Disclosure Statement The science and use for patient success...serious disorders. Fitzgerald Health...

Fitzgerald Health Education Associates 1 1

An Introduction to Biologics: The science and use for patient success

Victor Czerkasij, MA, MSN, FNP-CAssociate Lecturer

Fitzgerald Health Education AssociatesNorth Andover, MA

Skin Cancer and Cosmetic Dermatology, Dalton, GA and Cleveland, TN

Adjunct Faculty, Vanderbilt University

Disclosure Statement

• Abbvie Speaker’s Bureau

Fitzgerald Health Education Associates 2

Objectives

• By the end of the presentation, the participant will be able to:– Describe and understand the role of

cytokines and interleukins in the pathophysiology of psoriasis and list approved treatments for psoriasis that target these specific proteins.

– Understand efficacy data and safety issues associated with biologics.


Objectives(continued)

• By the end of the presentation, the participant will be able to: (cont.)– Differentiate TNF-α inhibitors with each

other and with other therapies based on the mechanism of action, efficacy, safety and clinical use.

– Describe the effects of comorbidities associated with psoriasis and how biologics relate to them.


References

Additional references at end of presentation


What is psoriasis?

• Hyperactive skin cell production– Normal cycle is 311 hours– In psoriasis – 36 hours

• Formerly considered skin disease only– Now understood as a specific skin

presentation due to elevated levels in the body of a protein known as TNF-a


No Shortage of OTC “Cures”


Persistent Inflammation


Scalp Psoriasis


Psoriasis on the Trunk


Nail Pitting and Onychorrhexis


Psoriatic Arthritis


Chronology of Psoriasis Treatments

• 1890s– Topical iron and cod liver oil application

• 1920s – Topical 5% coal tar followed by UVB

radiation (Goeckerman regimen)

• 1950s – Oral, topical, IV steroids


Chronology of Psoriasis Treatments

• 1970s – Oral methotrexate

• 1980s– Oral retinoids

• 1990s– Topical calcipotriene and oral cyclosporine


Classic Psoriasis Step Treatment

• Topical: Calcipotriene and steroid• Targeted laser or phototherapy• Oral regimen• TNF-a or interleukin antagonist (biologic)• Oral with biologic


Topical Treatment in Psoriasis


PUVA Treatment


Laser Treatment in Psoriasis


Oral Treatments


Biologics


Basics on Biologics

• Fastest growing class of drugs in the pharmaceutical industry– Enormous strides in cancer and

autoimmune disorders with intense targeting and selectivity of disease

– Staggering costs, cripplingadverse effects

• 1982 recombinant insulin first biologic


How Biologics are Made

• Disease-fighting protein spliced into cells of a living organism– Cells extracted from living organism– Cells multiply into large quantities

• Finally, the desired proteins are extracted and purified into a biologic medicine, and reintroduced into host


Biologic manufacturing is complex.


The 1994 Psoriasis/TNF Connection

• Study by Ettehadi P et al. “Elevated TNFa biological activity in psoriatic skin lesions” Clin Exp Immunol– Revealed high levels of TNFa in

psoriasis samples– Using anti-TNFa antibodies

showed conclusive evidence oflessened inflammation


The Challenge of Treatment


Tumor Necrosis Factor • Tumor necrosis factor (TNF) is a cell-

signaling protein AKA cytokine, that is involved in systemic inflammation.– TNF is one of the cytokines that make up

the “acute phase” response.

• TNF is produced by many types of cells including white blood cells, neutrophils, mast cells and eosinophils.


The Good News of TNF

• TNF works against bacteria, viruses, tumors, parasites and in cancers by inflammatory and suppressive means– It stimulates proliferation of other

antiinflammatory cytokines.

• TNF has a very important and active role in a healthy immune system.


The Bad News of TNF

• Overexpressionof TNF disruptsthe normalimmune response.

• Elevated levels of TNF are found in multiple chronic immune-mediated diseases.


Tumor Necrosis Factor-alpha

• Although initially discovered as an anticancer agent, TNF-α and its family members have now been linked to an array of conditions, including cancer, neurologic diseases, cardiovascular diseases, pulmonary diseases, autoimmune diseases and metabolic diseases when overexpressed.


TNF Implicated in Multiple Conditions


The Proliferation of TNF


Interleukins

• Much like TNF-a, these are also proteins or cytokines that are expressed in the inflammatory process of psoriasis

• Generally a smaller group than TNF-a• Very specific target in attempt to

lessen the adverse effects profile


The FDA Definition of a Biologic

• “Biologics are genetically-engineered proteins derived from human genes (living cells). They are designed to inhibit specific components of the immune system that play pivotal roles in fueling inflammation, which is a central feature of psoriasis.”


The Goldilocks Conundrum

• How can we balance an immune system dysfunction with an immunomodulator, without inducing any immune-system adverse effects?

• The key is: TARGETING


BiologicsWhy IV or injections?

• Because they do not have preservatives, biologics are extremely sensitive to heat and light.

• Biologics are easily destroyed by gastric acid, which negates the oral route.

• Generally safe in breast-feeding


“Biologics Affect the Immune System”

• Hopefully, yes. – The over expression of TNF is ruinous to

the body long-term.

• Hopefully, no. – Because biologics suppress the immune

system response, patients taking these drugs have an increased risk of infection.


Drugs vs. Biologics • A drug is a chemical synthesis between

specific ingredients.– Biologics are manufactured in living

systems (i.e., cells, using DNA technology)

• The “product is the process.”– Sensitive cells can affect final product and

how it functions in the body.

• Extremely expensive for consistencyFitzgerald Health Education Associates 37

Quick Goals to Attain

• Most trials report patients feeling better as early as their first or second injection.

• Biologics are not a cure, but slow the progression of the disease.

• Main goals are to reduce plaques, lessen morning joint stiffness and tenderness.


Can biologics be combined?

• Great question• No• Never• Next slide


What can be used with biologics?

• Methotrexate– Discussion

• Steroid– Discussion

• Cyclosporine– Not recommended due to renal toxicity

• Any patient on concomitant therapy has increased risks of multiple infections or serious disorders.


Biologics and Vaccines

• Live vaccines are contraindicated when using biologics because of lower vaccine immunogenicity.– Initiate vaccinations three months prior to

beginning biologics

• Vaccines OK during treatment if not live or inactivated, ie, pneumococcal, influenza, tetanus toxoid


Biologics with Surgery, Conceptionand Pregnancy

• A difficult discussion• General practice is to stop biologic

therapy up to a month before andafter surgery.

• Conception and pregnancy is a discussion of risk and benefit but a review of studies deems generally safe.


Preparing the Patient for a Biologic

• PPD/QuantiFERONTB Gold test

• CBC, CMP,lipid panel

• Why not ESR/ANA/SS-Aor SS-B?

• Chest x-ray• Hepatitis B, C


Traditional Systemic (Oral)Treatments for Psoriasis

• Acitretin (Soriatane®)– Adults with severe psoriasis not planning

to conceive– Two forms of birth control for women of

childbearing potential– 10 mg to 50 mg/day, once a day– Teratogenicity, liver, renal and

hyperlipidemia considerations



(continued)

• Cyclosporine (Neoral®)– Severe recalcitrant psoriasis– 2.5 mg/kg/day in two divided doses– Nephrotoxicity, hypertension,

contraindicated with PUVA, coal tarand immunosuppressant agents


Lab Orders

• Baseline CBC, CMP, and lipids• HIV, Hep B and Hep C• Chest x-ray and when to repeat• PPD/QuantiFERON• Methotrexate/cyclosporine/acitretin• When to repeat?



(continued)

•Methotrexate (Rheumatrex®)– Severe recalcitrant disabling psoriasis,

classic DMARD–5–25 mg weekly with daily 1 mg folic acid–Myelosuppression, hepatotoxicity, nausea,

fatigue, pulmonary fibrosis


Established Biologics

• Adalimumab (Humira®)– Ten indications currently from age 2 years

and up, and when other systemic indications are not appropriate

– Indicated in psoriasis and psoriatic arthritis– 80 mg subcutaneous first week and then

40 mg subq q other week


Established Biologics(continued)

• Alefacept (Amevive®)– Blocks T-cells– 15 mg IM weekly for 12 week cycles– Moderately successful for psoriasis

• No activity against psoriatic arthritis


• Etanercept (Enbrel®)– 50 mg subq twice a week for three

months, then weekly– Very commonly used in conjunction

with methotrexate– Temptation to use 50 mg subq after

three month period



• Golimumab (Simponi®)– 50 mg monthly subcutaneously– Not approved for plaque psoriasis– Most likely used in rheumatology



• Infliximab (Remicade®)– 5 mg/kg by IV at week 0, 2, 6, and then

every 8 weeks– Hospital setting or infusion center– Continues to show strong performance

over the years in chronic severeplaque psoriasis



(continued)

• Ustekinumab (Stelara®)– An interleukin and targets IL 12 and 23

for psoriasis and psoriatic arthritis– Weight based at 45 mg and 90 mg

subcutaneously every three months after initial bolus

– Remarkably low serious adverseeffects profile



(continued)

• Secukinumab (Cosentyx®) and ixekizumab (Taltz®)– New interleukins which target IL 17a – Secukinumab

• Weight based 150 mg/300 mg subq once a week for 5 weeks, then once a month for psoriasis and psoriatic arthritis



(continued)

• Secukinumab and ixekizumab (cont.)– Ixekizumab is subq two weeks for first 12

weeks, then every four weeks – Most common adverse effects in

clinical trials• Injection site reactions, upper respiratory

infections, nausea and fungal skin infections

– Ps/PsA coverage, high clearance rates



(continued)

Comment on NonbiologicApremilast (Otezla®)

• Unique oral PDE4 inhibitor, apremilastmaintains increased level of cAMP(cyclic adenosine monophosphate)

• Antagonistic effect on prior production of TNF-α and IL-2

• Interrupts the inflammatory cascade earlier as “small molecule”


The Risks of Biologics

• Serious infections much increased with concomitant immunosuppressants(i.e. methotrexate and corticosteroids)

• TB, fungal infections, bacterial and viral• Avoid pt with history of chronic infections• Lymphoma in pediatric population


Most Common Biologic Adverse Effects

• Injection site reaction• Sinusitis• Headache following injection• Diffuse rash on trunk


Why do some biologics lose efficacy?

• Immunogenicity– All foreign proteins are immunogenic by

definition, even those given for therapeutic reasons.

• These are called anti-drug antibodies(ADA) and rates are listed in literature.– Again, we are learning more about

immune system responses.


Why do some biologics lose efficacy? (continued)

• Suboptimal dosing• Lower serum drug levels• Intermittent or episodic therapy• Patient weight• Evolving theory

– Disease evolves within patient, requiring evaluation of the pathway treatment


When should we consider changingto another biologic agent?

• The adverse effect profile isnot tolerated.

• Lack of improvement after four months• Multiple flares• It doesn’t make sense to move from a

TNF-a antagonist that is not performing to another TNF-a– Consider the newer interleukins


The Saga of Psoriasis

• Most likely confused with leprosy throughout history

• Classic “skin” disease with serious systemic consequences

• What does constant inflammation mean?


Classic Psoriatic Comorbidities

• Cancer• Obesity• Atherosclerosis• Metabolic disease• Increased mortality• Dyslipidemia• Hypertension

• Complicationswith diabetes

• Myocardial infarction

• Stroke• Sexual dysfunction• Depression• CVD


The Risk of Status Quo

• We need to move from seeing psoriasis as a skin disorder with occasional flares, to treating psoriasis/psoriatic arthritis as it’s own serious disease akin to diabetes, congestive heart failure or COPD. The longer a systemic condition is undertreated, the greater the damage to the organs of the body.


Key Unintended Discovery

• The comorbidity, malignancy and death rate in psoriatic patients is higher than average in US population.

• In trials of patients on biologic therapy, all rates referenced above decreased to expected norms associated with the general population.


TNF and the Golden Spice

•Curcumin (diferuloylmethane) is isolated from turmeric.–Study shows it can block TNF-a and

suppress TNF production

•Also shown to inactivate TNF-aby binding–Currently in clinical trials


Observation on Biosimilars

• A generic drug is chemically identical to the branded counterpart.– A biosimilar is not

• Biologics can never be exactly replicated due to their inherent variability and status as living cells derived from DNA technology.


Observation on Biosimilars(continued)

• No less expensive to create• Safety will be projected and assumed.


Knowledge is power.


Summary

• TNF is a potent source of systemic inflammation and in psoriasis

• A lifetime condition requires alifetime treatment.

• Psoriasis often underrated• All conversations must begin and end

with risk vs. benefit• Biologic science very much the future


End of Presentation

Thank you for your time and attention.

Victor CzerkasijMA, MSN, FNP-C

www.fhea.com [email protected]


References

• Aggarwal BB. “Signaling pathways of the TNF superfamily: A double-edged sword.” Nat Rev Immunol (2003) 3(9):745-756.

• Baker C, Mack A, Cooper A, et al. “Treatment goals for moderate to severe psoriasis: An Australian consensus.” Australas J Dermatol (2013) 54(2):148-154


References(continued)

• Balkwill F. “TNF-alpha in promotion and progression of cancer.” Cancer Metastasis Rev (2006) 25(3):409-416.

• Bhardwaj A, Aggarwal BB. “Receptor-mediated choreography of life and death.” J Clin Immunol (2003) 23(5):317-332.

• Boehncke, Wolf-Henning, and Michael P. Schön. "Psoriasis." The Lancet 386.9997 (2015) 983-94.



• Brezinski EA, Dhillon JS, Armstrong AW. “Economic burden of psoriasis in the United States: a systematic review.” JAMA Dermatol (2015) 151(6):651-658

• Coley WB. “The treatment of malignant tumors by repeated inoculations of erysipelas: With a report of ten original cases.” Am J Med Sci. (2014) 1893;105:487–511.



• Doherty SD, Van Voorhees A, Lebwohl MG. National Psoriasis Foundation consensus statement on screening for latent tuberculosis infection in patients with psoriasis treated with systemic and biologic agents. National Psoriasis Foundation. J Am Acad Dermatol. (2012) Aug; 59(2):209-17. Epub (2012) May 15.


• Enamandram M, Kimball AB. ”Psoriasis epidemiology: The interplay of genes and the environment.” J Invest Dermatol. (2013) 133(2):287-289.

• Ettehadi, P et al. “Elevated tumour necrosis factor-alpha (TNF-alpha) biological activity in psoriatic skin lesions.” Clinical ExpImmunology, (1994) Apr(1):146-51.



• Fathi R, Armstrong AW. The Role of Biologic Therapies in Dermatology. Med Clin North Am. (2015) Nov; 99(6):1183-94. Epub(2015) Sep 2.

• Gaele, Kirk, Martin Henriksson, and Marcus Schmitt-Egenolf. "Evaluating Equality in Psoriasis Healthcare: A Cohort Study of the Impact of Age on Prescription Biologics." British Journal of Dermatology 174.3 (2016) 579-87.



• Gaur U, Aggarwal BB. “Regulation of proliferation, survival and apoptosis by members of the TNF superfamily.” BiochemPharmacol (2003) 66(8):1403-1408.

• Hsu S, Papp KA, Lebwohl MG, et al. “Consensus guidelines for the management of plaque psoriasis.” Arch Dermatol(2012)148(1):95-102.



• Kalb, R., D. Fiorentino, M. Lebwohl, et al. "Modelled Analysis of Serious Infection Risk in the Treatment of Psoriasis with Biologics and Systemic Treatments in the Psoriasis Longitudinal Assessment and Registry (PSOLAR)." British Journal Of Dermatology173 (2015): 63-64.



• Langan SM, Seminara NM, Shin DB, et al. “Prevalence of metabolic syndrome in patients with psoriasis: A population-based study in the United Kingdom.” J Invest Dermatol. (2012) 132 (3, pt 1):556-562.



• Lebwohl MG, Kavanaugh A, Armstrong AW, Van Voorhees AS. “US perspectives in the management of psoriasis and psoriatic arthritis: Patient and physician results from the population-based Multinational Assessment of Psoriasis and Psoriatic Arthritis (MAPP) survey.” Am J Clin Dermatol(2016) 17(1):87-97



• Leonardi C, Papp K, Strober B, et al. "The Long-term Safety of Adalimumab Treatment in Moderate to Severe Psoriasis." American Journal of Clinical Dermatology (2011) 12.5: 321-37.

• Locksley RM, Killeen N, Lenardo MJ. “The TNF and TNF receptor super families: Integrating mammalian biology.” Cell (2011) 104 (4): 487–501.



• Menter A. “The status of biologic therapies in the treatment of moderate to severe psoriasis.” Cutis. (2013) Oct; 84(4 Suppl):14-24.

• Micu MC, Micu R, Surd S, Gîrlovanu M, Sorana DB, and Ostensen M. "Tnf-α inhibitors do not impair sperm quality in males with ankylosing spondylitis after short-term or long-term treatment." Rheumatology 53.7 (2014): 1250-255.



• Novelli L, Sole Chimenti M, Chiricozzi A, Perricone R. “The new era for the treatment of psoriasis and psoriatic arthritis: Perspectives and validated strategies”Autoimmunity Reviews, (2015) Volume 13, Issue 1, Pages 64-69




• Papp KA, Dekoven J, Parsons L, Pirzada S, Robern M, Robertson L, Tan KL. “Biologic therapy in psoriasis: Perspectives on associated risks and patient management.” Journal of Cutaneous Medicine and Surgery. (2012) May-Jun;16(3):153-68.

• Razmaria A. "Psoriasis and the Risk of Depression in the US Population: National Health and Nutrition Examination Survey 2009-2012." Jama 315.13 (2016): 1410.


• Sivamani RK, Goodarzi H, Garcia MS, Raychaudhuri SP. “Biologic therapies in the treatment of psoriasis: A comprehensive evidence-based basic science and clinical review and a practical guide to tuberculosis monitoring.” Clin Rev Allergy Immunol. (2013) Apr; 44(2):121-40.



• St-Pierre J, Chadee K. ”How the Discovery of TNF-α Has Advanced Gastrointestinal Diseases and Treatment Regimes.” Dig Dis Sci (2014) 59:712.



• Svedbom A, Dalén J, Mamolo C, CappelleriJC, Petersson IF, and Ståhle M. "Treatment Patterns with Topicals, Traditional Systemicsand Biologics in Psoriasis – A Swedish Database Analysis." Journal of the European Academy of Dermatology and Venereology29.2 (2015): 215-23.



• Taylor WJ. ”Impact of psoriatic arthritis on the patient: through the lens of the WHO International Classification of Functioning, Health, and Disability.” Curr Rheumatol Rep. (2012) 14(4):369-374.



• Images/Illustrations: Unless otherwise noted, all images/ illustrations are from open sources, such as the CDC or Wikipedia or property of FHEA or author.

• All websites listed active at the time of publication.


Copyright Notice

Copyright by Fitzgerald Health Education AssociatesAll rights reserved. No part of this publication may be reproduced or transmitted

in any form or by any means, electronic or mechanical, including photocopy, recording or any information storage and retrieval system, without permission

from Fitzgerald Health Education Associates

Requests for permission to make copies of any part of the work should be mailed to:

Fitzgerald Health Education Associates85 Flagship Drive

North Andover, MA 01845-6184


Statement of Liability

• The information in this program has been thoroughly researched and checked for accuracy. However, clinical practice and techniques are a dynamic process and new information becomes available daily. Prudent practice dictates that the clinician consult further sources prior to applying information obtained from this program, whether in printed, visual or verbal form.

• Fitzgerald Health Education Associates disclaims any liability, loss, injury or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents of this presentation.


Fitzgerald Health Education Associates

85 Flagship Drive

North Andover, MA 01845-6154978.794.8366 Fax-978.794.2455

Website: fhea.com

Learning & Testing Center: fhea.com/npexpert

www.facebook.com/fitzgeraldhealth

@npcert


Biol

ogic

man

ufac

turin

g is

com

plex

.

Fitz

gera

ld H

ealth

Edu

catio

n As

soci

ates

23

The

Chal

leng

e of

Tre

atm

ent

Fitz

gera

ld H

ealth

Edu

catio

n As

soci

ates

25

TNF

Impl

icat

ed in

Mul

tiple

Con

ditio

ns

Fitz

gera

ld H

ealth

Edu

catio

n As

soci

ates

30

The

Prol

ifera

tion

of T

NF

Fitz

gera

ld H

ealth

Edu

catio

n As

soci

ates

31

Disclosure Statement The science and use for patient success...serious disorders. Fitzgerald Health...

Documents

Transcript of Disclosure Statement The science and use for patient success...serious disorders. Fitzgerald Health...