Intensive material on psoriasis, its pharmacotherapy and recent advances and future prospects and non pharmacological therapy

1. DR. SIDDHARTHA
DUTTA

2.  Introduction
 Etiology
 Pathophysiology
 Current treatment options
 Challenges
 When to switch?
 Newer targets
 New molecules
 limitations
 Summary

3.  “Psora” means itch
 Term used since 133 AD, earlier was grouped with leprosy
until 19th century
 In 1881, Thin described psoriasis
 Psoriasis is a chronic inflammatory immune-mediated
disease of skin and joints affecting around 0. 5-1% of
children and 2- 3% of adults worldwide

4.  A chronic, non-contagious disease of the skin, in
which silvery white masses of epidermic scales
are attached, more or less firmly to a reddish
vascular base

5.  Plaque psoriasis(90%)
 Guttate
 Pustular
 Erythrodermic
 Inverse psoriasis
 Psoriatic arthritis
 Sites -knees, elbows, scalp, hands, feet, and
lower back.

6.  Idiopathic
 Stress
 Genetic(HLA-cw6)
 local trauma(koebner phenomenon)
 Infections (streptococcus, HIV)
 Drugs (beta-blockers, lithium, chloroquine)
 Sunlight
 Alcohol & smoking

8.  Topical corticosteroids
 Vitamin D analogues
 Anthralin
 Coal tar
 Retinoids
 Light therapy (phototherapy)
 Oral therapy

9. DRUG M.O.A INDI
CATI
ON
LIMITATIONS
CORTICOSTEROI
D
binds to cytosolic receptors
modulates the regulatory proteins
& silencing gene transcription for
proinflammatory proteins
Ps Thinning of the skin,
telangiectasia, diabetes,
hypertension and HPA
suppression
VIT D
ANALOUGUES
• Calcipotriene
• Calcitriol
Binds to cytoplasmic receptor &
translocates into nucleus
regulates transcription of genes,
cell differentiation and causes
inhibition of cell proliferation and
inflammation
Ps Skin irritation, redness
Rarely increased urinary
calcium level
ANTHRALIN
(dithranol)
induce release of ROS with an
inhibiting effect on proliferation of
keratinocytes and leucocytes
Ps discolouration of hair,
irritates the skin and it
stains virtually anything it
touches
dithranol-induced
dermatitis
COAL TAR ↓ DNA replication & makes the
skin more sensitive to UV light
(?)
Ps messy, stains clothing
and bedding, and has a
strong odour

10. DRUG M.O.A INDI
CATI
ON
LIMITATIONS
METHOTREXAT
E
DHFRase inhibitor Ps
PsA
Myelosuppression, mucositis
Hepatotoxicity, pul fibrosis,
Nephotoxic, neurotoxic
CYCLOSPORIN
E
Inhibits the activation of
NFAT &inhibition of gene
transcription of of IL-2 by
t cells
Ps Nephrotoxicity, hepatotoxicity,
HTN, DM, neurotoxicity, hirsutism
risk of infection increases
RETINOIDS normalizes DNA activity
in skin cells and may
decrease inflammation
Ps skin irritation, increase sensitivity
to sunlight
C/I- pregnancy & lactation
PHOTOTHERAP
Y
Induces apoptosis &
enhanced transcription
and expression of IL-10 in
keratinocytes
Ps redness, itching and dry skin
PUVA
(2 to 3 sessions a
week)
Psoralen sensitizes the
skin to uv rays
More aggressive therapy
Ps headache, burning and itching
wrinkled skin, freckles & skin
cancer

11.  long-term safe control of psoriasis remains a problem
 Cumulative toxic effects are a limitation of classical treatment
 Traditional topical therapy, phototherapy systemic therapy has
low compliance among patients
 Past decade, treatment development has been based on
mechanisms of pathogenesis
 Pathogenesis-based treatments with a selective and focused
action are likely to cause fewer side-effects

13.  The recommendation are
 Patients being considered for treatment with
biologics should have severe disease defined by a total
psoriasis area and severity index (PASI) score of 10 or
more (20 for infliximab)
 Ineligible for phototherapy or traditional
systemic treatment due to contraindications, intolerance
or previous treatment failure

14. PSORIASIS
MODERATE TO SEVERE
(>15% BSA)
nUVB/PUVA
Methotrexate
Cyclosporin
retinoids
MILD TO MODERATE
(<10% BSA)
Vitamin D analogue
Retinoid
Coal-tar
Corticosteroid
DithranolBIOLOGICS
1ST LINE
2ND LINE
3rd LINE

15. ANTI TNF α AGENTS IL-17 A
INHIBITORS
INFLIXIMAB
SECUKINUMAB
ETANERCEPT IXEKIZUMAB
ADALIMUMAB
CERTOLIZUMAB
GOLIMUMAB JAK INHIBITOR
TOFACITINIB
IL-12 & IL-23 INHIBITORS PDE4
INHIBITOR
USTEKINUMAB APREMILAST
APILIMOD
IL-17 A RECEPTOR INHIBITOR MISC.

16. brodalumab

17.  INFLIXIMAB
 ETANERCEPT
 ADALIMUMAB
 CERTOLIZUMAB
 GOLIMUMAB

18.  Ist biologic, approved by FDA in sept 2006
 Chimeric anti–TNF-α MAb
 5 mg/kg as IV infusion at 0, 2 and 6 weeks followed by a
every 8 weeks thereafter
 Ist 3 infusion under supervision
 Adverse effects-Infusion reaction
within 1-2 hours after Ab administration
 The development of ANA and rarely
a lupus-like syndrome
 RA, Chohn’s, UC, Ank. spond
 Off label- Behcet’s disease

19.  FDA approved in jan 2002
 TNF α receptor fusion protein
 Lesser efficacy than infliximab
 S.C. inj twice weekly
 50mg/week
 C/I- Multiple sclerosis, CHF, immunosuppression,
hepatitis B
 RA, Ank spond

20.  FDA approved in oct 2005 for PsA & in 2008 for
plaque psoriasis
 S.C inj 40mg once weekly every other week
 Better efficacy than infliximab & etanercept
 C/I- CHF,Multiple sclerosis
T.B, immunosupression
 S/e- lymphoma,
lupus like syndrome
 Malignancy rate is lower
 RA, Chohn’s, UC, Ank. spond

21.  FDA approved in sept 2013 for PsA
 S.C inj
 400 mg taken at week 0,week2,week4 then every
2 weeks thereafter
 78.4 % vs 6% with placebo
 S/E- T.B, CHF,
lupus like syndrome,
hep b reactivation
easy bruising
 RA, Crohn’s

22.  FDA approved in april 2009 for PsA
 S.C, 50 mg once a month
 S/e- T.B, increased risk of infection,
increased risk of bruising &bleeding
CHF, lymphoma,
lupus like syndrome,
hepatotoxicity
 RA

23.  Ustekinumab
 Apilimod

24.  FDA approved in sept 2009 for PsA in sept 2013 for plaque
psoriasis
 Human MAb that targets the p40 subunit of both interleukin
(IL)-12 and 23
 Inj S.C
 Two initial doses at week 0 and week 4, then once every 12
weeks
 Efficacious than most TNF a agents
 74% vs 57% with etanercept
 Dose- 45mg for 220 lb or less
90 mg for > 220 lb
 C/I- T.B, lymphoma & PML

25.  Phase 3
 p19 subunit of both interleukin (IL)-12 and 23
 Administered Orally
 Apilimod 70 mg daily achieved a PASI-50 at 12
weeks

26.  SECUKINUMAB
 IXEKIZUMAB

27.  FDA approved in jan 2015
 Anti-IL-17A monoclonal antibody
 Efficacious than etanercept
82.8 % vs. 44%
 300mg/dose
 S.C Inj once a week for first
5 weeks, then every 4 weeks thereafter
 Screened for latent T.B
 Nasopharyngitis, headache, diarrhoea, URI, rarely
neutropenia

28.  FDA approved on 22 march 2016 for Ps
 Phase 3 for PsA
 68 to 71 % achieved virtually clear skin (PASI 90)
 35 to 42 % saw complete resolution(PASI 100) at week 12
 87 percent vs. 41 percent for PASI 75 with etanercept
 Inj S.C.
 160mg stat then 80 mg every 2 week

29.  BRODALUMAB

30.  Anti IL-17 receptor A MAb for the treatment of moderate to
severe plaque psoriasis
 Phase 3 development
 The week 12 PASI 100 response rates
were significantly higher with
210 mg of brodalumab than with
ustekinumab (44% vs. 22%)
 Neutropenia were higher
than with ustekinumab

32.  Oral
 Janus kinase inhibitor
 Phase 3
 Aprroved for RA in 2012

33.  Fusion protein
 Fda approved in jan 2003 for psoriasis

34.  LFA-3 portion of alefacept binds to CD2 on T
lymphocyte
 blocks the interaction between LFA-3 and CD2
and interfering with T-cell activation
 15 mg IM or 7.5 mg IV per week
 S/E- lymphopenia,
skin cancers,
lymphomas, hepatotoxicity

35.  Inhibitor of PDE4
 March 2014, the US FDA approved apremilast for
psoriatic arthritis

36.  Inhibition of IL-2, IL-4, IL-13, IFN- g, TNF- a
 Effective and well tolerated in clinical trials
in psoriasis (phase III)
 30mg BD
 Better than etanercept,
but less potent than cyclosporine
 S/e- diarrhoea, nausea,
URI, headache & wt loss
 Has been linked to depression
and suicidal thoughts

37.  Anti CD-6 MAb
 Blocks the signaling and differentiation of T cells into Th1 & Th
17
 Pre-clinical studies have shown It inhibits intracellular
mitogen-activated protein kinase (MAPK) and signal
transducer and activator of transcriptor3 (STAT-3) which are
involved in intracellular signaling pathways triggered by CD6
 Downregulates gene transcription of pro-inflammatory
cytokines and adhesion molecules

38.  Available as 25 mg/5 mL vials for (IV) injection (brand name
Alzumab™)
 Administered as IV infusion
 1.6 mg/kg once every 2 weeks for 12 weeks
& 1.6 mg/kg once in 4 weeks until 24 weeks
 S/e- infusion reaction, URI, UTI, lymphopenia
 Risk of infection is less
 No data on cancers

40.  Narrow band UVB therapy(311-313 nm)
 More effective than broadband UVB treatment
 Usually administered 2 to 3 times
a week until the skin improves,
then maintenance may require
only weekly sessions
 Narrow band UVB therapy may cause
more severe and longer lasting burns

41. Goeckerman therapy –
Combination of UVB treatment and coal tar treatment
 The two therapies together are more effective than either alone
because coal tar makes skin more receptive to UVB light
 Once in three-week, inpatient basis
 Safe and reliable, even in patients unresponsive to other conventional
therapies
 Results in long-term remissions
Targeted phototherapy
 The excimer laser—recently approved by FDA
for treating chronic, localized psoriasis
 Emits a high-intensity beam of ultraviolet light B (UVB)

42.  Voclosporin phase 3 Calcineurin inhibitor
 AN2728 phase 1 PDE-4 inhibitor
 Baricitinib phase 2 JAK inhibitor
 ASP015K phase 2 JAK inhibitor
 Ruxolintinib phase 1 JAK inhibitor
 CNTO 1959 phase 2 Anti-iL-23 (p19)
 MK-3222 phase 3 Anti-iL-23 (p19)
 SCH900222 phase 2 Anti-iL-23 (p19)
 APG2305 phase 2 Anti-iL-23 receptor

43.  Biologics do not cure Ps or PsA but can relieve symptoms and
may help to prevent further joint damage
 High cost(3000$ to 6000$ per month), a challenge especially
for early intervention
 Risk of infection is 20 to 40% higher than methotrexate
 CHF, MS, lupus- Most of the people improved after stopping
treatment, indicates the biologic drug was the cause
 Cancers of the breast, colon, skin, lymphoma
 Long-term risks of the biologics have not been identified yet