3. INTERLEUKIN 12/23 INHIBITORS
(Ustekinumab & Briakinumab)
• Interleukin 12 & 23 are secreted by APC’s and have
been identified as key ILs in development of psoriasis
• IL 12 & 23 causes diffrentiation of naïve T cells into Th1
and Th17 cells respectively
• This Th1 & Th17 T cells secrete various cytokines like IL
2, 6, 17, 21, 22, TNF alpha, IFN which are responsible
for inflammatory changes, keratinocyte
hyperproliferation and development of psoriatic
plaques
4. USTEKINUMAB
prefix-Uste, target-kin, origin-u
suffix-mab
• It is a newly developed, fully human monoclonal
IgG1 antibody directed against the comman p40
subunit of IL 12 & 23, thus inhibiting activity of
both interleukins on Tcell diffrentiation and
cytokine production
• Approved by US FDA in september 2009 for use
in moderate to severe plaque psoriasis
• As Ustekinumab and Briakinumab both are fully
humanised antibodies they are devoid of
decrease in efficacy due to antichimeric antibody
formation as seen with infliximab
6. INDICATIONS
• US FDA approved – mod. to severe plaque
psoriasis
• Off label indications – sarcoidosis
multiple sclerosis
7. Mode of administration & Dosage
• Indicated for treatment of adults (18 yrs and
above) with mod. to severe plaque psoriasis with
or without psoriatic arthritis who are candidates
for phototherapy and systemic therapy
• <100kg : 45mg SC initially, repeat after 4 wks and
then give 45mg SC every 12 wks
• >100kg : 90mg SC initially, repeat after 4 wks and
then give 90mg SC every 12 wks
• Can be combined with methotrexate in patients
with psoriatic arthritis
8. EFFICACY
• A double blind, placebo controlled phase 2
study in 320 pts with moderate to severe
plaque psoriasis showed PASI 90 score in
23% (one 45 mg dose),
30%(one 90mg dose),
44%(four weekly 45mg doses) and
52% (four weekly 90mg doses)
compared to 2% who received placebo
9. Adverse effects
Relatively less frequent like injection site
erythema, fatigue, myalgia, backache, mild
Infections (upper respiratory tract
infections), urticaria, rash
Rare reports of severe infections, malignancy,
precipitation of pustular or erythrodermic
Psoriasis and reversible posterior
leucoencephalopathy syndrome
10. CONTRAINDICATIONS
• Hypersensitivity
• Active serious infections
• Past h/o serious bacterial, fungal or viral infections – can
cause reactivation
• Concomitant live vaccines – discontinue atleast 15 wks
before live vaccines and resume atleast 2 wks later
• To be used cautiously in patients who are genetically
deficient in IL12 & 23
11. AVAILABILTY
Trade name – Inj. Stelara 45mg solution for
injection, SC use
Cost – 1 vial - 5500$ (3,33,000 INR)for
single
13. RITUXIMAB (anti CD20)
prefix-Ri, target-tu, origin-xi, suffix-mab
• It is a chimeric monoclonal antibody directed
against CD20 & acts by causing depletion of
CD20 positive cells by complement and
antibody dependent cytotoxicity.
• CD20 is expressed on the surface of B-cells
from pre B-cells to memory B-cells but not on
stem cells, pro B-cells nor on plasma cells
• Thus, Rituximab causes depletion of mature
B-cells which would transform into antibody
14. FDA approved :
CD20 +ve non-Hodgkins B cell lymphoma
Resistant rheumatoid arthritis
Wegeners granulomatosis
Microscopic polyangitis
Off label :Bullous dermatosis like -
Refractory pemphigus vulgaris
Paraneoplastic pemphigus
Bullous pemphigoid
Epidermolysis bulosa acquisita
Mucous membrane pemphigoid
Urticarial vasculitis
Connective tissue ds – SLE, Dermatomyositis
Primary cutaneous B-cell lymphoma
Acute and chronic graft versus host disease
INDICATION
S
15. CONTRAINDICATIONS
• Absolute - Known hypersensitivity to murine
proteins or rituximab
• Relative – h/o hypotension, bronchospasm,
angioedema
Pregnancy cat C
1 yr of contraception is advisable after
completion of Rituximab therapy.
16. No specific dosing regimen has been approved for
dermatologic uses
Usually given at a standard dose of 375 mg/m2
BSA i.v at weekly intervals
Monitoring blood counts & antibody levels should
be done every 2-3 months
17. • Pre-Rituximab evaluation
• Complete haemogram
• Liver function tests
• Renal function tests
• Chest X ray, Mantoux test
• Screening for viral infection including- HBsAg,
anti-HBc, anti- HCV, HIV-1 and HIV-2
• ECG and echocardiography
18. Pre-medication and rituximab
administration
• Premedications:
hydrocortisone 100 mg iv + pheniramine
maleate 22.75 mg iv + PCM 500 mg PO 30
min prior to infusion
• First infusion is administered at a rate of
50mg/h IV, escalated every 30min by 50mg/h
to a maximum infusion rate of 400mg/h,
total infusion time: 5–6h.
• Subsequent infusions are initiated at
100mg/h, with a 30-min escalation of 50mg/h
to a maximum infusion rate of 400mg/h.
19. Rituxan is a sterile, clear, colourless, preservative-free liquid
concentrate for IV administration.
Rituxan is supplied at a concentration of 10 mg/mL in either
100 mg (10 mL) or 500 mg (50 mL) single-use vials
• Reditux 100 mg(Rs. 10,000), 500 mg(Rs. 40,000)
20. Protocols
• Lymphoma protocol:
375mg/sqm BSA wkly for 4 wks
• RA protocol:
1 gm every 15 days
• Combination therapy:
combined with IVIG, immunoadsorption,
dexamethasone pulse therapy
Rheumatoid arthritis protocol is increasingly
used
21. ADVERSE EFFECTS
• Most comman a/e are infusion related like fever
and rigors. Others being flu like symptoms,
nausea, vomitting, abdominal pain,
hypotension.
• Treatment related s/e occurred most frequently
at first infusion(65%) and less often during 2nd
(15%), 3rd(5%) and 4th (5%) infusions.
• Other a/e like serious infections, SJS, TEN, sinus
tachycardia, dysrythmias, myocardial ischemia,
progressive multifocal leucoencephalopathy are
22. MANAGEMENT OF ADVERSE
REACTIONS
• In immediate reactions – treatment should be
discontinued. If possible after waiting for 30
mins rituximab infusion can be continued at
slow rate(half the initial rate). cortisone and
antihistamines should be readministered
23. BLyS INHIBITOR
(BELIMUMAB)
• BLyS family of proteins and their receptors plays a
key role in the survival and development of B
lymphocyte into mature B cells that produce
antibodies
• An over expression of BLyS in patients with SLE has
been observed with potential correlation between
serum levels of BLyS and SLE disease activity
• Belimumab is a fully human monoclonal antibody
that binds BLyS ,inhibits BLyS stimulation of B cell
development and finally restores the potential for
24. INDICATION
• Cases of SLE resistant to treatment or
frequently relapsing even after treatment with
corticosteroids, antimalarials,
immunosupressives and non steroidal anti-
inflammatory drugs
25. AVAILABILITY AND DOSING
• Premedications – antihistamines and
corticosteroids for prophylaxis against infusion
and hypersensitivity reactions
• Available as 120mg/vial and 400mg/vial
• Reconstituted in 0.9%NS and infused IV over
1 hr
Dose – 10mg/kg iv every 2 wks for 3 doses
Maintenance – 10 mg/kg iv every 4 wks
Cost for 1 yr treatment – 28000$ (1700000
26. Adverse effects
• Infusion related reactions like nausea, pyrexia,
skin rash, diarrhea are comman
• Other less comman A/E are nasopharyngitis,
bronchitis, insomnia, serious infections, pain
in extremities, depression, migraine
• Anaphylaxis and serious infusion reactions are
rare
• Pregnancy cat C drug
27. BIOLOGICALS FOR SLE
• Anti CD20 Ab – Rituximab, ocrelizumab
• Anti B lymphocyte stimulator – Belimumab,
Atacicept
• Anti CD22 Ab – Epratuzumab
• Anti CD11a Ab – Efalizumab
• Anti TNF alpha Ab – Infliximab, Etanercept,
Adalimumab, Certolizumab, Golimumab
• Anti IFN alpha Ab – sifalimumab, rontalizumab
• Anti IL1 Ab – Anakinra
• Anti IL6 Ab - Tocilizumab
• CD28-B7 interaction blocker – Abatacept
• Tolerogens – Abetimus, Edratide
28. DENILEUKIN DIFTITOX (
ONTAK )
It is an antineoplastic agent
consisting of a fragment of diphtheria toxin,
(which is involved in translocation and adenosine
diphosphate ribosyltransferase activity) , fused to
IL-2
29. • MOA – malignant cells of some leukemias and
lymphomas express IL2 receptors
-DENILEUKIN DIFTITOX binds to this IL-2
receptors and introduce diptheria toxin into
the cells, thus causing apoptosis of this
malignant cells
-inhibition of protein synthesis and cell
death
30. FDA approved –
Persistent or recurrent cutaneous T-cell
lymphoma (stage 3 and 4)
Administered -18 mcg/kg/day by iv infusion
over 30-60 minutes for 5 consecutive days every
21 days for 8 cycles
INDICATIONS
31. Anti IgE: Omalizumab
• It’s a recombinant, humanized, monoclonal
antibody against immunoglobulin IgE,
representing a unique approach for the
treatment of allergic diseases
• Prevents IgE from binding to its high affinity
mast cell receptor prevents mast cell
degranulation
33. • Omalizumab is approved for the treatment of
moderate to severe persistent asthama in
adults and adolescents older than 12 years of
age who have positive skin test to a perrenial
antigen
• It can be used in treatment of chronic
idiopathic urticaria and atopic dermatitis who
remain symptomatic despite of H1
antihistamine treatment
INDICATIONS
34. AVAILABILITY AND DOSAGE
• Doses: 150-375 mg SC at 2-4 wkly interval
• Available as Xolair (novartis), 150 mg/1.2ml inj
• Cost – 541$ (32,460 INR) for 150mg inj
35. First-line:
Second-generation H1-antihistamines
If symptoms persist after 2 weeks
Second-line:
Increase dosage of second generation
H1-antihistamines up to four-fold
If symptoms persist after further 1–4 weeks
Third-line:
Add omalizumab, cyclosporine A or leukotriene
antagonist
Short course (maximum 10 days) systemic corticosteroids may be used
at all times if exacerbations demand it
36. Second generation H1 Antihistamine (sgAH)
Increase sgAH (up to 4x)
Add Omalizumab, Cyclosporine, leukotriene
Antagonist
Short course of systemic corticosteroid may be tried for
exacerbations
If symptoms persist after 2 weeks
If symptoms persist after 1-4 weeks
Add Methotrexate, Dapsone, Autoserum therapy ,
H2 antihistamines
Indian Guidelines