New Pharmacologic Treatment Options for Managing Rheumatoid Arthritis Devra Dang, Pharm.D. Department of Pharmacy National Institutes of Health

New Pharmacologic Treatment New Pharmacologic Treatment Options for Managing Options for Managing Rheumatoid ArthritisRheumatoid Arthritis

Devra Dang, Pharm.D.Devra Dang, Pharm.D.Department of PharmacyDepartment of Pharmacy

National Institutes of HealthNational Institutes of Health

Rheumatoid ArthritisRheumatoid Arthritis

Affects approximately 1% of the adult U.S. population

Incidence increases with age

Occurs 2-3 times more often in women

Shortens lifespan by 3-18 years (average of 10 years)

Rheumatoid ArthritisRheumatoid Arthritis

Unknown etiology

– Genetics

– Environmental

– Possible infectious component

Autoimmune disorder

Signs and SymptomsSigns and Symptoms

Joint inflammation– Tender, warm swollen joints– Symmetrical pattern

Pain and stiffness Symptoms in other parts of the body

– Nodules– Anemia

Fatigue, occasional fever, malaise

Joint DestructionJoint Destruction

Modified from Immunex Corporation

Treatment GoalsTreatment Goals

Relieve pain

Reduce inflammation

Prevent/slow joint damage

Improve functioning and quality of life

Treatment ApproachesTreatment Approaches

Lifestyle modifications

Rest

Physical and occupational therapy

Medications

Surgery

Drug TreatmentsDrug Treatments

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Disease-modifying antirheumatic drugs (DMARDs)

Biologic response modifiers

Corticosteroids

Nonsteroidal Anti-Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)Inflammatory Drugs (NSAIDs)

Traditional NSAIDs

Aspirin Ibuprofen (Motrin®,

Advil®) Ketoprofen (Orudis®) Naproxen (Naprosyn®)

COX-2 Inhibitors

Celecoxib (Celebrex®) Meloxicam (Mobic®) Rofecoxib (Vioxx®)

Nonsteroidal Anti-Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)Inflammatory Drugs (NSAIDs)

To relieve pain and inflammation

Use in combination with a DMARD

Gastrointestinal side effects

PhospholipidsPhospholipids

Arachidonic AcidArachidonic AcidLipoxygenase COX-1

(Constitutive)

LeukotrienesLeukotrienes

Phospholipase A2

COX-2 (Inducible)

Stomach Stomach Intestine Intestine Kidney Kidney PlateletsPlatelets

Inflammation, Inflammation, Swelling, PainSwelling, Pain

COX-2 InhibitorsCOX-2 InhibitorsCelebrexCelebrex®®, Mobic, Mobic®®, Vioxx, Vioxx®®

As effective as older NSAIDs in relieving pain and inflammation

Associated with a lower incidence of gastrointestinal ulcers than older NSAIDs

Do not increase bleeding time


More expensive than traditional NSAIDs

Usually reserved for patients at increased risk of serious upper GI ulcerations and complications


May cause an allergic reaction in patients who are allergic to other NSAIDs

Celebrex® may cause an allergic reaction in patients who are allergic to sulfa drugs

Vioxx® and Mobic® are not FDA-approved for the treatment of rheumatoid arthritis

Disease-Modifying Antirheumatic Disease-Modifying Antirheumatic Drugs (DMARDs)Drugs (DMARDs)

Azathioprine (Imuran®)

Gold Hydroxychloroquine

(Plaquenil®)

Leflunomide (Arava)

Methotrexate Sulfasalazine

Disease-Modifying Antirheumatic Disease-Modifying Antirheumatic Drugs (DMARDs)Drugs (DMARDs)

Control symptoms No immediate analgesic effects Can delay progression of the disease

(prevent/slow joint and cartilage damage and destruction)

Effects generally not seen until a few weeks to months

AravaArava (Leflunomide) (Leflunomide)

Reduces signs and symptoms Slows structural damage to joints Actions

– Antiproliferative– Anti-inflammatory– Immunosuppressive


As effective as methotrexate or sulfasalazine– In decreasing signs and symptoms– In slowing radiographic progression

Relatively fast onset of action (1 to 2 months)

Sustained duration of action


Administration: once a day orally

Adverse effects– Diarrhea– Skin rash– Hair loss– Elevation of liver enzymes and possible liver

damage


Not recommended for patients with– Immunodeficiency– Bone marrow disorder– Severe, uncontrolled infections

Pregnancy must be avoided while using this medication

Biologic Response ModifiersBiologic Response Modifiers

Etanercept (Enbrel®)

Infliximab (Remicade®)

Anakinra (Kineret®)

Biologic Response ModifiersBiologic Response Modifiers

Etanercept (Enbrel®) and infliximab (Remicade®) target tumor necrosis factor alpha (TNF-)

Anakinra (Kineret®) targets interleukin-1 receptor

Role of Tumor Necrosis Factor in Role of Tumor Necrosis Factor in Rheumatoid ArthritisRheumatoid Arthritis

TNF

bone resorptionbone resorption

bone erosionbone erosion

joint joint inflammationinflammation

cartilage cartilage degradationdegradation

joint space joint space narrowingnarrowing

pain/joint pain/joint inflammationinflammation

EnbrelEnbrel®® (Etanercept) (Etanercept)

Tumor necrosis factor (TNF) inhibitor

Effective in patients with moderately to severely active rheumatoid arthritis who have failed one or more DMARD

Can be used with methotrexate in patients who do not respond adequately to methotrexate alone


In patients with early, active, rheumatoid arthritis, Enbrel® – Reduces signs and symptoms more rapidly

than methotrexate – Delays the rate of progression of joint erosions

better than methotrexate

Effective in patients with juvenile rheumatoid arthritis


Administration: twice a week subcutaneous injection

Adverse effects– Injection site reactions (pain, swellling, itching)– Infections (including serious infections and

death)

Very expensive

RemicadeRemicade®® (Infliximab) (Infliximab)

Tumor necrosis factor inhibitor

Use with methotrexate in patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to methotrexate


Effective in decreasing symptoms and X-ray changes that are refractory to methotrexate

Magnitude of clinical response with Remicade® plus methotrexate is similar to when Arava or Enbrel® is added to methotrexate

RemicadeRemicade®® Administration Administration

Infusion reactions are occasionally observed (fever, chest pain, nausea, and rash)

Most reactions respond to: slowing the infusion rate,and/or antihistamines and/or acetaminophen

Modified from Centacor


Adverse effects– Infusion reactions– Infections (including serious infections and

death)– Serum sickness-like reaction

– Worsening of heart failure

Very expensive

KineretKineret®® (Anakinra) (Anakinra)

Inhibits binding of cytokine to the interleukin-1 receptor

Proposed indication– Reduction of signs and symptoms of

moderately to severely active rheumatoid arthritis who have failed one or more DMARDs


Effective in reducing signs and symptoms by 24 weeks when used alone

Combination therapy with methotrexate is more effective than methotrexate alone


Subcutaneous injection daily Long-term safety unknown Adverse effects

– Injection site reactions– Infections (including serious infections)– Decreased white blood count (leukopenia)

DrugDrug DoseDose Cost/Month*Cost/Month*

Methotrexate 15-25mg/wk $64-$108

Leflunomide 20mg/d $245

Etanercept 25mg 2x/wk $1187

Infliximab 3 mg/kg q8 wks $99810mg/kg q4 wks $4660

*2001 AWP

Cost of Newer Antirheumatic DrugsCost of Newer Antirheumatic Drugs

Documents

New Pharmacologic Treatment Options for Managing Rheumatoid Arthritis Devra Dang, Pharm.D. Department of Pharmacy National Institutes of Health