use of biologicals in rheumatoid arthritis
TRANSCRIPT
USE OF BIOLOGICALS IN
RHEUMATOID ARTHRITIS
ILHAR HASHIM, M PHARM-CLINICAL RESEARCHNATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), MOHALI, INDIA-160062
BIOLOGICS &
RHEUMATOID ARTHRITIS
• Biological response modifiers: newest class of drugs for
the treatment of rheumatoid arthritis (RA)
• Term Biological: Treatments developed and produced in
live cell systems
• Also referred as biological therapies or cytokine
modulators
RHEUMATOID ARTHRITIS
• One of the common disease showing increased morbidity
globally
• Chronic, progressive and disabling auto-immune disease
• Every person’s disease is different
• Etiopathology:
-Exact causes not known
-A genetic element combined with environmental
trigger cause the immune system to malfunction
Antibodies called rheumatoid factors Activate
complement system Chemotaxis, phagocytosis and
release of lymphokines Amplifies immune response
Activation of T and B cells
- TNF, IL-1 and IL-6 are important in the initiation and
continuance of inflammation
EXISTING THERAPIES & GOALS
• The ultimate goal: To induce a complete remission,
although this may be difficult to achieve
• The primary objectives:
To reduce signs, symptoms & mordidity
Preserve range of motion and joint function
Improve quality of life
Prevent systemic complications and slow destructive
joint changes
• At present the drugs used are:
DMARDs - Biologicals and non biologicals
NSAIDs & Corticosteroids for symptomatic relief
• As per the present approach:
DMARD should be started within the first 3 months
Biologic agents when other DMARDs fail
Combination therapy when required
EPIDEMIOLOGY & COSTS
• Affects 0.5–1% of population
• Prevalence higher in women & elderly
• Incidence found varying across globe
• Financial impact on health-care systems and national
economies
• The national audit office estimate in England:
Direct health service costs -£560 million/yr
Work-related disability costs -£1,800 million/yr
BIOLOGICS: HISTORYDiscovery of different chemicals inflamed joints
Cytokines & their functions
Laboratory experiments using tissues
Role of TNF & Interleukins
Clinical trials using biologics
Positive results obtained
Approval by regulatory
IMPORTANCE OF BIOLOGICS IN
RHEUMATOID ARTHRITIS
• Made using biotechnology
• Genetically engineered proteins
• They can behave like natural immune system proteins
• Target specific activity & less ADRs
• Also focus on T & B cells
• Large molecules capable of inhibiting cytokines
Main biologics used in RA
Biologic ClassDrugs &
brand name Nature & Mechanism
TNF inhibitors
Adalimumab
[Humira]
Recombinant human IgG1 monoclonal antibody against
TNFα. Binds to human TNF-α with high affinity and, as
a consequence, it inhibits the cytokine from binding to
its receptors. It also lyses cells that express TNF-α
Etanercept
[Enbrel]
Soluble TNF-receptor fusion protein against TNFα.
Binds to both TNF-α and TNF-β. It prevents them from
interacting with their receptors.
Infliximab
[Remicade]
Chimeric IgG1 anti-TNF-α antibody. It binds to soluble
and membrane-bound TNF-α with high affinity, thereby
impairing the binding of TNF-α to its receptor.
Infliximab also kills cells that express TNF-α.
Certolizumab
[Cimzia]
Recombinant humanized Fab’fragment of a TNF-
antibody coupled to polyethylene glycol. It binds and
neutralizes membrane-bound and soluble human TNF-α.
Golimumab
[simponi]
Recombinant human IgG1 monoclonal antibody specific
for TNF-α. It binds and neutralizes membrane-bound
and soluble human TNF-α.
Biologic ClassDrugs &
brand name Nature & Mechanism
Interleukin
Inhibitor
Tocilizumab
[Actemra]
Recombinant humanized antihuman interleukin-6
receptor monoclonal antibody of the IgG1 subclass. It
binds to both membrane-bound and soluble IL-6
receptors, preventingtheir activation by Il-6.
Anakinra
[Kineret]
Blocking the action of the chemical messenger
interleukin1. IL 1 receptor antagonist protein.
B-cell inhibitorRituximab
[Rituxan]
Chimeric monoclonal antibody. It depletes the B-cell
population by targeting cells bearing the CD20 surface
marker. This binding interferes with the activation and
differentiation of B cells.
T-cell Co-
stimulation
inhibitor
Abatacept
[Orencia]
Immunoglobulin fused to the extracellular domain of
cytoxic T-lymphocyte antigen 4. The abatacept molecule
blocks the interaction between the antigen-presenting
cell’s CD80/86 ligand and the CD28 ligand on the T cell,
which is necessary for T-cell activation.
Janus kinase
inhibitor
Tofacitinib
[Xeljanz]
Block the body’s production of enzymes called Janus
kinases (JAKs).
Reference: Scott D. Biologics-based therapy for the treatment of
rheumatoid arthritis
NICE: National Institute For Health And Clinical Excellence
RA Guidelines
• To be eligible for biologics, patients with RA should
have:
1. High levels of persistent disease activity
-Measured by DAS 28 on two occasions
-Should have a score over 5.1 on both occasions
2. Failed on two DMARDS
-One of which must be methotrexate.
3. Stay on biologic therapy in the long term
- Patients need to have a drop in DAS 28 of 1.2 in 6
months
- Should maintain this lower score in every assessment.
-If occurrence of side effect on 1st line drug in 6 months
switch on to alternative.
-Non responders to 1st line drug are not accessed to a 2nd
one.
MONITORING SAFETY OF BIOLOGICS
• The British Society for Rheumatology (BSR)
• BSR Biologics Register established in 2001
• A national database is keeping track of patient response
to biologics
• To study their long term safety
• NICE endorsed and recommended
IMPACT OF BIOLOGICALS IN
TREATMENT OF RAOn an overall:
• Biologics were associated with higher achievement of
ACR50 response compared to placebo
• DAS28 responder rates were near to 70%
• Biologics were shown to increase the frequency of remission.
• Strong evidence that biologics reduce the progression of
erosive damage as assessed using X-ray
• Favourable results related to quality of life focused on HAQ
scores
IMPACT ON HEALTH ECONOMY
• Seven of the top eight best selling drugs in 2014 were
biologics
• Globally proportion of RA patients using biologics is
increasing
0
2
4
6
8
10
12
14
16
18
20
2000 2002 2004 2006 2008 2010
%
of
pa
tien
ts u
sin
g B
iolo
gic
als
• This scenario has resulted in an overall increase in the direct
costs of RA treatment
• But the main consequence of RA work productivity loss is
decreasing
• R & D expense on biologics is increasing year by year
0
10
20
30
40
50
1990 1994 1998 2002 2006 2010
R &
D E
xp
ense
(U
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)
COMPARATIVE AND RESEARCH
STUDIES• TNF inhibitors are found to be most clinical & cost-effective
choice
• With short-term treatment, etanercept and adalimumab had
higher efficacy results
• With long-term treatment, adalimumab appeared to be the most
effective
• Rituximab was found to be most effective after the failure of a
1st line biologic
DRUGS IN DETAIL
Biologic TypeDrug &
brand name
Approval
date &
Status
Nature & Mechanism of
ActionDosage
Side
EffectsIndications
TNF
inhibitors
Adalimumab
[Humira]
31/10/2002
USFDA
Recombinant human IgG1
monoclonal
antibody against TNFα
40
mg/wk-
sc
Bruising, pain,
redness, rash,
head ache,
infections
RA, psoriatic arthritis, juvenile
arthritis, Crohn’s and ulcerative
colitis,ankylosing spondylitis
and psoriasis.
Etanercept
[Enbrel]
02/11/1998
USFDA
Soluble TNF-receptor fusion
protein against
TNFα
5 mg/wk
or 25 mg
twise
wkly-sc
Bruising, pain,
redness, rash,
head ache,
infections
RA, psoriatic arthritis, juvenile
arthritis, ankylosing
spondylitis
Infliximab
[Remicade]
24/08/1998
USFDA
Chimeric IgG1 anti-TNF-α
antibody
3-5
mg/kg-iv
infusion
at 0,2 &
6 wks
Bruising, pain,
redness, rash,
head ache,
infections
RA, psoriatic arthritis, juvenile
arthritis, ankylosing
spondylitis
Certolizumab
[Cimzia]
30/09/2013
USFDA
Recombinant humanized
Fab’fragment of a TNF-
antibody coupled to
polyethylene glycol
200-400
mg-iv inj
at 0,2 &
4 wks
Bruising, pain,
redness, rash,
head ache,
infections
RA, psoriatic arthritis, juvenile
arthritis, ankylosing
spondylitis
Golimumab
[simponi]
24/04/2009
USFDA
Recombinant human IgG1
monoclonal
antibody specific for TNF-α
50 mg
once/mo
nth-sc
Bruising, pain,
redness, rash,
head ache,
infections
RA, psoriatic arthritis, juvenile
arthritis, ankylosing
spondylitis
Biologic TypeDrug &
brand name
Approval
date &
Status
Nature & Mechanism of
ActionDosage
Side
EffectsIndications
Interleukin
Inhibitor
Tocilizumab
[Actemra]
22/10/2013
USFDA
Recombinant humanized
antihuman interleukin-6
receptor monoclonal
antibody of the IgG1
subclass
162 mg-iv
inj/wk
Redness, itching,
rash,pain,
infections, head
aches & infusion
reactions
RA, Polyarticular
Juvenile Rheumatoid
Arthritis, Systemic
Form of Juvenile
Idiopathic Arthritis
Anakinra
[Kineret]
27/06/2003
USFDA
Blocking the action of
the chemical messenger
interleukin1.IL 1receptor
antagonist protein
100 mg/day-sc
Redness, itching,
rash,pain,
infections, head
aches
RA, Neonatal-Onset
Multisystem
Inflammatory Disease,
other autoimmune
diseases
B-cell inhibitorRituximab
[Rituxan]
26/11/1997
USFDA
Chimeric monoclonal
antibody targeting
cells bearing CD20
surface marker
1000 mg-iv
infusions given
2 wks apart
every 24 wks
Itching, pain,
chills, fever, head
ache, infections
RA, Microscopic
Polyangiitis severe
forms of vasculitis
T-cell
Co
stimulation
inhibitor
Abatacept
[Orencia]
23/10/2005
USFDA
Immunoglobulin fused to
the extracellular domain
of cytoxic T-lymphocyte
antigen 4
125 mg as single
iv infusion in aday
followed by 125
mg once a wk
Headache
common cold,
sore throat
nausea.
Moderate- severe RA
Janus kinase
inhibitor
Tofacitinib
[Xeljanz]
06/11/2002
USFDA
Block the body’s
production of enzymes
called Janus kinases
(JAKs).
5 mg oral twice
a day
Signs of
infections fever,
chills, muscle
aches, cough,
diarrhea
Moderate-severe active
RA
THERAPEUTIC GUIDELINES FOR USE OF
BIOLOGICS IN RA
Poor response
Poor response
*Algorithm For Treatment Of Rheumatoid Arthritis
Methotrexate or other DMARD
± NSAID ± Prednisolone
within first 3 months
Other DMARD Monotherapy
(MTX if not used above)
Combo
DMARD therapy
Biologic DMARD
mono or combo with
DMARD
Try other combination, triple drug (DMARD + biologic), add low dose
prednisolone for longer term, consider second line DMARD
INSTRUCTIONS TO RA PATIENTS ON BIOLOGICS
• Dosing instructions in case of self administered
drugs.
• Proper storage instructions.
• Importance of medication adherence.
• Regular Monitoring by your rheumatologist & lab is
necessary.
• Posible side effects and their management.
• Use skin protectives and check skin regularly while
taking any of these drugs.
• Dicuss with the physician on other suffering conditions or
medications.
• Patients exposed to risk of infections & those who displaying
symptoms of an infection should notify their doctors.
• Patients should not receive any live vaccines while receiving
biologics.
• Patients with diabetes mellitus may have false high blood
sugar levels due to biologics.
• Women on biologics should discuss birth control methods with
their primary doctor or gynecologist.
• Blood pressure monitoring
• Etanercept was found to be comparatively safer
• SYK kinase may be an important new therapeutic target
in RA and related autoimmune conditions
LOOKING AHEAD• Many new biologics are being developed, including inhibitors of
IL-17
• Biosimilars are likely to be introduced within the next few years
• SYK (Spleen tyrosine kinase) inhibitors may well move from
clinical trials into clinical practice in the near future
• Concept of ‘personalised (or stratified) medicine’
• Now a days research is focused on ‘treatment-to-target’ (T2T)
strategies
• Treatment at the very early stages of inflammatory arthritis, at
stage of undifferentiated arthritis(UDA)
Thank you……