Use of biologicals in rheumatoid arthritis

1. USE OF BIOLOGICALS IN
RHEUMATOID ARTHRITIS
ILHAR HASHIM, M PHARM-CLINICAL RESEARCH
NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), MOHALI, INDIA-160062

2. 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

3. 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

4. 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

5. 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

6. • 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

7. 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

8. BIOLOGICS: HISTORY
Discovery 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

9. 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

10. Main biologics used in RA
Biologic Class
Drugs &
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.

11. Biologic Class
Drugs &
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 inhibitor
Rituximab
[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).

12. Reference: Scott D. Biologics-based therapy for the treatment of
rheumatoid arthritis

13. 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.

14. 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.

15. 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

16. IMPACT OF BIOLOGICALS IN
TREATMENT OF RA
On 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

17. 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
%ofpatientsusingBiologicals

18. • 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&DExpense(USDBillion)

19. 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

20. DRUGS IN DETAIL
Biologic Type
Drug &
brand name
Approval
date &
Status
Nature & Mechanism of
Action
Dosage
Side
Effects
Indications
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

21. Biologic Type
Drug &
brand name
Approval
date &
Status
Nature & Mechanism of
Action
Dosage
Side
Effects
Indications
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 inhibitor
Rituximab
[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

22. 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

23. 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.

24. • 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

25. • Etanercept was found to be comparatively safer
• SYK kinase may be an important new therapeutic target
in RA and related autoimmune conditions

26. 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)

27. Thank you……