# Presentation: 541451

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

- New Pharmacologic Treatment Options for Managing Rheumatoid ArthritisDevra Dang, Pharm.D.Department of PharmacyNational Institutes of Health

## Rheumatoid 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 Arthritis

- Unknown etiology
- Genetics
- Environmental
- Possible infectious component
- Autoimmune disorder

## Signs 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 Destruction

- Modified from Immunex Corporation

## Treatment Goals

- Relieve pain
- Reduce inflammation
- Prevent/slow joint damage
- Improve functioning and quality of life

## Treatment Approaches

- Lifestyle modifications
- Rest
- Physical and occupational therapy
- Medications
- Surgery

## Drug Treatments

- Nonsteroidal anti-inflammatory drugs (NSAIDs)
- Disease-modifying antirheumatic drugs (DMARDs)
- Biologic response modifiers
- Corticosteroids

## Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

- Traditional NSAIDs
- Aspirin
- Ibuprofen (Motrin®, Advil®)
- Ketoprofen (Orudis®)
- Naproxen (Naprosyn®)

- COX-2 Inhibitors
- Celecoxib (Celebrex®)
- Meloxicam (Mobic®)
- Rofecoxib (Vioxx®)

## Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

- To relieve pain and inflammation
- Use in combination with a DMARD
- Gastrointestinal side effects

## Phospholipids

**Arachidonic Acid**

***Lipoxygenase***

***COX-1 (Constitutive)***

**Leukotrienes**

***Phospholipase A******2***

***COX-2 (Inducible)***

**Stomach Intestine Kidney Platelets**

**Inflammation, Swelling, Pain**

## COX-2 InhibitorsCelebrex®, Mobic®, 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

## COX-2 InhibitorsCelebrex®, Mobic®, Vioxx®

- COX-2 InhibitorsCelebrex®, Mobic®, Vioxx®

- More expensive than traditional NSAIDs
- Usually reserved for patients at increased risk of serious upper GI ulcerations and complications

## COX-2 InhibitorsCelebrex®, Mobic®, Vioxx®

- 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 Drugs (DMARDs)

- Azathioprine (Imuran®)
- Gold
- Hydroxychloroquine (Plaquenil®)

- Leflunomide (Arava)
- Methotrexate
- Sulfasalazine

## Disease-Modifying Antirheumatic 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

## Arava (Leflunomide)

- Arava (Leflunomide)

- Reduces signs and symptoms
- Slows structural damage to joints
- Actions
- Antiproliferative
- Anti-inflammatory
- Immunosuppressive

## Arava (Leflunomide)

- Arava (Leflunomide)

- 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

## Arava (Leflunomide)

- Arava (Leflunomide)

- Administration: once a day orally
- Adverse effects
- Diarrhea
- Skin rash
- Hair loss
- Elevation of liver enzymes and possible liver damage

## Arava (Leflunomide)

- Arava (Leflunomide)

- Not recommended for patients with
- Immunodeficiency
- Bone marrow disorder
- Severe, uncontrolled infections
- Pregnancy must be avoided while using this medication

## Biologic Response Modifiers

- Etanercept (Enbrel®)
- Infliximab (Remicade®)
- Anakinra (Kineret®)

## Biologic 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 Rheumatoid Arthritis

- TNF

**bone resorption**

**bone erosion**

**joint **
**inflammation**

**cartilage **
**degradation**

**joint space **
**narrowing**

**pain/joint **
**inflammation**

## Enbrel® (Etanercept)

- Enbrel® (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

## Enbrel® (Etanercept)

- Enbrel® (Etanercept)

- 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

## Enbrel® (Etanercept)

- Enbrel® (Etanercept)

- Administration: twice a week subcutaneous injection
- Adverse effects
- Injection site reactions (pain, swellling, itching)
- Infections (including serious infections and death)
- Very expensive

## Remicade® (Infliximab)

- Remicade® (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

## Remicade® (Infliximab)

- Remicade® (Infliximab)

- 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

## Remicade® 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

## Remicade® (Infliximab)

- Remicade® (Infliximab)

- Adverse effects
- Infusion reactions
- Infections (including serious infections and death)
- Serum sickness-like reaction
- Worsening of heart failure
- Very expensive

## Kineret® (Anakinra)

- Kineret® (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

## Kineret® (Anakinra)

- Kineret® (Anakinra)

- Effective in reducing signs and symptoms by 24 weeks when used alone
- Combination therapy with methotrexate is more effective than methotrexate alone

## Kineret® (Anakinra)

- Kineret® (Anakinra)

- Subcutaneous injection daily
- Long-term safety unknown
- Adverse effects
- Injection site reactions
- Infections (including serious infections)
- Decreased white blood count (leukopenia)

## Drug				Dose			      Cost/Month*

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

Leflunomide		20mg/d		      $245

Etanercept			25mg 2x/wk	      $1187

Infliximab			3 mg/kg q8 wks	      $998
					10mg/kg q4 wks	      $4660
*2001 AWP

- Methotrexate 		15-25mg/wk	      $64-$108
- Leflunomide		20mg/d		      $245
- Etanercept			25mg 2x/wk	      $1187
- Infliximab			3 mg/kg q8 wks	      $998
- 					10mg/kg q4 wks	      $4660
- *2001 AWP

- Cost of Newer Antirheumatic Drugs