This PPT encompasses the recent biologics overview & their uses in various rheumatological diseases according to recent guidelines. Special focus has been given to RA, SpA & SLE

1. Biologics in Rheumatological
diseases
Dr. Shinjan Patra

2. Biopharmaceutical
• A drug created by means of biotechnology,
especially genetic engineering- Primarily rDNA
protein & Monoclonal antibody
• Typically derived from living organisms- animal cells,
bacteria, viruses & yeast
• Include: Therapeutic proteins (cytokines, hormones
& clotting factors), Insulin, DNA vaccines,
monoclonal antibodies
• New experimental modalities such as gene therapy,
stem cell therapy

3. Biologics
• Biologics are genetically engineered
medications from a living organism, such as a
virus, gene or protein, to simulate the body’s
natural response to infection and disease
targeting cytokines and cell-surface molecules.
• Typically the 2nd line drug following the failure
of conventional NSAID’s, corticosteroids &
DMARD’s.

4. Modern day various uses
• Immune system disorders: Rheumatoid
arthritis, SLE, Spondyloarthropathy,
Inflammatory bowel disease.
• Blood conditions: Leukemia’s/ Lymphoma’s.
• Neurological disease- Multiple sclerosis
• Others- Alzheimer’s, Dyslipidemia etc.
• In 2010, sales of biologics reached $100
billion worldwide with the top 12 biologics
generating $30 billion.

5. Procedures in biologics production
 Identify the human DNA sequence for the desired
protein
 Isolate the DNA sequence
 Select a vector to carry the gene
 Insert the gene into the genome of a host
 Modification of cells→ “recombinant” technology
 The exact DNA sequence & type of host cell used will
significantly influence the characteristics of the product

6. Biosimilars
• Legally approved subsequent versions of
innovator biopharmaceutical products made
by a different sponsor following patent &
exclusivity expiry of the innovator product
• US-FDA named it as Follow-on-biologics
• Basically functions like the original
biopharmaceutical product in an affordable
price.
• Global market for biosimilars are $2 billion-
$2.5 billion in 2015

7. Indian Scenario
• Leading contributors in the world biosimilar
market.
• Cost effective manufacturing & huge demand
• Highly skilled, reasonably priced workforce
• Notable bio-similars- Rituximab, Insulin
Glargine, Darbopoetin, Alteplase.
• Concerns regarding their efficacy, long-term
safety & immunogenicity

8. Key pre-requisites/ points
• Safety issues most important- Serological
status and latent tuberculosis (Mantaux, Chest
X-ray, CECT Thorax, QuantiFERON-TB Gold
assay) ruled out before infusion.
• All parenterally given SC/ IV infusion.
• Needs strict follow-up schedule & periodic
assessment of reactivation of infection.

9. BIOLOGICS : FUNCTION AT A GLANCE

10. TNF-alpha Inhibitors
• Critical upstream mediator of joint
inflammation- acts on endothelial cells,
activated fibroblasts, metallo-proteases & T-
cells.
• Approved Examples-
Infliximab
Etanercept
Adalimumab
Golimumab
Certolizumab

12. A little bit….
• Infliximab- Chimeral (human + mouse) IgG1
monoclonal antibody that binds with TNFα.
• Etanercept- Recombinant fusion protein
consisting of two soluble TNF p75 receptor
moieties linked to Fc portion of human IgG1
• Adalimumab- Fully human IgG1 anti TNF
monoclonal antibody complexes with soluble
TNFα and prevents its interaction with cell
surface receptors

13. • Certolizumab- Pegylated humanized ‘Fab’
fragment that binds TNF-alpha
• Golimumab- Humanized monoclonal Ab binds
to TNF-alpha
• S/E- Reactivation of latent tuberculosis,
opportunistic fungal/ bacterial infection,
hypersensitivity reactions, avoided in NYHA
grade III/ IV CCF.

14. Rituximab
• Chimeric monoclonal antibody directed
against CD20- most common cell-surface
molecule expressed by mature B-lymphocytes
• Works by depleting B-cells- resultant
reduction of auto-antibodies, inhibition of T-
cell activation & cytokine production
• S/E- Infusion related reactions- Angioedema,
hypotension, chills, fever, headache.

15. IL-1R antagonists: Anakinra

16. Anakinra
• Recombinant human IL-1 receptor antagonist
• Initially approved only for RA but now tried in
Adult-onset Still’s disease, Systemic juvenile-
onset inflammatory arthritis, Muckle-Wells
syndrome.
• Shouldn’t be combined with TNF-alpha
inhibitors.
• S/E- Local reaction on s/c inj. & chest infection

17. IL-6 receptor antagonist- Tocilizumab
• Humanized monoclonal antibody directed
against membrane & soluble forms of IL-6
receptor- Decreases joint inflammation/
damage, cytokine production and osteoclast
activation
• S/E- Hematological (neutropenia &
thrombocytopenia)

18. T-cell co-stimulation inhibitor-
Abatacept
• Soluble fusion protein consisting of the extra-
cellular domain of human CTLA-4 linked to the
modified portion of human IgG- inhibits the
co-stimulation of T-cells by blocking CD28-
CD80/86 interactions.
• S/E- increased risk of infection

19. Others- New discoveries
• Belimumab- Binds soluble BLyS/ BAFF which is
required for maturation of naïve and
transitional B cells to plasma/ memory cells.
• Ustekinumab (Anti IL-12/23) & Secukinumab
(Anti IL-17) showed some efficacy in
spondyloarthropathy.
• Canakinumab- Human Mab targeted against
IL-1ß- Approved for CAPS, FCAS, MWS.

20. Biologics in RA- Treatment options

24. Dosage of the various biologics
Agent Class Dose Frequency
INFLIXIMAB TNF-alpha
inhibitor
3 mg/kg IV
infusion
Weeks 0, 2 and 6; then every 8 weekly
ETANERCEPT TNF-alpha
inhibitor
50 mg SC; 25 mg
SC
Weekly; twice weekly
ADALIMUMAB TNF-alpha
inhibitor
40 mg SC Biweekly. May increase dose to 40 mg
weekly in patients not taking
Methotrexate
CERTOLIZUMAB TNF-alpha
inhibitor
400 mg SC,
followed by 200
mg SC
400 mg SC weeks 0, 2, and 4, followed by
200 mg SC every 2 weeks
ANAKINRA IL-1 receptor
antagonist
100 mg SC Daily
TOCILIZUMAB IL-6 receptor
antagonist
IV: 4 mg/kg; may
increase to 8
mg/kg
Monthly
ABATACEPT T-Cell
co-stimulation
inhibitor
IV: < 60 kg: 500 mg
60–100 kg: 750 mg
> 100 kg: 1000 mg
Weeks 0, 2, 4, then monthly
RITUXIMAB CD20
inhibitor
1000 mg IV
infusion
2 doses 2 weeks apart.

25. Biologics in Spondyloarthropathy
• Important predictors-
Elevated CRP
MRI inflammatory changes
• Response calculated in inflammatory markers &
clinical scoring only, not radiographically.
• Infliximab, Etanercept, Golimumab,
Adalimumab, Certolizumab approved for AS.
• All except Certolizumab approved for PsA
additionally Ustekinumab + secukinumab
• All except Etanercept approved for IBD associated
arthritis

27. Biologics therapy in SLE
• 2 principally used-
Prospective placebo-controlled randomized
trials (both renal & non-renal) failed to show
benefits in Rituximab to placebo
Belimumab likely to benefit in SLEDAI >10,
Anti-ds DNA+, low complements, failure in
standard treatments.
Rituximab 1 g of two doses 2 weeks apart
Belimumab 10 mg/kg at 0,2,4 then monthly to continue

28. Other Indications
• Sarcoidosis- Infliximab as previous dosage
schedule.
• Granulomatosis with polyangitis-
Mepolizumab ( Anti-IL-5 Ab)
• TRAPS (TNF-Receptor associated Periodic
Syndrome)/ HIDS - TNF-alpha inhibitors +
Anakinra
• FCAS/ MWS- Anakinra/ Canakinumab

29. Thank you…….