Cost Considerations of Biologics · Infliximab (Inflectra®, Remicade®, Renflexis®) FDA indication CD/UC CD UC CD/UC Product availability SC Prefilled syringe • SC Vial • Prefilled

Copyright © 2019, Tabula Rasa HealthCare, Inc., all rights reserved. These materials are confidential and proprietary information of Tabula Rasa HealthCare, Inc. and may not be reproduced in whole or in part without the written consent of Tabula Rasa HealthCare, Inc. These materials may contain recommendations which are not intended to be a substitute for clinical judgement or a physician’s medical decisions and advice. For all medical emergencies, contact local emergency services. | NASDAQ – TRHC.

Cost Considerations of BiologicsJamie Puglisi, PharmD, BCGPEugene Lammers, MDPeter Degolia, MD

Medication Risk Identification and Mitigation

Copyright © 2019 Tabula Rasa HealthCare, Inc., All Rights Reserved. May not be used without permission. | NASDAQ – TRHC.

Disclosures

I, Jamie Puglisi, Eugene Lammers, and Peter Degolia, declare to not have any real or apparent conflicts of interest or financial interests with any pharmaceutical manufacturers, medical device companies, or in any product or service, including grants, employment, gifts, stock holdings, and honoraria related to the content of this presentation.

Each of the planning committee members has listed no financial interest/arrangement or affiliation that would be considered a conflict of interest.

Objectives

• Provide a brief overview of Inflammatory Bowel Disease and Rheumatoid/Psoriatic Arthritis including pathophysiology, epidemiology, risk factors, and diagnosis

•Review guideline-based approaches to treating Inflammatory Bowel Disease and Rheumatoid/Psoriatic Arthritis

•Discuss details of medication classes used to treat Inflammatory Bowel Disease and Rheumatoid/Psoriatic Arthritis including expected efficacy, mechanism of action, adverse effects, contraindications, and their relative cost

•Compare cost-effectiveness across medication classes used to treat Inflammatory Bowel Disease and Rheumatoid/Psoriatic Arthritis

Inflammatory Bowel Disease (IBD)




• Idiopathic disease caused by an altered immune response to host intestinal microflora

•Relapsing and remitting, chronic, inflammatory condition

•Symptoms:

•Diarrhea

•Abdominal pain/cramping

•Rectal bleeding (possibly resulting in anemia) or passage of mucus/pus

•Weight loss, fatigue

•Perianal disease (fistulas and/or abscesses in CD)


Pathophysiology

•Two types:




Pathophysiology

•Several inflammatory mediators identified:

•Helper T cells

• Type 1 (Th-1) CD

• Type 2 (Th-2) UC

•TNF-α

• Interleukins 12 and 23




Epidemiology

•Highest rates are in Western countries

•Male-to-female ratio 1:1

•Both UC and CD commonly diagnosed in young adults

•Bimodal age distribution

•First peak in patients aged 15-40

•Second peak in patients aged 55-65



Risk Factors for IBD

Infectious

• Shift toward pro-inflammatory bacteria in gut

• Decreased diversity of microbiota

Genetic

• Significant ↑ risk for 1°relative

• Several genes implicated

• Permissive, not causative

Immunologic

• Immune mediated mucosal damage

• ↑ TNF-α in mucosa

• Dysregulation of cytokines

Psychological

• Stress

• Pain

• Anxiety

• Depression

Dietary

• Increased protein/sugar

• ↓ fruits and veggies

Lifestyle

• Smoking?

• +/-

Medications

• NSAIDs

• Antibiotics



Diagnosis of IBD•No specific laboratory test to make the diagnosis

• Labs may be used as markers of inflammation and to identify nutritional deficiencies

• CBC (↑WBC, anemia)

•Albumin, prealbumin

• ESR, CRP

• pANCA and ASCA

• Stool sample

• Radiographic studies

• Colonoscopy, upper GI endoscopy, enteroscopy

UC

• + pANCA

• - ASCA

CD

• - pANCA

• + ASCA



Goals of Treatment

•Target underlying inflammatory process

•Short-term goals in an acute episode:

• Alleviate signs and symptoms

• Suppress inflammation

•Long-term goals of remission:

• Maintain remission and prevent relapse

• Improve QOL

• Prevent surgical intervention and/or hospitalization

• Manage extraintestinal manifestations (i.e. – joint pain, fatigue, etc.)

• Prevent malnutrition (may include vitamin supplementation)

• Prevent treatment associated adverse effects





Medications for the Treatment of IBD

•Aminosalicylates

•Corticosteroids

• Immunosuppressants

•Antimicrobials

•Biologics

• Tumor necrosis factor (TNF)-α inhibitors

• Integrin receptor antagonists

• Interleukin (IL)-12 and 23 antagonist

• Janus kinase (JAK) inhibitor





Aminosalicylates

•Mechanisms:

•Modulates local chemical mediators of the inflammatory response

• Possibly inhibits TNF-α

• Free radical scavenger

•Allergy considerations: sulfa, salicylates

•No specific dosing considerations for geriatrics

•No dose reduction necessary for renal impairment (use with caution)



Sulfasalazine (Azulfidine®)Mesalamine (Apriso®, Asacol HD®, Canasa®, Delzicol®,

Lialda®, Pentasa®, Rowasa®)Olsalazine (Dipentum®) Balsalazide (Colazal®)

FDA indication• UC• Off-label: mild to moderate CD

• PO: treatment and maintenance of remission in UC• Rectal: distal UC• Off-label: treatment and maintenance of remission in CD

Maintenance of UCMild to moderate active UC

Product availability• Oral tablet • Delayed release tablet

• 24 hour extended release capsule• Delayed release capsule• Delayed release tablet• Extended release capsule • Rectal enema• Rectal suppository

Oral capsule • Oral capsule

Dosing

• 1g PO QID induction, 1g PO BID maintenance

• 3 to 4g PO divided daily induction, 2g PO daily maintenance

• 1.5 g PO per day• 800mg PO TID induction, 1.6g PO divided daily maintenance• 1.6g PO TID induction• 1g PO QID induction• 4g rectally QHS induction, 2 to 4 g rectally QHS maintenance • 1g rectally QD

1.5 to 3g PO divided daily induction, 500mg PO BID maintenance

• 2.25g PO TID induction, 3 to 6g POdivided daily maintenance

Adverse effects

• Decreased appetite, dyspepsia, headache, nausea, vomiting, rash, anemia, leukopenia, thrombocytopenia, hepatitis, pneumonitis

• Headache, eructation, abdominal pain, constipation, dizziness

• Watery diarrhea, abdominal pain and cramping, nausea, bloating

• Headache, abdominal pain

Cost (30 days, AWP pricing, may vary depending on product/dose)

~ $29 to $52

• Tablets and capsules: ~ $612- $838• Enema: ~ $1926• Suppository: ~ $558

~ $1952-$5857 • ~ $384-$432



Site of Action

Rectum Distal Colon

ProximalColon

Terminal Ileum

Ileum Jejunum

Mesalamine suppository (Canasa®) X

Mesalamine enema (Rowasa®) X X

Sulfasalazine (Azulfidine®) X X X

Balsalazide (Colazal®) X X X

Mesalamine, DR products and 24hr caps (Delzicol®, Asacol®, Apriso®)

X X X X

Olsalazine (Dipentum®) X X X X

Mesalamine ER capsule (Pentasa®) X X X X X X





Corticosteroids

•Quick onset of action to suppress acute inflammation

•Should be used for short-term symptom control and then tapered to discontinuation

•Will NOT maintain remission

•Manage systemic AND local manifestations



Hydrocortisone (Colocort®, Cortenema®, Cortifoam®)

Prednisone (Deltasone®, Rayos®) Prednisolone ((Pediapred®, Millipred®, Orapred ODT®)

Methylprednisolone (SOLU-Medrol®, Medrol®)

Budesonide (Entocort EC®, Uceris®)

FDA IndicationAnti-inflammatory, immunosuppressive

• Active mild to moderate CD• Active UC

Product Availability • Enema• IV• Rectal foam• Suppository

• Tablet• Delayed release tablet• Disintegrating tablet• Oral concentrate• Solution• Syrup

• IV• Tablet

• 24 hour ER tablet• Delayed release particle

capsule• Rectal foam

Dosing • 1 enema rectally QPMinduction

• 1 application rectally daily to BID

• 40-60mg daily Varied • 9mg daily induction, 6mg daily maintenance

• 2mg rectally BID for 2 week induction or 4 week maintenance

Adverse Effects • Short-term: hypertension, hyperglycemia, fluid retention• Long-term: osteoporosis, glaucoma, depression, Cushing’s syndrome, impaired skin healing

Cost (30 days, AWP) • Enema: ~$10 each

• Foam: ~$400 (14 doses)

~$30 to $20,000 ~$5 to $400 ~$500 to $1800





Immunosuppressants

•Target excessive immune response and cytokines

•Used for long-term treatment and maintaining remission

•Onset of action in 3 to 12 months

•Reserved for patients who fail aminosalicylate therapy or are refractory to/dependent upon corticosteroids





Azathioprine (Azasan®, Imuran®) Mercaptopurine (Purinethol®) Methotrexate (Otrexup®, Rasuvo®)

Cyclosporine (Gengraf®, Neoral®, SandIMMUNE®)

FDA indicationCD/UC (off-label) CD/UC (off-label) CD (off-label) UC (off-label)

Product availability

Oral tablet • Oral Tablet• Oral suspension

IM/SC injectable IV capsules

Dosing

2 to 2.5mg/kg PO QD maintenance 1 to 1.5mg/kg PO QD maintenance • 25mg IM/SC once weekly induction

• 15 to 25mg IM/SC once weekly maintenance

2 to 4 mg/kg IV daily induction

Adverse effects

Myelosuppression, hepatotoxicity, nausea, vomiting, diarrhea, rash, pulmonary edema, increased of lymphoma/non-melanoma skin cancer

Myelosuppression, alopecia,stomatitis, diarrhea, blurred vision, toxic epidermal necrolysis, GI hemorrhage

Nephrotoxicity, increased risk of infection, diarrhea, nausea, vomiting, gingival hyperplasia

Additional considerationsTPMT genotyping Folic acid supplementation

Cost (30 days, AWP)~$41 to $600 ~$135 to $1300 ~$3 to $470 ~$160 to $230





Antimicrobials

•Used as adjunctive therapies

•Preferred agents: ciprofloxacin, metronidazole

•Rifamycin antibiotics have shown some efficacy

•Given after resections to prevent recurrence





TNF-α inhibitors

•Decrease TNF-α activity which improves underlying inflammation

•Preferred in steroid refractory patients or for patients not responsive to other immunosuppressants

• If response is lost to one, can switch to another in the class

•Costly

•Some agents have biosimilar products available



Adalimumab (Humira®) Certolizumab pegol (Cimzia®) Golimumab (Simponi®)Infliximab (Inflectra®,

Remicade®, Renflexis®)

FDA indicationCD/UC CD UC CD/UC


SC Prefilled syringe • SC Vial• Prefilled syringe

• Auto-injector• Prefilled syringe

Vial

Dosing

• Induction: 160mg SC at wk0, 80mg wk 2

• Maintenance: 40mg SC every other week

• Induction: 400mg SC 0, 2, 4 weeks

• Maintenance: 400mg SC Q4 weeks

• Induction: 200mg SC 0, 100mg at wk 2

• Maintenance: 100mg SC Q4 weeks

• Induction: 5mg/kg IV at 0, 2,6 weeks

• Maintenance: 5 to 10mg/kg IV Q8 weeks

Adverse effects

Serious infections (Reactivation of tuberculosis and hepatitis B, invasive fungal infections, opportunistic infections), injection and infusion reactions, non-ischemic heart failure, demyelinating disorders, increased risk of malignancy

Cost (4 weeks of maintenance,AWP)

~ $3105 ~ $5193 ~ $6636 ~ $3616-$7232



Integrin Receptor Antagonists

• Block the alpha-4 subunit of integrin molecules which are important to adhesion and migration of cells from vasculature into inflamed tissue

Natalizumab (Tysabri®) Vedolizumab (Entyvio®)

FDA indicationCD CD, UC

Product availabilityIV solution vial

Dosing• Induction: 300mg IV week 0• Maintenance: 300mg IV Q4 weeks

Adverse effects

Progressive multifocal leukoencephalopathy, hypersensitivity reactions, severe infections (tuberculosis, meningitis), increased transaminases and bilirubin

Cost (4 weeks of maintenance, AWP)

~ $7945 ~ $7763



IL-12 and -23 Antagonist

Ustekinumab (Stelara®)

FDA indication Moderate to severe CD patients who have failed other agents

Product availability IV solutionsPrefilled syringes

Dosing Induction: 260mg, 390mg or 520mg IV at week 0 (weight based)Maintenance: 90mg SQ every 8 weeks

Adverse effects vomiting, nasopharyngitis, vulvovaginal candidiasis, pruritus, noninfectious interstitial pneumonia, serious infections (tuberculosis), malignancies


~ $26,405



JAK Inhibitor

Tofacitinib (Xeljanz®)

FDA indicationmoderate to severe active UC who have failed other agents

Product availabilityImmediate release tabletExtended release tablet (not approved for UC or CD)

Dosing

Induction: 10mg PO twice daily for 8 weeks (minimum)Maintenance: 5 or 10mg PO BID

Adverse effects

nasopharyngitis, upper respiratory tract infection, elevated cholesterol levels, rash, headache, diarrhea, tuberculosis and other opportunistic infections, lymphocytopenia, neutropenia**new safety alert/Black Box Warning regarding blood clots/PE**


~ $5376



Treatment Strategies for UC•Low risk:

Induction:• Oral 5ASA and/or• Rectal 5ASA and/or• Oral steroids and/or • Rectal steroids

**for distal disease only use rectal 5ASA as first line therapy

RemissionMaintenance:

• Maintain with oral 5-ASA and/or rectal • Taper steroids over 60 days

No remission

Induction and maintenance for high risk/outpatient

Relapse

Induction and maintenance for high risk/outpatient

Adapted from the Ulcerative Colitis Clinical Care Pathwayhttps://s3.amazonaws.com/aga-guidelines/pdf/ibd/Ulcerative_Colitis_Care_Pathway.pdf

https://s3.amazonaws.com/aga-guidelines/pdf/ibd/Ulcerative_Colitis_Care_Pathway.pdf



Treatment Strategies for UC•High risk, outpatient:

Induction:• Short course steroids with initiation of

thiopurine OR• Anti-TNF +/-thiopurine OR• Vedolizumab +/- immunomodulator

Remission Maintenance:• Continue thiopurine and taper steroids over 60 days• Anti-TNF +/- thiopurine• Vedolizumab +/- thiopurine or MTX

RelapseNo remission

Therapy for high risk, outpatient not in remission:• Anti-TNF +/- thiopurine• Thiopurine (optimize concentrations)• Vedolizumab +/- immunomodulatory• Proctocolectomy





Treatment Strategies for UC

High risk, inpatient:

Induction:• IV steroids• Infliximab• IV cyclosporine


Therapy failure

• Trial different agent

• Colectomy




Treatment Strategies for CD

Patients are stratified as low risk or moderate/high risk to guide therapy

•https://cpms.bbinfotech.com/clients/aga_web_tools/interactive_0000542.html

https://cpms.bbinfotech.com/clients/aga_web_tools/interactive_0000542.html

Rheumatoid and Psoriatic Arthritis





Rheumatoid Arthritis (RA)

•Most common autoimmune arthritis in adults

•Most commonly affects the joints, tendons, and bones but can affect ANY organ resulting in a myriad of extra-articular manifestations

Rheumatoid Arthritis (RA) Osteoarthritis (OA)

Onset Any ageRelatively rapid onset

Usually later in lifeSlow onset over years

Joints Painful, stiff, SWOLLEN Achy, tender, no swelling

Joints affected Usually symmetrical; small and large joints

Often starts asymmetrically and spreads to the other side

Morning stiffness Usually > 1 hour Usually < 1 hour; stiffness may return at the end of the day

Systemic Frequent fatigue that may affect ADLs, weakness, low grade fevers, loss of appetite

Whole body symptoms not present






Pathophysiology

•Autoimmune reaction set off by an external trigger

•Resulting in synovial hypertrophy and chronic joint inflammation +/- extra-articular manifestations inflammation leads to destruction of tissues

•Several inflammatory mediators identified:• Tumor necrosis factor alpha (TNF-α)

• Interleukin (IL)-1

• IL-6

• IL-8

• Transforming growth factor beta (TGF-ß)

• Fibroblast growth factor (FGF)

• Platelet-derived growth factor (PDGF)






Epidemiology

Incidence

• 3 cases per 10,000 per year worldwide

Prevalence

• 1%; increasing with age

• More prevalent in Native Americans (5-6%); less prevalent in others (blacks from the Caribbean)

• Female to male ratio 3:1 (ratio diminishes as age ↑)

Onset

• Can occur at any age

• Most common age of onset is 35-50



Risk Factors for RA

Genetic

• Accounts for 50% of risk

• MHC and several other genes implicated

Infectious

• Mycoplasma

• Epstein-Barr virus

• Rubella

Hormonal

• Sex hormones

• Female:male ratio

• Pregnancy and postpartum trends

Immunologic

• T and B cell involvement

• Various cytokines involved



Diagnosis of RA

•Physical exam

•Serology:

• Rheumatoid factor (Rf)

•ACPA

• CRP

• ESR

•ANA

•Anti-CCP antibodies

•X-ray, MRI, ultrasound

THE 2010 ACR-EULAR CLASSIFICATION CRITERIA FOR RHEUMATOID ARTHRITISARTHRITIS & RHEUMATISMVol. 62, No. 9, September 2010, pp 2569–2581DOI 10.1002/art.27584© 2010, American College of Rheumatology



Goals of Treatment

• Target low disease activity or remission

Treat-to-target

To control disease activity and joint pain

To maintain ability to function in activities of daily living

To slow destructive joint changes and delay disability



Treatment of RA

Non-Pharmacological Treatment

Pharmacological Treatment

Rest

Assisted devices

Weight reduction

PT/OT

Surgery

NSAIDs

Corticosteroids

Symptom Management

Slow disease progression

DMARDs

Conventional Biologics



Symptom Management



NSAIDsMechanism of Action

Inhibition of cyclooxygenase-1 and 2 (COX-1 and 2) enzymes, which decreases formation of prostaglandins

Drug(s)

Non-selective Cox Inhibitor Examples: ibuprofen (Motrin®, Advil®), naproxen (Aleve®, Naprosyn®), and diclofenac (Zorvolex®, Cambia®, Voltaren®)Selective Cox Inhibitor Examples: celecoxib (Celebrex®)

Dosing Variable, dependent upon NSAID used

Adverse Effects GI ulceration and bleeding, renal damage

Monitoring Parameters Scr, CBC

Clinical Considerations

• Used as an adjunct to DMARD therapy; *never used as monotherapy*

• Increased risk of CV events• Caution use in patients with renal insufficiency• Not recommended for chronic use in patients


Tablets (IR and ER)CapsulesTopical gelInjectable

Cost (AWP)Oral (4 weeks): ~$4Topical: ~$52 per 100g tubeInjectable: single dose as expensive as ~$265



Corticosteroids

Mechanism of ActionInterfere with antigen presentation to T lymphocytes, inhibit prostaglandin and leukotriene synthesis, and inhibit neutrophil and monocyte superoxide radical generation

Drug(s)Oral: prednisone (Deltasone®, Rayos®) and methylprednisolone (Medrol®)Intraarticular, Intramuscular: Hydrocortisone (Solu-CORTEF®), triamcinolone (Kenalog®, Zilretta®), and methylprednisolone (SOLU-Medrol®)

Dosing Variable, dependent upon corticosteroid used

Adverse Effects Hyperglycemia, hypertension, insomnia and osteoporosis

Monitoring Parameters Blood glucose and blood pressure

Clinical Considerations

High-dose oral or IV bursts may be used to suppress a flareCan be used as “bridging therapy” for DMARD to gain effectCaution with long-term useAlways use lowest effective dose

Cost (AWP)Prednisone (5mg, 30 tablets): ~ $6Methylprednisolone (dosepak): ~ $30Triamcinolone (10mg injection, single joint): ~ $3



Slowing Disease Progression





Disease-Modifying Antirheumatic Drugs (DMARDs)

•1st line agents

•Helps to suppress synovitis

•Prevents articular bone erosions and joint space narrowing

•Reduce swelling & inflammation

• Improve pain and function

•**Should be started as early in treatment as possible**

•Must undergo pre-treatment testing prior to initiation

•Hepatitis B, Hepatitis C, latent TB



Conventional Synthetic DMARDsMethotrexate (Trexall®, Otrexup®, Rasuvo®)

Sulfasalazine (Azulfidine®) Hydroxychloroquine(Plaquenil®)

Leflunomide (Arava®)

Mechanism Inhibits cytokine production, inhibits purine biosynthesis, and may stimulate release of adenosine

Sulfapyridine moiety is responsible for the agent’s antirheumaticproperties, although the exact mechanism of action is unknown

Increases pH to interfere with lysosomal degradation and dampen antigen–antibody reactions at sites of inflammation

Inhibits pyrimidine synthesis to reduce lymphocyte proliferation, and modulation of inflammation

Onset As early as 2-3 weeks Usually within 2 months 6 weeks to 6 months Within first month if load given

Products/Dosing Tablets: 7.5-10mg once a WEEKIV/SQ: for doses > 15mg

Tablets: 0.5 – 3 gm/dayDoses >2 gm/day used if inadequate response after 12 weeks

Tablets: 200 – 300mg twice daily, NTE 5 mg/kg/day or 400mg doses

Tablets: [loading dose] 100mg daily x 3 days then 10 – 20mg*Loading dose can be omitted for select patients

Adverse effects • GI (stomatitis, N/V/D)• Myelosuppression • Hepatic • Pulm. fibrosis, pneumonitis• Renal failure • Malaise, dizziness

• Headache • GI (N/V/D, anorexia)• Myelosuppression• Hepatic• Rash

• GI (N/V/D)• Ocular • Neurological headache• Vertigo• Insomnia• Rash

• Hepatotoxicity• Myelosuppression• GI (N/V/D)• alopecia

Clinical pearls • Black box warnings regarding pregnancy, bone marrow suppression, renal impairment, hepatotoxicity, pneumonitis, GI toxicity, skin reactions

• Causes folate deficiency; need to supplement

• Caution in sulfa allergy• Minimize GI effects by starting

low dose and/or dividing doses• Can discolor skin and urine

(yellow/orange)• May decrease folic acid

absorption

• Take with food or divide doses to manage GI effects

• Baseline and annual opthscreenings

• Lacks myelosuppressive, hepatic, and renal toxicities that may be seen with other DMARDs

• Black box warnings regarding hepatotoxicity and embryofetaltoxicity

• Monitor LFTs every 4 weeks initially then every 6-8 weeks

• Use cholestyramine for drug elimination

Cost ( 4 weeks, AWP) • Tablets: ~ $57• Injections: ~ $148

$27 ~ $103 ~ $168





Biologics

•Complex protein molecules created using molecular biology methods

•Effective when nonbiologic DMARDs fail to achieve adequate responses

•Considerably more expensive

• Indicated in moderate to severe RA not responding to one or more of the synthetic DMARDs

•Classes

•Anti Tumor Necrosis Factor-α (TNF-α) agents

• Janus Kinase (JAK) inhibitors

• Costimulation Modulator

• Interleukin-6 Antagonists

• CD-20 Monoclonal Antibody



TNF-α InhibitorsMechanism: Binds to TNF-α and prevents its interaction with TNF receptors on inflammatory cellsBlack Box Warning: Infection (increased risk for serious infections which may result in hospitalization and/or fatality); tuberculosis (active and reactivation of latent TB have been reported); malignancy (lymphomas and other malignancies, sometimes fatal)

Onset: as early as 2-4 weeks

Adverse effects: Infection, immune reaction, GI upset (N/V/D, abdominal pain; less with golimumab), headache, rash

Infliximab (Remicade®, Renflexis®)

Adalimumab(Humira®)

Certolizumab(Cimzia®)

Golimumab(Simponi®)

Etanercept(Enbrel®)

Products/Dosing IV: (with MTX) 3mg/kg at 0, 2, and 6 weeks Maintenance: every 8 weeks

SQ: 40mg every other week SQ: 400mg initially, repeat at 2 and 4 weeksMaintenance: 200mg every other week or 400mg every 4 weeks

SQ: 50mg once a monthIV: 2mg/kg at weeks 0 and 4 Maintenance: every 8 weeks

SQ: 50mg weekly

Clinical Pearls • Can increase AST• Used in combination with MTX due to

immunogenicity• Acute infusion-related reactions can occur

(premedication)• Lupus-like syndrome

• Increased CPK• Local injection site reaction

• Local injection site reaction

• Used in combination with MTX



• Has a biosimilar but not yet on the market

Cost (AWP) ~ $ 905-$1401 per 100mg vial

80kg patient: ~ $2715 per treatment

~ $6208 (4 weeks) Kit: ~ $5192 per kit (2x200mg/ml)

SQ: ~ $5770 (auto-injector or prefilled syringe)IV: 50mg/4ml ~ $546

~ $6208 ( 4 weeks)



Janus Kinase (JAK) InhibitorsMechanism of Action: Inhibits Janus kinase (JAK) enzymes resulting in modulation and suppression of the immune system through preventing the activation of signal transducers and activators of transcription (STATs) proteins

Black Box Warnings: Infection (increased risk for serious infections which may result in hospitalization and/or fatality); tuberculosis (active and reactivation of latent TB have been reported); malignancy (lymphomas and other malignancies, sometimes fatal)

Onset of Action: 4 to 8 weeks

Adverse Effects: Infection, malignancy, headache, GI (N/V/D, GI perforation), hepatic (increased ALT), increased lipids, anemia

Tofacitinib (Xeljanz®) Baricitinib (Olumiant®)

Products/Dosing PO (IR and ER formulations)IR: 5mg twice a dayER: 11mg daily

PO (IR only)IR: 2mg once a day

Clinical Pearls Frequency is reduced to once daily in patients with moderate or severe renal dysfunction (not studied with CrCl<40ml/min), moderate hepatic dysfunction, concurrent therapy with moderate or strong CYP3A4 and strong CYP2C19 inhibitors; not recommended with strong CYP3A4 inducers

Do not initiate therapy in patients with an absolute lymphocyte count <500 cells/mm3, absolute neutrophil count <1,000 cells/mm3, or hemoglobin <9 g/dL.

Substrate of CYP3A4 and CYP2C19

Cost (4 weeks, AWP) IR: ~ $5018ER: ~ $5018

IR: ~ $2394



Costimulation modulator

Mechanism of Action: Binds to CD80/CD86 receptors on APCs, preventing interaction between APCs and T cells

Black Box Warnings: None

Onset of Action: 3 months

Adverse effects: Infection, local injection site reaction, rash, headache, GI (nausea), URIs

Abatacept (Orencia®)

Products/Dosing IV (uses weight-based ranges for dosing): loading doses at 0, 2, 4 weeks then every 4 weeks thereafter<60 kg: 500 mg60 to 100 kg: 750 mg>100 kg: 1,000 mgSQ: 125mg once a week (no loading dose)

Clinical Pearls Can exacerbate COPD; higher incidences of infection and malignancy were observed in the elderly.

Cost (4 weeks, AWP) IV (750mg dose): ~ $3993SQ: ~ $5255



Interleukin-6 Antagonists

Mechanism of Action: Antagonizes IL-6 receptor

Black Box Warnings: Infection (increased risk for serious infections which may result in hospitalization and/or fatality); tuberculosis (active and reactivation of latent TB have been reported)

Onset of Action: As early as 4 to 8 weeks

Adverse Effects: Increased serum cholesterol, increased serum ALT & AST, infusion-related reaction, infection, GI perforation

Tocilizumab (Actemra®) Sarilumab (Kevzara®)

Products/Dosing IV: 4 mg/kg once every 4 weeks; may be increased to 8 mg/kg once every 4 weeks based on clinical response (maximum dose: 800 mg).

SQ: 100 kg: 162 mg once every other week; increase to 162 mg once every week based on clinical response≥100 kg: 162 mg once every week

SQ: 200mg once every 2 weeks

Clinical Pearls Do not initiate if ANC is <2,000/mm³, Plt <100,000/mm³, or if ALT or AST > 1.5 times ULNAdditional dosage adjustments required for elevated ALT, decreased ANC or platelets

Cost (4 weeks, AWP) IV: ~ $5373 (800mg every 4 weeks)SQ: ~ $4868 (if given weekly)

SQ: ~ $3498



Anti-CD20 Monoclonal Antibody

Mechanism of Action: Binds to CD20 antigen, activating B-cell cytotoxicity

Black Box Warnings: Hepatitis B reactivation, infusion reactions, mucocutaneous reactions, progressive multifocal leukoencephalopathy

Onset of Action: 3 months (effects can last 6 months to 2 years per dose)

Adverse Effects: Peripheral edema, hypertension, CNS (fatigue, chills, neuropathy, headache), rash, GI (N/V/D, abdominal pain), infusion-related reaction, immune reaction, infection

Rituximab (Rituxan®)

Products/Dosing IV: 1,000 mg on days 1 and 15 (in combination with methotrexate); subsequent courses may be administered every 24 weeks (based on clinical evaluation), if necessary may be repeated no sooner than every 16 weeks. Premedication with methylprednisolone 100 mg IV (or equivalent) is recommended 30 minutes prior to each dose.

Clinical Pearls • Must be given with methotrexate• Pre-medicate with acetaminophen and an antihistamine prior to infusion.

Cost (AWP) ~ $1127 for 1000mg dose**other cost considerations**



Choosing an Appropriate Therapy

•Choices between treatment options are based upon

•multiple factors, including:

• Level of disease activity

• Presence of comorbid conditions

• Stage of therapy

• Patient preferences

• Presence of adverse prognostic signs



Early RA

Singh JA, Saag KG, Bridges SL Jr, Akl EA, Bannuru RR, Sullivan MC, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol [Internet].

• Disease duration < 6 months• Goal: low disease activity or

remission• MTX is the preferred initial DMARD• * indicates glucocorticoids• indicates glucocorticoids for flares



Established RA

Singh JA, Saag KG, Bridges SL Jr, Akl EA, Bannuru RR, Sullivan MC, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol [Internet].

• Disease duration >/= 6 months• Goal: low disease activity or remission• MTX is still the preferred initial DMARD• * indicates glucocorticoids• indicates glucocorticoids for flares



Switching Therapy or Tapering

• Initial therapy should be given for a minimum 3 months prior to switching therapy

•Tapering:

• Must be conducted slowly, monitoring for increased disease activity or flare

• No predetermined tapering schedule

• Benefits:

• Decrease toxicity

• Decrease cost

• Lowers risk of unnecessary treatment

• DISCONTINUING ALL THERAPIES IS NOT RECOMMENDED DUE TO THE RISK OF FLARE

• https://www.rheumatology.org/Learning-Center/Medication-Guides

https://www.rheumatology.org/Learning-Center/Medication-Guides



Psoriatic Arthritis (PsA)






•Most commonly a seronegative oligoarthritis found in patients with arthritis

•One in 5 patients with psoriasis has psoriatic arthritis

Onset

Psoriasis before arthritis

60-80%

Arthritis before psoriasis

15-20%

Simultaneous appearance

Occasional






Signs and symptoms

•May present with or without obvious skin lesions, with minimal skin involvement or with only nail malformations

•Several different patterns of joint involvement:

• Asymmetrical oligoarticular arthritis

• Symmetrical polyarthritis

• Distal interphalangeal arthropathy

• Arthritis mutilans

• Spondylitis with or without sacroilitis

•May be localized to the foot (can be mistaken for gout)

•Nail involvement in 80% of patients




Epidemiology

Incidence

• 6 per 100,000 per year

• Incidence rising

Prevalence

• 1% of the general population (1 million in US)

• 6-41% of patients with psoriasis

• Whites more commonly affected

• General male-to-female ratio is 1:1 (spondylitic form 3:1)

Onset

• Can occur in at almost any age

• Typically develops between 35-55






Pathophysiology

•Etiology still unknown

•Differences in the vascular patterns of joints suggest a different etiology than RA

•Risk factors

Genetic

• 40% have a family history

• Heritability 30-55% in a first degree relative

Immunologic

• Presence of autoimmunity

• TNF-α, IL-1 beta, IL-10 more prevalent than in RA

Infectious

• Streptococcal infections

• HIV

Trauma

• Occurrence of arthritis after physical trauma in patients with psoriasis

Environmental

• Superantigensreacting with autoantigens





Diagnosis of Psoriatic Arthritis (PsA)•No specific diagnostic tests

•Based on clinical and radiographic criteria

•Mild erosive disease compared to RF

• Bone growth (unlike in RF)

•Elevated ESR and CRP

•Typically seronegative for RF

•Serum IgA elevated in two-thirds of patientsLaboratory Studies Psoriatic Arthritis Rheumatoid Arthritis

Erythrocyte sedimentation rate Elevated (< 100) Elevated (< 100)

Rheumatoid factor Negative Positive (85% of patients)

Antinuclear antibody Negative Positive (30% of patients)

C-reactive protein Elevated Elevated

SynoviumWBC count 5000-15,000/µL, >50%

polymorphonuclear leukocytesWBC count 2000/µL

Adapted from: https://emedicine.medscape.com/article/2196539-workup#c6



Treatment of Psoriatic Arthritis

NonpharmacologicTreatment

Pharmacologic Treatment

PT/OT

Smoking cessation

Weight loss

Massage therapy

Exercise

Symptomatic Treatments

NSAIDs

Glucocorticoids

Local steroid injections

Pharmacologic Treatments

Oral small molecules (OSMs)

Biologics



Who do we treat?

•Patients with active PsA

• Symptoms at an unacceptably bothersome level as reported by the patient

• Presence of at least 1 of the following:

• Actively inflamed joints

• Dactylitis

• Enthesitis

• Axial disease

• Active skin and/or nail involvement

• And/or extraarticular manifestations (i.e.- uveitis, IBD)

Arthritis & RheumatologyVol. 71, No. 1, January 2019, pp 5–32DOI 10.1002/art.40726© 2018, American College of Rheumatology



Treatment-Naïve

Start TNFi over OSM, IL17i or IL12/23i

biologic

Switch to a different TNFi

Switch to an IL17i over IL 12/23i, abatacept or

tofacitinib

Switch to an IL12/23i over abatacept or

tofacitinib

Start OSM over IL17i or IL 12/23i biologic

Switch to TNFi over another OSM or any

other agent

Switch to IL17i over another OSM,

IL12/23i, abatacept or tofacitinib

Switch to IL 12/23i over another OSM,

abatacept, or tofacitinib

Start MTX over NSAIDs

Start IL17i over IL12/23i

Switch to TNFi over IL12/23i, different

IL17i or adding MTX

Alternatives may be considered in light of contraindications, patient preference, comorbidities, etc.

TNFI > OSM > IL17i > IL12/23i > abatacept/tofacitinib



Cost ConsiderationsDrug Dosing Cost (4 weeks, AWP)

Methotrexate (Trexall®, Otrexup®, Rasuvo®)

10 to 25mg orally given once weekly; adjust dose gradually to optimal response; in general, doses >30mg per week should not be exceeded

20mg/wk (oral): ~ $114

Sulfasalazine (Azulfidine®)*off-label

Initial: 500mg orally once daily; may increase up to 2 to 3 g daily in divided doses 2g/day: ~ $27

Leflunomide (Arava®)*off-label

20mg orally daily ~ $168

Apremilast (Otezla®) Initial: 10mg in the morning on day 1. Titrate upward by additional 10mg per day on days 2 to 5 as follows: Day 2: 10mg twice daily; Day 3: 10mg in the morning and 20mg in the evening; Day 4: 20mg twice daily; Day 5: 20mg in the morning and 30mg in the evening. Maintenance dose: 30mg twice daily starting on day 6

30mg twice a day: ~ $3806

Etanercept (Enbrel®) 50mg SQ weekly ~ $6208

Infliximab (Remicade®)Biosimilar: Renflexis®

IV: 5mg/kg at 0, 2, and 6 weeks, followed by 5 mg/kg every 8 weeks thereafter ~ $ 905-$1401 per 100mg vial80kg patient: ~ $3616 per treatment

Adalimumab (Humira®) 40mg SQ every other week ~ $6208

Golimumab (Simponi®) IV: 2mg/kg at weeks 0, 4, and then every 8 weeks thereafterSubQ: 50mg once a month

IV: 50mg/4ml ~ $546 (depends on weight)SQ: ~ $5770 (auto-injector or prefilled syringe)

Certolizumab pegol (Cimzia®) Initial: 400mg, repeat dose 2 and 4 weeks after initial dose; Maintenance: 200mg every other week. May consider maintenance dose of 400 mg every 4 weeks

Kit: ~ $5192 per kit (2x200mg/ml)

Ustekinumab (Stelara®) 45 mg at 0 and 4 weeks, and then every 12 weeks thereafter. ~ $13,203

Secukinumab (Cosentyx®) With or without a loading dose 150 mg every 4 weeks; consider an increase to 300 mg in patients who continue to have active psoriatic arthritisCoexistent moderate to severe plaque psoriasis: 300 mg once weekly at weeks 0, 1, 2, 3, and 4 followed by 300 mg every 4 weeks. Some patients may only require 150 mg per dose.

150mg: ~ $6214

Ixekizumab (Taltz®) 160 mg once, followed by 80 mg at weeks 2, 4, 6, 8, 10, and 12, and then 80 mg every 4 weeks. 80mg: ~ $6442

Abatacept (Orencia®) IV per body weight or 125mg SQ weekly SQ: ~ $5255

Tofacitinib (Xeljanz®) Immediate release: 5mg orally twice dailyExtended release: 11mg orally once daily

IR: ~ $5018ER: ~ $5018

Case Study and Discussion

Eugene Lammers, MDMedical Director Mercy LIFE Alabama

Peter Degolia, MDMedical Director, McGregor PACE





RHEUMATOID ARTHRITIS (RA): OVERVIEW

•An inflammatory arthritis linked to increased risk of cardiovascular disease and premature death

•Most older adults with late-onset RA present similarly to younger adults

•Two presentations are unique to older adults:

“RS3PE” syndrome remitting seronegative symmetrical synovitis with pitting edema; accounts for ~10% of late-onset cases

Acute-onset, seronegative, inflammatory arthritis of the shoulder and hips can be difficult to distinguish from polymyalgia rheumatica (PMR); accounts for ~25% of late-onset cases





RA: Diagnosis

•Compared with younger adults, older adults more frequently present with constitutional symptoms: malaise, fever, fatigue, weight loss, in addition to the characteristic synovitis of RA

•Older adults with RA also more likely to have a higher initial erythrocyte sedimentation rate (ESR)

•Check autoantibodies, including rheumatoid factor (RF) and anti-cyclic citrullinatedpeptide (anti-CCP) antibodies

•Radiographic evaluation can be helpful to demonstrate erosions or deformities that appear in more aggressive and long-standing disease





RA: Assessment of Disease Activity

•Symptoms pain intensity and location, duration of morning stiffness, severity of fatigue, functional status

•Physical exam number of tender and swollen joints; evaluation for extra-articular manifestations, including rheumatoid nodules and other cutaneous manifestations, interstitial lung disease, pleuropericardial disease, vasculitis, ocular disease, neuropathy

•Lab monitoring acute phase reactants, such as ESR and C-reactive protein (CRP); CBC; metabolic panel; liver function tests if the patient is on disease-modifying antirheumatic drugs (DMARDs)

•Radiographs periodically to assess for progression of disease





Patient Case

•75 yo woman, good health

•Pain in many joints but worse in hands

•Exam of hands reveals a single red, tender, bony area right 3rd PIP joint

•Working DX?

•Osteoarthritis





Case continued…

•Patient initially improved with naproxyn

•2 months later, pain worsens especially in morning

•Severe stiffness

•Swelling in knees and wrists

•Bilateral knee effusions



OA or RA?





Work-up

•knee arthrocentesis- clear, fluid, no crystals, WBC 5K

•Elevated Sed Rate, CRP

•+RF

•+APCA (anti-citrulated peptide antibodies)

•Radiographs of hands show periarticular osteoporosis

•DX: Rheumatoid Arthritis





Treatment?

•Prednisone

•Methotrexate





Management of Seropositive RA

•Start treatment as soon as the diagnosis is made, with the goal of achieving remission or the lowest level of disease activity possible

• Initial approach to treatment should include initiation of one or more oral DMARDs, depending on disease severity and comorbidities

• In general, patients should be optimized on with oral or SQ DMARDs

before moving on to biologic treatments





Management of Seronegative RA

•Prednisone (10–20 mg/day) may be used as the primary treatment for seronegative PMR-like disease and the “RS3PE” syndrome

• In contrast to classic PMR, late-onset RA may not respond promptly to low-dose prednisone

• In general, avoid chronic use of prednisone, because its use is associated with increased risk of infectious complications, fluid retention, and osteoporosis





DMARDs

•Disease-modifying antirheumatic drugs (DMARDs).

•May slow the progression of rheumatoid arthritis

•Can save the joints from permanent damage.

•Examples include:

•methotrexate (Trexall®, Otrexup®, others)

• leflunomide (Arava®)

• hydroxychloroquine (Plaquenil®)

• sulfasalazine (Azulfidine®)





Biologic Agents

• Includes: abatacept (Orencia®), adalimumab (Humira®), anakinra (Kineret®), baricitinib (Olumiant®), certolizumab (Cimzia®), etanercept (Enbrel®), golimumab(Simponi®), infliximab (Remicade®), rituximab (Rituxan®), sarilumab (Kevzara®), tocilizumab (Actemra®) and tofacitinib (Xeljanz®).





How to Choose Biologics

•Try not to

• Is it really needed?

• Failed methotrexate?

• Failed plaquenil?

• Cannot taper steroids?

•Good relationship with Rheumatology

• Is it on label?

• Second opinion





CHOOSING WISELY

Recommendations based on the American Board of Internal Medicine Foundation’s Choosing Wisely® Campaign:

•Do not test ANA sub-serologies without a positive ANA and clinical suspicion of immune-mediated disease.

•Do not perform MRI of the peripheral joints to routinely monitor inflammatory arthritis.

•Use biologic DMARDs only after failure of nonbiologic DMARDs.

•Do not routinely repeat DXA scans more than once every 2 years.



References

• Al Hammadi A, Badsha H. Psoriatic Arthritis. Medscape Drugs & Diseases. Updated Oct 8, 2018. Available at: https://emedicine.medscape.com/article/2196539-overview.

• Basson MD. Ulcerative Colitis. Medscape Drugs & Diseases. Updated July 26, 2019. Available at: https://emedicine.medscape.com/article/183084-overview.

• Clinical Resource, Clinical Decision Support Tool [Crohn] https://cpms.bbinfotech.com/clients/aga_web_tools/interactive_0000543.html

• Clinical Resource, Demystify Treatments for Ulcerative Colitis. Pharmacist’s Letter, April 2019.

• Clinical Resource, Treatment of Mild to Moderate Ulcerative Colitis. Pharmacist’s Letter/Prescriber’s Letter. April 2019.

• Clinical Resource, Ulcerative Colitis Clinical Care Pathway. https://s3.amazonaws.com/aga-guidelines/pdf/ibd/Ulcerative_Colitis_Care_Pathway.pdf

• Ghazi LJ. Crohn Disease. Medscape Drugs & Diseases. Updated July 26, 2019. Available at: https://emedicine.medscape.com/article/172940-overview

• Jasvinder, A. Singh, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care & Research.DOI10.1002/acr.22783.

• Jasvinder, A. Singh, et al. 2018 American College of Rheumatology/National Psoriasis Foundation Guideline for the Treatment of Psoriatic Arthritis. Arthritis & Rheumatology. Vol. 71, No. 1, January 2019, pp 5–32

• Ko, Cynthia W.Crockett, Seth et al. AGA Clinical Practice Guidelines on the Management of Mild-to-Moderate Ulcerative Colitis. Gastroenterology, Volume 156, Issue 3, 748 – 764.

• Smith HR, Brown A. Rheumatoid Arthritis. Medscape Drugs & Diseases. Updated Aug 23, 2019. Available at: https://emedicine.medscape.com/article/331715-overview.

• Terdiman, Jonathan P. et al. American Gastroenterological Association Institute Guideline on the Use of Thiopurines, Methotrexate, and Anti–TNF-α Biologic Drugs for the Induction and Maintenance of Remission in Inflammatory Crohn's Disease. Gastroenterology, Volume 145, Issue 6, 1459 – 1463.

https://cpms.bbinfotech.com/clients/aga_web_tools/interactive_0000543.html


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Cost Considerations of Biologics · Infliximab (Inflectra®, Remicade®, Renflexis®) FDA indication CD/UC CD UC CD/UC Product availability SC Prefilled syringe • SC Vial • Prefilled