammatory diseases
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Adalimumab
In RA
It decreases the rate of formation of
new erosions
Effective both as monotherapy and in
combination with
Methotrexate (MTX)
other nonbiologic csDMARDs
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Infliximab
Mechanism of Action
It is a chimeric (25% mouse, 75%
human) IgG1 monoclonal antibody
Mechanism of action is probably the
same as that of adalimumab
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Infliximab – P’kinetics
Intravenous infusion
Half-life is 9–12 days
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Infliximab
Human antichimeric antibodies are
formed in up to 62% of patients
Concurrent therapy with MTX decreases
the prevalence of these antibodies
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Infliximab
In RA
Infliximab plus MTX decreases the rate of
formation of new erosions (recommended)
Can also be combined with csDMARDs
Can be used as monotherapy
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Infliximab
Contraindicated in multiple sclerosis due
to reports of demyelinating syndromes
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Etanercept
It binds to both TNF- α & lymphotoxin-α
Antibodies formed against drug do not
interfere with efficacy
SC, slowly absorbed
peak concentration 72 hours after drug
administration
t½ = 4.5 days
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Etanercept
Etanercept decreases the rate of
formation of new erosions
It can be used as monotherapy
May be combined with methotrexate
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Certolizumab
Mechanism of Action:
It is a recombinant humanized antibody
with specificity for human TNF-α
It neutralizes membrane-bound and
soluble TNF-α
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Certolizumab
Subcutaneous route
Half-life = 14 days
Methotrexate decreases the appearance
of anti-certolizumab antibodies
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Certolizumab
Indicated for moderately to severely
active RA
It can be used as monotherapy
Or
In combination with nonbiologic
DMARDs
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Golimumab
Mechanism of Action
It is a human monoclonal antibody with
a high affinity for TNF-α
It neutralizes the inflammatory effects
produced by TNF-α
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Golimumab – P’kinetics
Subcutaneous
Half-life = 14 days
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Golilumab
Golimumab + methotrexate are used
for treatment of moderately to severely
active RA
Combination with methotrexate
increases golimumab serum levels
decreases anti-golimumab antibodies
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TNF-α–blocking agents -AEs
They have multiple adverse effects in
common
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TNF-α–blocking agents
The risk of bacterial infections is
increased
eg TB, fungal, and other opportunistic
infections
Activation of latent TB is lower with
etanercept
All patients should be screened for TB
before starting these drugs
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TNF-α–blocking agents
Also associated with increased risk of
Hepatitis B virus (HBV) reactivation
Screen for HBV before starting the
treatment
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TNF-α–blocking agents
Increased risk of skin cancers
Eg melanoma
Periodic skin examination is recommended
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TNF-α–blocking agents
Associated with newly formed dsDNA
antibodies and antinuclear antibodies
(ANAs)
But clinical systemic lupus erythematosus
(SLE) is extremely rare
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TNF-α–blocking agents
Can exacerbate heart failure
Can induce the immune system to develop
antidrug antibodies in about 17% of cases
These antibodies
May interfere with drug efficacy
Are associated with infusion site reactions
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Skin
Alopecia areata
Hypertrichosis
GIT
Ulcers
Large bowel perforation
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Nonspecific interstitial pneumonia
Psoriasis
Sarcoidosis like syndrome
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Haematologic
Leukopenia
Neutropenia
Thrombocytopenia
Pancytopenia
The precipitating drug should be
discontinued
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Abatacept
It inhibits the activation of T-cells
IV infusion
Subcutaneous
half-life is 13–16 days
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Abatacept
For moderate to severe RA
Use as monotherapy
or
in combination with methotrexate or
other DMARDs
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Abatacept
Most patients respond to abatacept
within 12–16 weeks after the initiation
of the treatment
Some patients can respond in 2–4
weeks
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Abatacept
Ab formation against the drug does not
change clinical outcome
Adverse effects
Risk of URTIs, UTIs
?? Lymphomas
Infusion related reaction
Hypersensitivity reactions
Anaphylaxis
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Abatacept
Don’t combine with anti-TNF drugs or
other biologics due to infection risk
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Abatacept
All patients should be screened for TB
and viral hepatitis before starting
abatacept
Live vaccines should be avoided in
patients while taking abatacept and up
to 3 months after discontinuation
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Rituximab
A monoclonal antibody that targets
CD20 B lymphocytes
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Rituximab
Mechanism of Action
Rapidly depletes B lymphocytes
This reduces inflammation by
decreasing the presentation of antigens to
T lymphocytes
inhibiting the secretion of proinflammatory
cytokines
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Rituximab
IV infusion
Pretreatment with
Acetaminophen,
An antihistamine, and
IV glucocorticoids (usually IV
methylprednisolone)
given 30 minutes prior to infusion
decreases infusion reactions
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Rituximab
Indicated for the treatment of
moderately to severely active RA in
patients with an inadequate response to
one or more TNF-α antagonists
Combine with methotrexate
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Rituximab
AEs
Rash (30%)
Immunoglobulins (IgG and IgM) may
decrease
Serious bacterial, fungal, and viral
infections are reported for up to one year
of the last dose of rituximab
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Rituximab
AEs
Patients with severe and active
infections should not receive rituximab
Associated with reactivation of HBV
NOT associated with
Activation of TB
Lymphomas or other tumors
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Rituximab
AEs
Fatal mucocutaneous reactions
Cytopenias
CBC every 2–4 months
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Tocilizumab
Mechanism of Action
Binds to & inhibits IL-6 receptors
IL-6 is a proinflammatory cytokine
produced by different cell types
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Tocilizumab
Pharmacokinetics:
IV infusion
Half life = 11-13 days
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Tocilizumab
IL-6 can suppress several CYP450
isoenzymes
The use of tocilizumab
May increase CYP450 activity
Dose adjustment for drugs with narrow
therapeutic window (eg, cyclosporine or
warfarin)
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Tocilizumab
Moderately to severely active RA who
have had an inadequate response to one
or more DMARDs
Monotherapy
Or
Combine with non biologic DMARDs
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Tocilizumab
Adverse Effects:
Most common adverse reactions
URTIs
Headache
Hypertension
Elevated liver enzymes
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Tocilizumab
Adverse Effects:
Infections: TB, fungal, viral, and other
opportunistic infections
Screen for TB before use
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Tocilizumab
Adverse Effects:
Rare
Neutropenia, thrombocytopenia
GI perforation
Demyelinating disorders
multiple sclerosis
Anaphylaxis
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Anti-tocilizumab antibodies can develop
May be associated with hypersensitivity
reactions requiring discontinuation
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Sarilumab
It is an IL-6 receptor antagonist
bDMARD
It binds to both soluble and membrane-
bound IL-6 receptors, thus inhibiting IL-6-
mediated signalling
IL-6 is a pro-inflammatory cytokine active
in the pathogenesis of RA
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Sarilumab
Half-life of 8–10 days
SC every 2 weeks
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Sarilumab
RA
As monotherapy or
in combination with methotrexate or other
csDMARDs
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Sarilumab - AEs
The most common adverse effect is infection
Neutropenia, thrombocytopenia, and anemia
Elevated liver enzymes
Elevated triglycerides and LDL
Monitoring of CBC and LFTs & lipid profiles
required
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Sarilumab - AEs
Perforation with diverticulitis
Possibly due to concomitant use of
corticosteroids
Patients with diverticulitis should not be
given sarilumab
Malignancies have been observed
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IL-1 inhibitors
IL-1α plays a major role in the
pathogenesis of RA
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Anakinra
A recombinant IL-1 RA (receptor
antagonist)
Mechanism of Action:
It blocks the effect of IL-1α and IL-1β
on IL-1 receptors hence decreasing the
immune response in inflammatory
diseases
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Pharmacokinetics:
SC
Half life = 4-6 hrs
Administered daily
Treatment adjusted in renal
insufficiency
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Canakinumab and rilonacept are not
used in RA
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IL-1 inhibitors
The most common adverse effects are
injection site reactions (up to 40%)
URTIs
Serious infections are rare
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IL-1 inhibitors
Rare
Headache
Abdominal pain, N, D
Arthralgia
Flu-like illness
Hypersensitivity reactions
Transient neutropenia
Regular monitoring of neutrophil counts
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Tofacitinib
Mechanism of Action
It selectively inhibits all members of the
Janus kinase family
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Tofacitinib
Mechanism of Action
This interrupts the JAK-STAT signaling
pathway
A major pathway in the pathogenesis of RA
This prevents transcription of several
genes that are crucial for the
differentiation, proliferation, and function
of NK cells and T and B lymphocytes
Rapidly reduces C-reactive protein
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Tofacitinib – P’kinetics
Oral
Bioavailability of 74%
Half-life is about 3 hours
Metabolism in the liver
mainly by CYP3A4
CYP2C19
Excreted via the kidneys
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Tofacitinib – P’kinetics
Reduce dose if
CYP enzyme inhibitors coadministered
Moderate hepatic or renal impairment
Contraindicated in severe hepatic
disease
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Tofacitinib
Used in RA patients who have failed or
are intolerant to methotrexate
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Tofacitinib -AEs
Slightly increases the risk of infection
Should not be used with potent
immunosuppressants or biologic DMARDs due
to added immunosuppressive effects
URTI and UTI are the most common
Others: pneumonia, cellulitis, esophageal
candidiasis, and other opportunistic infections
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Tofacitinib -AEs
Screen for latent or active TB before the
initiation of treatment
? Cancer risk
Lymphoma, lung and breast cancer have
been reported
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Tofacitinib -AEs
Increases LDL, HDL and total
cholesterol
Monitor lipid levels
Neutropenia and anemia
Drug discontinuation
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Baricitnib
Mechanism of Action: It is a targeted
synthetic small molecule (tsDMARD)
that inhibits members of the Janus
kinase family
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Baricitinib
10% is metabolized via CYP3A4
Check for drug interactions
Should not be used routinely in those with
severe liver disease
It is excreted mainly by the kidneys
Avoid or use cautiously in renal failure
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Baricitinib
RA in TNF-α inadequate responders
Used as monotherapy or in combination
with methotrexate or other csDMARDs
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Baricitinib - AEs
Increases the risk of infection and of
herpes virus reactivation
Screen for tuberculosis prior to initiation
of treatment
Lymphoma and other malignancies
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Baricitinib - AEs
GIT perforations have been reported
Use with caution in patients with a history
of diverticulitis
Neutropenia, lymphopenia, anemia
Liver enzyme elevation
Lipid elevation
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