chronic inflammatory diseases3.proce.com/res/pdf/cid/cid.pdf · 2 objectives 1. summarize available...

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Chronic Inflammatory Disease: An Introduction

Developed by Mike Crowe, PharmD, MBA, CSP, FMPA &

Alissa Johnson, PharmD CandidatePresented by

Mike Crowe , PharmD, MBA, CSP, FMPA

Speaker Disclosure

Michael Crowe has nothing to disclose.

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Objectives

1. Summarize available treatments for the chronic inflammatory diseases (CIDs) rheumatoid arthritis (RA), plaque psoriasis, and Crohn’s disease.

2. Describe the etiology of CIDs.

3. Outline the pathophysiology of CIDs.

4. Explain the pharmacologic approach to treating CIDs.

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Chronic Inflammatory Diseases (CIDs)

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3

Immunology Introduction

Rheumatoid Arthritis

Inflammatory Bowel Disease

Psoriasis

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Tumor Necrosis Factor (TNF)‐α InhibitorsMedication Name

Drug ClassRoute


Plaque Psoriasis

Psoriatic Arthritis

Crohn’s Disease

Ulcerative Colitis

Remicade® (infliximab)

TNFα InhibitorIV

*, MTX

q 4‐8 wks*

q 8 wks*

q 8 wks*

q 8 wks*

q 8 wks

Enbrel® (etanercept)

TNFα InhibitorSC

q week*

q week

q week

Humira®(adalimumab)TNFα Inhibitor

SC

q 1 or 2 wks*

qowqow

*

qow*

qow

Simponi® [AriaTM] (golimumab)TNFα Inhibitor

SC [IV] [*], MTX

q 4 [8] wks

q 4 wks

*

q 4 wks

Cimzia®(certolizumab pegol)

TNFα InhibitorSC *

q 2 or 4 wks*

qow*

q 4 wks

Micromedex [database online]. Greenwood Village, CO: Truven Health Analytics ; 2017. http://www.micromedexsolutions.com/. Accessed February 8, 2017. Drugs@FDA [database online]. Silver Spring, MD: FDA; 2017. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed February 9, 2017.

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*Induction dose is indicated; MTX = dosed with methotrexate

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Specialty Medications for CIDsMedication Name

Drug ClassRoute


Plaque Psoriasis

Psoriatic Arthritis

Crohn’s Disease

Ulcerative Colitis

Kineret® (anakinra)

IL‐1 InhibitorSC

qd

Actemra® (tocilizumab)IL‐6 Inhibitor

SC [IV]

q 1 or 2 wks

Cosentyx® (secukinumab)IL‐17A inhibitor

SC *

q 4 wks* +/‐MTX

q 4 wks

Taltz™ (ixekizumab)

IL‐17A InhibitorSC *

q 4 wks

Stelara® (ustekinumab)

IL‐12/23 InhibitorSC, IV *

q 12 wks*

q 12 wks*

q 8 wks

Otezla® (apremilast)

PDE‐4 InhibitorPO *

bid*

bid



Specialty Medications for CIDsMedication Name

Drug ClassRoute


Plaque Psoriasis

Psoriatic Arthritis

Crohn’s Disease

Ulcerative Colitis

Xeljanz® [XR](tofacitinib)JAK Inhibitor

PO *

qd or bid

Rituxan® (rituximab)

CD20 of B cellIV

* , MTX

q 16‐24 wks

Orencia® (abatacept)

CD80/CD86 of T cellSC, IV

qw

Tysabri® (natalizumab)

Integrin AntagonistIV

q 4 wks

Entyvio® (vedolizumab)

Integrin Receptor Antagonist

IV *

q 8 wks*

q 8 wks



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Biologic Product Safety

Common Adverse Effects

• Infection • Upper respiratory tract

• Sinusitis

• Injection site reactions• Pain, redness, itching

• Infusion reactions

• Headache

Warnings/Precautions

• Serious infections

• Hepatitis B virus reactivation

• Allergic reactions

• Malignancies

• Moderate to severe CHF• TNFα Inhibitors

• Demyelinating disease

• Few drug interactions

Micromedex [database online]. Greenwood Village, CO: Truven Health Analytics ; 2017. http://www.micromedexsolutions.com/. Accessed February 8, 2017.

Self‐Administered Biologic Products

• Injection technique • Remove device from fridge for 15‐30 minutes prior to injection

• Wash and dry hands

• Select an appropriate injection site

• Do not inject into skin that is bruised, sore, red, or hard

• If you have psoriasis, do not inject directly into any lesions

• Rotate injection sites each time you inject

• Wipe the injection site with an alcohol swab and allow area to dry

• Inject using the technique appropriate for the specific device

• Dispose the device in a sharps disposal container immediately after use

• Do not rub the injection site


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Biologic Product Counseling Points

• Storage

• Avoid live vaccines during treatment

• Notify physician of signs/symptoms of the following:

• Infection

• Hypersensitivity

• Hepatitis B reactivation

• Heart failure

• Demyelination

• Malignancy

• Expectations 11


RHEUMATOID ARTHRITIS

Chronic Inflammatory Disease

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• Chronic autoimmune disorder of the joints

• Symmetrical presentation

• Painful inflammation

• Joint deformity

• 1.3 million affected in US

• Women > Men (3:1)

• Races equally affected

Singh JA, et al. American College of Rheumatology. Arthritis Care & Research. 2015;68(1):1‐25. Wahl K, Schuna AA. Rheumatoid Arthritis. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e. New York, NY: McGraw‐Hill; 2017.

Articular Presentation

• Pain/tenderness

• Swelling

• Morning stiffness

• Walking difficulties

• Joint deformity

Hands Wrists

Elbows Shoulders

Knees Ankles

14Singh JA, et al. American College of Rheumatology. Arthritis Care & Research. 2015;68(1):1‐25. Wahl K, Schuna AA. Rheumatoid Arthritis. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e. New York, NY: McGraw‐Hill; 2017.

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Pathophysiology

Immune System Fails to Recognize

Self

Increased Inflammatory Response

Inflammation of Synovial Tissues

Cartilage and Bone Erosion

15Singh JA, et al. American College of Rheumatology. Arthritis Care & Research. 2015;68(1):1‐25.

Symptomatic Therapies

Non‐Steroidal Anti‐Inflammatory Drugs

(NSAIDs)Corticosteroids

Disease Modifying Antirheumatic Drugs (DMARDs)

Traditional DMARDs Biologics

Rheumatoid Arthritis Treatment Options

Singh JA, et al. American College of Rheumatology. Arthritis Care & Research. 2015;68(1):1‐25.

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DMARD monotherapy^

Combo DMARD tx (double/triple tx)‡^ orAnti‐TNF +/‐MTX^ or

Non‐TNF Biologic +/‐MTX^

LOW Disease Activity

MODERATE or HIGHDisease Activity

DMARD = disease modifying antirheumatic drug (includes hydroxychloroquine [HCQ], leflunomide [LEF], methotrexate [MTX], and sulfasalazine [SSZ])Anti‐TNF = anti–tumor necrosis factor (TNFα inhibitor)# Treatment target should ideally be low disease activity or remission^ Consider adding short‐term glucocorticoids (defined as <3 months) for RA disease flares‡ Combina on DMARD therapy with 2 DMARDs, which is most commonly MTX based, with some excep ons (e.g., MTX + HCQ, MTX + LEF, MTX + sulfasalazine, and sulfasalazine + HCQ), and triple therapy (MTX + HCQ + sulfasalazine)

American College of Rheumatology Guidelines

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Treat to Target#

Another Anti‐TNF +/‐MTX^ orAnother Non‐TNF Biologic +/‐MTX^ or

Tofacitinib +/‐MTX

Singh JA, et al. American College of Rheumatology. Arthritis Care & Research. 2015;68(1):1‐25. Adapted from Figures 3 and 5.

Counseling

Avoid pregnancy (women/partners) X X

Take with food X X

Hydrate and report renal toxicity X X

Urine/skin discoloration may occur X

Report vision changes X

May cause photosensitivity X X

Report rashes immediately X X

Hepatic toxicity X X X

GI toxicity X X

Hematologic toxicity X X X

MTX LEF SSZ HCQ

Traditional DMARD Counseling

18Micromedex [database online]. Greenwood Village, CO: Truven Health Analytics; 2017. http://www.micromedexsolutions.com/. Accessed February 9, 2017.

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TNFα Inhibitors

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Agent Route Dosing

Remicade®(infliximab)

IV • 3‐10 mg/kg at weeks 0, 2, and 6 then every 8 weeks

Humira®(adalimumab)

SC • 40 mg every week or every other week

Enbrel®(etanercept)

SC • 50 mg weekly or 25 mg sc twice weekly

Simponi®(golimumab)

SC • 50 mg monthly

Cimzia®(certolizumab

pegol)SC

• 400 mg at weeks 0, 2, and 4 then 200 mg every other week


Non‐TNFα Products

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Agent Route Dosing

Orencia®(abatacept)

IV/SC• IV: Adults weighing >100 kg: 1000 mg IV weeks 0, 2, and

4 then every 4 weeks after• SC: 125 mg once weekly with or without IV loading dose

Kineret®(anakinra)

SC • 100 mg once daily

Rituxan®(rituximab)

IV• 1000 mg on days 1 and 15; administer subsequent

courses every 16‐24 weeks

Actemra®(tocilizumab)

IV/SC

• IV: 4 mg/kg every 4 weeks • SC: Adults weighing <100 kg: 162 mg every other week;

may increase to weekly• SC: Adults weighing >100 kg: 162 mg weekly

Xeljanz®(tofacitinib)

PO• IR tablet: 5 mg twice daily• ER tablet: 11 mg once daily


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Health Assessment Questionnaire II (HAQ‐II)

• 10‐item validated questionnaire

• Common tool for measuring functioning status in rheumatology

• Looks at difficulty of completing common activities of daily living

Routine Assessment of Patient Index Data (RAPID) 3

• Validated patient questionnaire

• Uses the multidimensional HAQ (MD‐HAQ)

Patient Activity Scale (PAS)

• Validated patient questionnaire

• Includes the HAQ‐II

RA Treatment Goals and Efficacy Evaluation

21Singh JA, et al. American College of Rheumatology. Arthritis Care & Research. 2015;68(1):1‐25.

Menter A, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 1. J Am Acad Dermatol. 2008;58:826‐50

PSORIASISChronic Inflammatory Disease

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Psoriasis (PsO)

• Chronic, inflammatory, autoimmune disease of skin

• Hallmark sign is plaques

• Irritating, painful, emotionally debilitating

• Concurrent joint involvement

• Psoriatic arthritis (PsA)

• 7.4 million affected in US (~2% of population)

• Genders equally affected

• Prevalence difference by race

• Onset typically 15‐35 years of age

Rachakonda TD, Schupp CW, Armstrong AW. Psoriasis prevalence among adults in the United States. J Am Acad Dermatol. 2014;70(3):512‐516. Menter A, Gottlieb A, Feldman S, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 1: overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58(5):826‐50.

Pathphysiology

Inappropriate autoreactive

T-cell activation

Release of growth factors and

inflammatory cytokines

Increased rate of skin cell

proliferation

The skin cell cycle is shortened almost 10-fold, from an average of 311 hours to just 36 hours.

Tsuruta D. NF‐ĸB links keratinocytes and lymphocytes in the pathogenesis of psoriasis. Recent Pat Inflamm Allergy Drug Discov. 2009;3(1):40‐48. Nickoloff BJ, Nestle FO. Recent insight into the immunopathogenesis of psoriasis provide new therapeutic opportunities. J Clin Invest. 2004;113(12):1664–1675.

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Disease Severity

Mild psoriasis covers less than 3 percent of

the body

Mild

Moderate psoriasis covers between 3 and 10 percent of the body

Moderate

Severe psoriasis covers more than 10 percent

of the body

Severe

Mentor A, et al.; American Academy of Dermatology Work Group. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 6. J Am Acad Dermatol. 2011;65(1):137‐174. Thomas CL, Finlay AY. The “handprint” approximates to 1% of the total body surface area whereas the “palm minus the fingers” does not. Br J Dermatol. 2007;157(5):1080‐1081.

Topical

Creams & OintmentsLight

Therapy

Systemic

Traditional Oral Biologics

Psoriasis Treatment Options

26Menter A, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 3. J Am Acad Dermatol. 2009; 60(40):643‐656.Menter A, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 1. J Am Acad Dermatol. 2008;58:826‐50

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Treatment Guidelines

Menter A, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. J Am Acad Dermatol. 2008;58(5):826‐50. Saad AA, Symmons DP, Noyce PR, Ashcroft DM. Risks and benefits of tumor necrosis factor‐alpha inhibitors in the management of psoriatic arthritis: systematic review and metaanalysis of randomized controlled trials. J Rheumatol. 2008;35(5):883‐890.

Limited PsOTopicals or Targeted

Phototherapy

Lack of Effect

UVB/PUVA

Systemic

Biologic

Extensive PsO

UVB/PUVA

Systemic

Biologic

PsO with PsA TNFi +/‐MTX TNFi= tumor necrosis factor inhibitor; MTX = methotrexate; PsA = psoriatic arthritis

Topical and Oral Systemic Psoriasis Treatments

CategoryPotential Therapies

AAD‐Preferred Alternatives

Topical Therapies Retinoids (Tazorac®) Corticosteroids Vitamin D Analogs

‐Calcipotriene‐Calcitriol

Calcineurin Inhibitors KeratolyticsCoal tar Anthralin

Traditional Oral Systemic Therapies

MethotrexateCyclosporine Acitretin (Soriatane®)

LeflunomideSulfasalazine Tacrolimus Azathioprine Hydroxyurea Mycophenolate

28Menter A, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 3. J Am Acad Dermatol. 2009; 60(40):643‐656.Menter A, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. J Am Acad Dermatol. 2009; 61(3):451‐480.

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TNFα Inhibitor Therapies

Agent Route Dosing

Humira®(adalimumab)

SC• 80 mg at week 0 • 40 mg on week 1 and every other week

Enbrel®(etanercept)

SC• 50 mg twice weekly for 3 months then by

50 mg once weekly

Remicade®(infliximab)

IV• 5 mg/kg at 0, 2 and 6 weeks, then every 8

weeks

29Humira [package insert]. North Chicago, IL: AbbVie Inc.; 2016.Enbrel [package insert]. Thousand Oaks, CA: Immunex Corporation; 2016.Remicade [package insert]. Horsham, PA: Janssen Biotech, Inc.; 2015.

IL‐Targeting Therapies

Agent/Target Route Dosing

Taltz™(ixekizumab)

IL‐17ASC

• 160 mg at week 0• 80 mg at weeks 2, 4, 6, 8, 10, and 12 then 80 mg

every 4 weeks

Cosentyx®(secukinumab)

IL‐17ASC

• 300 mg weeks 0, 1, 2, 3, and 4 then 300 mg every 4 weeks A dose of 150 mg may be acceptable for some patients

Stelara®(ustekinumab)

IL‐12/23SC

For patients weighing ≤100 kg (220 lbs)•45 mg initially and 4 weeks later•45 mg every 12 weeks Use 90 mg for patients weighing >100 kg

30Taltz [package insert]. Indianapolis, IN: Eli Lilly and Company; 2017.Cosyntyx [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2016.Stelara [package insert]. Horsham, PA: Janssen Biotech, Inc.; 2016.

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PDE4‐Targeting Therapies

Agent/Target Route Dosing

Otezla®(apremilast)

PDE4PO

30 mg twice daily after completion of 5‐daytitration dosing:

• Day 1: 10 mg in AM• Day 2: 10 mg in AM, 10 mg in PM• Day 3: 10 mg in AM, 20 mg in PM• Day 4: 20 mg in AM, 20 mg in PM• Day 5: 20 mg in AM, 30 mg in PM

31Otezla [package insert]. Summit, NJ: Celgene Corporation; 2015.

Treatment Goals

Primary Goal

• Skin normalization

Secondary Goals

• Itching relief• Reducing flare-ups• Managing adverse events• Improving quality of life

Mrowietz U, Kragballe K, Reich K, et al. Definition of treatment goals for moderate to severe psoriasis: a European consensus. Arch Dermatol Res. 2011;303(1):1–10.Armstrong AW, Siegel MP, Bagel J, et al. From the medical board of the National Psoriasis Foundation: Treatment targets for plaque psoriasis. J Am Acad Dermatol. 2017;76:290‐8.

Treat‐to‐Target

• Body surface area (BSA)• Evaluate 3 months post-new

therapy• Acceptable response: BSA 3%

or less or 75% improvement in BSA

• Target response: BSA 1% or less

• Evaluate every 6 months during maintenance period

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INFLAMMATORY BOWEL DISEASES

Hemstreet BA. Chapter 41. In: DiPiro JT, et al. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw‐Hill; 2016.

Chronic Inflammatory Disease

Etiology

• Irritable bowel disease (IBD) most prevalent in Western Countries

• Crohn’s Disease (CD) Incidence

• 6 ‐ 15.5 cases per 100,000 persons/year

• Ulcerative colitis (UC) Incidence

• 1.2 ‐ 20 cases per 100,000 persons/year

• Males and females equally affected by IBD

• 20‐30% more women CD

• 60% more men UC


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Presentation

• Malaise and fever

• Mild abdominal cramping

• Frequent small‐volume bowel movements

• Weight loss and malnutrition

• Hematochezia common with colonic involvement


Distinguishing Factors

Ulcerative Colitis (UC)

• Any part of GI tract

• Discontinuous lesions

• Transmural process – Fistulas

– Perforations

– Strictures

Crohn’s Disease (CD)

• Confined to rectum and colon

• Continuous lesions

• Mucosa and submucosaaffected

Hemstreet BA. Chapter 41. In: DiPiro JT, et al. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw‐Hill; 2016. Kornbluth A, et al. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010: 501‐23.

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Topical

Enemas Suppositories

Systemic

Traditional Oral Biologics

IBD Treatment Options

37Lichtenstein GR, et al. Management of Crohn’s Disease in Adults. Am J Gastroenterol. 2009:1‐19.Kornbluth A, et al. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010: 501‐23.

Traditional IV

Surgical Intervention

Traditional Treatment Options

Medication Brand Name(s) Indication(s) Dose

Azathioprine Imuran® CD, UC 1.5–2.5 mg/kg per day orally

Budesonide Various CD, UC Varies by formulation

Cyclosporine Sandimmune® CD, UC 4 mg/kg per day IV continuous infusion

Mercaptopurine Purinethol® CD, UC 1.5–2.5 mg/kg per day orally

Mesalamine Various CD, UC Varies by formulation

Methotrexate Trexall® CD 15–25 mg weekly (IM/SC/orally)

Sulfasalazine Sulfazine® UC 3‐4 grams/day divided TID

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Appropriate treatment options and dosing vary based on disease location, severity, presence of complications, induction vs. maintenance

and other patient‐specific factors.


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TNFα Inhibitor Therapies

MedicationDrug Class

Route Dosing

Remicade® (infliximab)

TNFα InhibitorIV UC/CD: 5 mg/kg week 0, 2, and 6 then every 8 weeks

Humira®(adalimumab)TNFα Inhibitor

SCUC/CD: 160 mg on day 1, 80 mg at week 2, then 40 mg every other week

Simponi® (golimumab)TNFα Inhibitor

SCUC: 200 mg day 1, then 100mg two weeks later then every 4 weeks starting at week 6

Cimzia®(certolizumab

pegol)TNFα Inhibitor

SC CD: 400 mg at week 0, 2, 4, then every 4 weeks

39Micromedex [database online]. Greenwood Village, CO: Truven Health Analytics ; 2017. http://www.micromedexsolutions.com/. Accessed February 10, 2017.

Non‐TNF Inhibitor Biologics

40

Medication

Drug ClassDosing Counseling Points

Tysabri®

(natalizumab)CD: 300 mg IV every 4 weeks

• Available only through the TOUCH™

Prescribing Program (REMS program)

• Has been linked to cases of PML

• Report signs/symptoms of infection

• Report signs/symptoms of hepatotoxicity

Stelara®

(ustekinumab)

CD: Induction: ≤55 kg: 260 mg IV,

56‐85 kg: 390 mg IV, >85 kg: 520 mg IV

Maintenance: 90 mg SC every 8 weeks

thereafter

• (Please refer to psoriasis section)

Entyvio®

(vedolizumab)

CD/UC: 300 mg IV at weeks 0, 2, 6 then

every 8 weeks thereafter

• Hypersensitivity reactions

• Has been linked to cases of PML

• Report signs/symptoms of infection

Micromedex [database online]. Greenwood Village, CO: Truven Health Analytics ; 2017. http://www.micromedexsolutions.com/. Accessed February 10, 2017. Kornbluth A, et al. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010: 501‐23.

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IBD Treatment Goals and Efficacy Evaluation

• Goals of treatment

• Resolve inflammation and complications

• Alleviate systemic manifestations

• Maintain remission

• Measures of treatment effectiveness

• Crohn’s Disease Activity Index (CDAI)

• Harvey Bradshaw Index (HBI)

• Inflammatory Bowel Disease Questionnaire (IBDQ)

41Hemstreet BA. Chapter 41. In: DiPiro JT, et al. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw‐Hill; 2016.

Conclusion

• CIDs result from overactive or malfunctioning immune system

• Mild disease can usually be treated with non‐targeted, non‐specialty meds

• Moderate to severe disease often includes oral and/or biologic targeted therapies

– Symptom management

– Non‐curative

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