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

2. 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)

3. Rheumatoid Arthritis Unknown etiology –Genetics –Environmental –Possible infectious component Autoimmune disorder

4. 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

5. Joint Destruction Modified from Immunex Corporation

6. Treatment Goals Relieve pain Reduce inflammation Prevent/slow joint damage Improve functioning and quality of life

7. Treatment Approaches Lifestyle modifications Rest Physical and occupational therapy Medications Surgery

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

9. Nonsteroidal Anti- Inflammatory Drugs (NSAIDs) Traditional NSAIDs Aspirin Ibuprofen (Motrin ®, Advil ® ) Ketoprofen (Orudis ® ) Naproxen (Naprosyn ® ) COX-2 Inhibitors Celecoxib (Celebrex ® ) Meloxicam (Mobic ® ) Rofecoxib (Vioxx ® )

10. Nonsteroidal Anti- Inflammatory Drugs (NSAIDs) To relieve pain and inflammation Use in combination with a DMARD Gastrointestinal side effects

11. Phospholipids Arachidonic Acid Lipoxygenase COX-1 (Constitutive) Leukotrienes Phospholipase A 2 COX-2 (Inducible) Stomach Intestine Kidney Platelets Inflammation, Swelling, Pain

12. 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

13. COX-2 Inhibitors Celebrex ®, Mobic ®, Vioxx ® More expensive than traditional NSAIDs Usually reserved for patients at increased risk of serious upper GI ulcerations and complications

14. 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

15. Disease-Modifying Antirheumatic Drugs (DMARDs) Azathioprine (Imuran ® ) Gold Hydroxychloroquine (Plaquenil ® ) Leflunomide (Arava  ) Methotrexate Sulfasalazine

16. 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

17. Arava  (Leflunomide) Reduces signs and symptoms Slows structural damage to joints Actions –Antiproliferative –Anti-inflammatory –Immunosuppressive

18. 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

19. Arava  (Leflunomide) Administration: once a day orally Adverse effects –Diarrhea –Skin rash –Hair loss –Elevation of liver enzymes and possible liver damage

20. Arava  (Leflunomide) Not recommended for patients with –Immunodeficiency –Bone marrow disorder –Severe, uncontrolled infections Pregnancy must be avoided while using this medication

21. Biologic Response Modifiers Etanercept (Enbrel ® ) Infliximab (Remicade ® ) Anakinra (Kineret ® )

22. Biologic Response Modifiers Etanercept (Enbrel ® ) and infliximab (Remicade ® ) target tumor necrosis factor alpha (TNF-  ) Anakinra (Kineret ® ) targets interleukin-1 receptor

23. Role of Tumor Necrosis Factor in Rheumatoid Arthritis TNF bone resorption bone erosion jointinflammationcartilagedegradation joint space narrowing pain/jointinflammation

24. 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

25. 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

26. Enbrel ® (Etanercept) Administration: twice a week subcutaneous injection Adverse effects –Injection site reactions (pain, swellling, itching) –Infections (including serious infections and death) Very expensive

27. 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

28. 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

29. 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

30. Remicade ® (Infliximab) Adverse effects –Infusion reactions –Infections (including serious infections and death) –Serum sickness-like reaction –Worsening of heart failure Very expensive

31. 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

32. Kineret ® (Anakinra) Effective in reducing signs and symptoms by 24 weeks when used alone Combination therapy with methotrexate is more effective than methotrexate alone

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

34. DrugDose Cost/Month* Methotrexate 15-25mg/wk $64-$108 Leflunomide20mg/d $245 Etanercept25mg 2x/wk $1187 Infliximab3 mg/kg q8 wks $998 10mg/kg q4 wks $4660 *2001 AWP Cost of Newer Antirheumatic Drugs