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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 + +