Psoriasis: Which Drug for Which Patient?

Mark Lebwohl, MD

Sol and Clara Kest ProfessorAnd Chairman

Kimberly and Eric J. Waldman Department of Dermatology

Icahn School of Medicine at Mount Sinai

DRUG PsA OBESITY CARDIAC CA +ANA LUPUS MS CROHNUC

HEPATITIS CAb +

HBsAg+ Anti-HBc+

ETANERCEPT + + + - + +/- X + +* - +/-*

ADALIMUMAB + + + - + +/- X + +* - +/-*

INFLIXIMAB + + + - + +/- X + +* - +/-*

CERTOLIZUMAB + + + - + + X + +* - +/-*

USTEKINUMAB + + + - + + + + - ?+/-* ?/+*

SECUKINUMAB + + ? +/- + + + X ?/+* ?+* ?/+*

IXEKIZUMAB + + ? +/- + + + X ?/+* ?+* ?/+*

BRODALUMAB + + ? +/- + + + X ?/+* ?+* ?/+*

GUSELKUMAB + + ? +/- + + + + ? ? ?

TILDRAKIZUMAB ?+ + ? +/- + + + + ? ? ?

RISANKIZUMAB ?+ + ? +/- + + + + ? ? ?

MIRIKIZUMAB ?+ + ? +/- + + + + ? ? ?

APREMILAST + + ? +/- + + + + ?/+* ? ?

METHOTREXATE + X + - + + + + X X X

CYCLOSPORINE +/- + ?/- X + +/- + + +/-* X X

ACITRETIN +/- + ?/- + + + + ? X + + +

Preferred treatment +

Second line +

Third line +

Inadequate data ?

avoid -

contraindicated X

Monitoring of liver function and viral titers required+ antiviral prophylaxis

*

Psoriasis: Which Therapy for Which Patient:

Psoriasis comorbidities and preferred systemic agents.

Kaushik SB, Lebwohl MG.

J Am Acad Dermatol. 2019;80:27-40.

Psoriasis: Which Therapy for Which Patient. Focus on

special populations and chronic infections.

Kaushik SB, Lebwohl MG.

J Am Acad Dermatol. 2019;80:43-53.

S

DRUG CHF Latent TB Pregnancy Pediatric HIV Speed Palm/Sole Pustular Erythrodermic

ETANERCEPT

ADALIMUMAB

INFLIXIMAB

CERTOLIZUMAB

USTEKINUMAB

SECUKINUMAB

IXEKIZUMAB

BRODALUMAB

GUSELKUMAB

TILDRAKIZUMAB

RISANKIZUMAB

MIRIKIZUMAB

APREMILAST

METHOTREXATE

CYCLOSPORINE

ACITRETIN

CONTRAINDICATIONS

REMICADE at doses >5 mg/kg should not be administered to patients with

moderate to severe heart failure. In a randomized study evaluating REMICADE

in patients with moderate to severe heart failure (New York Heart Association

[NYHA] Functional Class III/IV), REMICADE treatment at 10 mg/kg was

associated with an increased incidence of death and hospitalization due to

worsening heart failure (see WARNINGS and ADVERSE REACTIONS ,

Patients with Heart Failure ).

INFLIXIMAB LABEL: CHF

Randomized, double-blind, placebo-controlled, pilot trial of

infliximab, a chimeric monoclonal antibody to tumor

necrosis factor-alpha, in patients with moderate-to-severe

heart failure: results of the anti-TNF Therapy Against

Congestive Heart Failure (ATTACH) trial.

Chung ES, et al.

Circulation. 2003 Jul 1;107(25):3133-40.

• 10 mg infliximab group → more hospitalizations or death than placebo.

1. Chung ES et al. Circulation. 2003;107:3133-40.

Placebo

(n = 49)

Infliximab

5 mg/kg

(n = 50)

Infliximab

10 mg/kg

(n = 51)

Week 14 2 (4%) 2 (4%) 9 (18%)

Week 28 5 (10%) 4 (8%) 14 (27%)

ATTACH Trial

Death or Hospitalization in patients with NYHA class III - IV

Etanercept Label: CHF

PRECAUTIONS: Patients with Heart Failure

Two large clinical trials evaluating the use of ENBREL® in the treatment of heart failure were terminated early due to lack of efficacy. Results of one study suggested higher mortality in patients treated with ENBREL® compared to placebo. Results of the second study did not corroborate these observations. Analyses did not identify specific factors associated with increased risk of adverse outcomes in heart failure patients treated with ENBREL®. There have been post-marketing reports of worsening of congestive heart failure (CHF), with and without identifiable precipitating factors, in patients taking ENBREL®. There have also been rare reports of new onset CHF, including CHF in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age. Physicians should exercise caution when using ENBREL® in patients who also have heart failure, and monitor patients carefully.

Incidence of Congestive Heart Failure in

Adalimumab Pivotal Studies

Placebon (%)

Adalimumabn (%)

Prior history of CHFRelapse CHF

70 (0)

180 (0)

No prior history of CHFNew onset CHF

6835 (0.7)

1,3622 (0.1)

FDA AAC March 2003.

Heart failure in rheumatoid arthritis:

rates, predictors, and the effect of

anti-tumor necrosis factor therapy.Wolfe F, Michaud K.

Am J Med. 2004 Mar 1;116(5):305-11.

• Heart failure↑‘d in RA vs OA.

• Heart failure significantly less common in anti-TNF-treated patients.

• “Rheumatoid arthritis increases the risk of heart failure, which may be ameliorated by anti-TNF therapies.”

Treatment with tumor necrosis factor

blockers is associated with a lower incidence

of first cardiovascular events in patients with

rheumatoid arthritis.

Jacobsson LT, et al

Rheumatol. 2005;32:1213-8.

Anti-tumor necrosis factor alpha therapy and

heart failure: what have we learned and

where do we go from here? Khanna D et al.

Arthritis Rheum. 2004;50:1040-50 .

•NYHA I or II:Echocardiogram

ejection fxn<50%→no TNF blocker

•NYHA III or IV→ no TNF blocker

•new onset CHF→ hold TNF blocker

Association between biologic therapies for

chronic plaque psoriasis and cardiovascular

events: a meta-analysis of randomized

controlled trials.Ryan C, et al.

JAMA.2011;306(8):864-71.

Nonsignificant↑ in MACE events in

ustekinumab-treated patients

Results: Unadjusted Cumulative Rates of MACE per 100 Patient-Years (PY)

Based on any Exposure to Therapy or Within 91 Days of Therapy Administration

0.29(0.17, 0.47)

0.31(0.14, 0.62)

0.28(0.19, 0.40)

0.45(0.35, 0.58)

0.36(0.30, 0.43)

0.00

0.10

0.20

0.30

0.40

0.50

0.60

Ustekinumab Infliximab/

Golimumab*Other Biologics** No Biologic All

PSOLAR

8/2558 29/10341 61/13421 114/3181816/5497

0.34(0.23, 0.48)

0.38(0.22, 0.62) 0.33

(0.24, 0.44)

0.36(0.30, 0.43)

0.00

0.10

0.20

0.30

0.40

0.50

0.60

Un

ad

juste

d R

ate

s o

f M

AC

E

per

10

0 P

Y (

95%

CI)

Exposure Within 91 Days

Any Exposure

Ustekinumab Infliximab/

Golimumab*ADA/ETN** No Biologic All

30/8870 16/4205 43/13167 25/5576 114/31818

*Sponsor biologics, other than ustekinumab, approved for PsO &/or PsA; includes almost exclusively infliximab patients (n=1400); few patients were exposed

to golimumab (n=35). **95% (n=4374) are adalimumab &/or etanercept patients, with the remainder exposed to efalizumab, alefacept, or other non-sponsor

biologic.

0.45(0.29, 0.66)

Tuberculosis associated with infliximab, a tumor necrosis factor a -neutralizing agent.Keane J, et al.N Eng J Med 2001;345(15):1098-1104

• 70/147,000

• 48 < 3 infusions

• Test for TB!

Keane J, et al.

N Eng J Med 2001;345(15):1098-1104

• Tb has occurred with all of the TNF blockers

• Tb is commonly extrapulmonary in patients on TNF blockers

• Test for Tb before starting anti-TNF therapy

Risk and case characteristics of tuberculosis

in rheumatoid arthritis associated with tumor

necrosis factor antagonists in Sweden.

Askling J, Fored CM, Brandt L et al.

Arthr Rheum 2005;52:1986-1992.

• TB risk up to 4x

Tumor necrosis factor blockade in chronic murine

tuberculosis enhances granulomatous inflammation and

disorganizes granulomas in the lungs.

Chakravarty SD, et al

Infect Immun. 2008;76:916-26.

• Tumor necrosis factor-alpha is required in the protective

immune response against Mycobacterium tuberculosis

in mice.

Flynn JL, et al

• Immunity 1995;2:561-72.

TNF is necessary for normal granuloma

formation and function.

Risk of tuberculosis is higher with anti-tumor necrosis

factor monoclonal antibody therapy than with soluble tumor

necrosis factor receptor therapy: the three-year prospective

French research axed on tolerance of biotherapies registry.Tubach F et al.

Arthritis & Rheumatism 2009;60:1884-94.

• IFX: SIR 18.6

• ADA: SIR 29.3

• ETN: SIR 1.8

WARNING

RISK OF INFECTIONS TUBERCULOSIS (FREQUENTLY DISSEMINATED OR EXTRAPULMONARY AT CLINICAL PRESENTATION), INVASIVE FUNGAL INFECTIONS, AND OTHER OPPORTUNISTIC INFECTIONS, HAVE BEEN OBSERVED IN PATIENTS RECEIVING REMICADE. SOME OF THESE INFECTIONS HAVE BEEN FATAL (SEE WARNINGS ). PATIENTS SHOULD BE EVALUATED FOR LATENT TUBERCULOSIS INFECTION WITH A TUBERCULIN SKIN TEST. 1 TREATMENT OF LATENT TUBERCULOSIS INFECTION SHOULD BE INITIATED

PRIOR TO THERAPY WITH REMICADE.

Infliximab

WARNING

RISK OF INFECTIONS

Cases of tuberculosis (frequently

disseminated or extrapulmonary at clinical

presentation) have been observed in patients

receiving HUMIRA.

Patients should be evaluated for latent

tuberculosis infection with a tuberculin skin

test. Treatment of latent tuberculosis

infection should be initiated prior to therapy

with HUMIRA.

Adalimumab

TB Rates in Adalimumab Clinical Studies

1.3

0.08 0.13

0.0

0.5

1.0

1.5

2.0

EU North America EU

Ra

te p

er 1

00

pt-

yrs

Pre-screening Post-screening

# cases 7 3

Exposure (pt-yrs) 534 3978

6

4447

Etanercept PI

Patients need to be evaluated for tuberculosis risk factors and for latent or active tuberculosis infection with a tuberculin skin test both before and during treatment.

Cases of tuberculosis have occurred in patients who received etanercept; therefore, treatment of latent infection should be started before etanercept initiation.

Consider antituberculosis therapy before etanercept initiation in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed.

Some patients who tested negative for latent tuberculosis before etanercept receipt have developed active tuberculosis.

Low penetrance, broad resistance, and favorable

outcome of interleukin 12 receptor beta1 deficiency:

medical and immunological implications. Fieschi C,et al.

J Exp Med. 2003;197:527-35.

• 41 patients - IL12 receptor β1 deficiency

• Salmonellosis

• Tuberculosis

“Individuals genetically deficient in interleukin (IL)-

12/IL-23 are particularly vulnerable to disseminated

infections from mycobacteria (eg, nontuberculous,

environmental mycobacteria), salmonella (eg, nontyphi

strains), and Bacillus Calmette-Guerin (BCG)

vaccinations; consider appropriate diagnostic testing.

Evaluate for tuberculosis (TB) infection prior to, during,

and after treatment; do not administer to patients with

active TB. Consider anti-TB therapy prior to initiation in

patients with history of latent or active TB when an

adequate course of treatment cannot be confirmed.”

Ustekinumab PI

Essential role of IL-17A in the formation of a

mycobacterial infection-induced granuloma in the

lung.

Okamoto Yoshida Y, Umemura M, et al.

J Immunol. 2010;184(8):4414-4422.

• IL-17A deficiency may reduce

formation of granulomas

IL-23 compensates for the absence of IL-

12p70 and is essential for the IL-17 response

during tuberculosis but is dispensable for

protection and antigen-specific IFN-ɣ

responses if IL-12p70 is available.

Khader SA, Pearl JE, Sakamoto K, et al.

J Immunol. 2005;175(2):788-795.

• depletion of IL-17A–producing CD4+ T

cells →no effect on disease progression

during primary M. tuberculosis infection

Secukinumab in study patients with LTBI

• At BL, 25 subjects who received SKB w/ hx of pulmonary

TB, LTBI or a positive TB test

• negative QFN Gold at screening → No TB prophylaxis

• → No reactivation of TB; median SKB Rx 363 d.

Tsai T-F, et al. AAD 2015, P607 Sponsored by Novartis Pharma AG

No reactivation of tuberculosis in psoriasis

patients with latent tuberculosis infection while

on ixekizumab treatment: a report from 11

clinical studies

Elisabeth Riedl, Stefan Winkler, Wen Xu, Noah

Agada, Mark G Lebwohl

• Included 16 patients who developed +PPD?QFt p 52 w.

Presented at EADV2018 Paris poster 1827

Inborn errors of human IL-17

immunity underlie chronic

mucocutaneous candidiasis. Puel A, et al.

Allergy Clin Immunol. 2012;12:616-22.

“Pre-treatment Evaluation for Tuberculosis

Evaluate patients for tuberculosis (TB) infection prior to

initiating treatment with COSENTYX. Do not administer

COSENTYX to patients with active TB infection. Initiate

treatment of latent TB prior to administering COSENTYX.

Consider anti-TB therapy prior to initiation of COSENTYX

in patients with a past history of latent or active TB in whom

an adequate course of treatment cannot be confirmed.

Patients receiving COSENTYX should be monitored closely

for signs and symptoms of active TB during and after

treatment.”Secukinumab PI

Safety in Psoriasis Patients with Latent Tuberculosis (TB) Treated with Guselkumab and Anti-TB Treatments in the Phase 3 VOYAGE Trials

Luis Puig, Tsen-fangTsai, Tina Bhutani, Jonathan Uy, ParaneedharanRamachandran, Michael Song, Yin You, Melinda Gooderham, Mark Lebwohl

130 patients randomized to PBO, GUS or ADA at baseline tested positive for LTBI &

received concomitant anti-TB treatments.

No cases of TB reactivation

Presented at FC18

Tuberculosis

Evaluate all potential recipients of guselkumab for tuberculosis

infection before initiating treatment. Do not administer

guselkumab to patients with active tuberculosis infection. For

patients with latent tuberculosis, antituberculosis therapy

should be administered before initiating guselkumab. Consider

antituberculosis treatment for patients with a past history of

latent or active tuberculosis in whom an adequate course of

treatment cannot be confirmed. Monitor patients closely for

signs and symptoms of active tuberculosis infection during and

after treatment.[

Guselkumab PI

Apremilast Package Insert

No mention of tuberculosis

Late reactivation of spinal tuberculosis by

low-dose methotrexate therapy in a patient

with rheumatoid arthritis.Binymin K, Cooper RG

Rheumatology (Oxford).

2001;40:341-2.

Methotrexate and reactivation

tuberculosis.

Lamb SR.

J Am Acad Dermatol. 2004;51:481-2.

Impact of pulmonary and

extrapulmonary tuberculosis infection in

kidney transplantation: a nationwide

population-based study in Taiwan. Ou SM, et al

Transpl Infect Dis. 2012 Oct;14(5):502-9.

• “independent risk factors for post-

transplant TB included cyclosporine-

based immunosuppressant agents

during the first year after kidney

transplantation (odds ratio [OR]: 1.98,

P = 0.001)”

DRUG CHF Latent TB Pregnancy Pediatric Speed Palm/Sole Pustular Erythrodermic

ETANERCEPT -/+ +

ADALIMUMAB -/+ +

INFLIXIMAB -/+ +

CERTOLIZUMAB -/+ +

USTEKINUMAB + +

SECUKINUMAB + +

IXEKIZUMAB + +

BRODALUMAB + +

GUSELKUMAB + +

TILDRAKIZUMAB + +

RISANKIZUMAB + +

MIRIKIZUMAB + +

APREMILAST + +

METHOTREXATE + +

CYCLOSPORINE + +

ACITRETIN + +