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

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• This scenario has resulted in an overall increase in the direct

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• But the main consequence of RA work productivity loss is

decreasing

• R & D expense on biologics is increasing year by year

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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……