1. LSU Clinical Pharmacology
Drug Therapy of Rheumatoid Arthritis (RA)
Reginald D Sanders, MD

2. Drug therapy of RA - overview
what is rheumatoid arthritis (RA)?
what happens to patients with RA?
what drugs are available?
how are those drugs used?
where are we going with therapy?

3. What Is Rheumatoid Arthritis?
Drug therapy of RA
What Is Rheumatoid Arthritis?

4. Drug therapy of RA
Case Presentation

5. Case presentation 25 years old dental hygienist
6 months history of pain & swelling in the MCP & PIP joints of both hands
recent onset swelling in knees, wrists, elbows & ankles
very stiff for 2 hours in the morning
very stiff after sitting

6. Case presentation pain present daily but varies day to day
hurts when weather changes abruptly
with worsening pain, is missing work
exam shows multiple swollen joints
incomplete fist formation bilaterally
small olecranon nodules

7. Case presentation laboratory studies sedimentation rate = 66 mm/hr
rheumatoid factor + (1:2560)
antibody to CCP + (>200 units)
hand X-rays show small, discrete bony erosions

8. Case presentation
What does she have?
What do we do?

9. synovitis of MCP & PIP joints
RA - clinical picture
synovitis of MCP & PIP joints

10. RA - clinical picture persistent arthritis
hands & feet usually involved
morning stiffness
rheumatoid factor & antibody to CCP
sedimentation rate
extra-articular disease

11. symmetrical joint involvement
RA - joint involvement
symmetrical joint involvement

12. RA - essential features
normal
abnormal
synovial inflammation

13. RA - extra-articular disease
rheumatoid nodule

14. RA - extra-articular disease
rheumatoid vasculitis

15. RA - extra-articular disease
rheumatoid (epi)scleritis

16. RA - severe arthritis
disabling arthritis

17. bone & joint damage (erosions)
RA - severe arthritis
bone & joint damage (erosions)

18. RA - severe arthritis
“arthritis mutilans”

19. RA - outcome
with inadequate treatment, a significant number of patients with RA will experience significant disability due to joint destruction

20. What Drugs Are Available?
Drug therapy of RA
What Drugs Are Available?

21. Drugs used to treat RA Disease-Modifying Drugs (DMARDs)
biologic modifiers
methotrexate
Disease-Modifying Drugs (DMARDs)
antimalarials
sulfasalazine
NSAID’s & Other Drugs
steroids
analgesics
non-selective NSAIDs
COX-2 selective inhibitors

22. Traditional DMARDs hydroxychloroquine (anti-malarial) sulfasalazine
methotrexate
leflunomide

23. Biologic response modifiers
etanercept (Enbrel®)
infliximab (Remicade®)
adalimumab (Humira®)
anakinra (Kineret®)
abatacept (Orencia®)
rituximab (Rituxan®)

24. DMARDs - characteristics
no direct analgesic effect
no direct anti-inflammatory effect
delayed onset of benefits
narrow range of effectiveness
unique adverse effect profiles
able to prevent progression of RA

25. Antimalarial agents main drug - hydroxychloroquine
excellent safety profile
minor side effects
best-known side effect - retinopathy
mechanism of action unknown

26. Antimalarial agents slow, gradual improvement (8-16 weeks)
effective in mild-to-moderate RA
effective in other conditions
often used in combination therapy

27. Antimalarial agents - toxicity
rash
marrow suppression
headache, diarrhea
retinopathy
transient muscle weakness

28. Sulfasalazine useful in mild-to-moderate RA
side effects frequent, but usually mild
alternative to hydroxychloroquine
usually takes 8-16 weeks to begin working
mechanism of action unknown

29. Sulfasalazine - toxicity
rash
abdominal pain
marrow suppression
allergic reaction

30. Methotrexate most widely used remittive agent for RA advantages
disadvantages
favored drug for severe RA
mechanism of action in RA unknown (inhibits folic acid metabolism)

31. Methotrexate - toxicity
hepatic toxicity
pneumonitis
bone marrow suppression
nausea, stomatitis
“the yucks”

32. Methotrexate - toxicity
accelerated rheumatoid nodulosis

33. RA - extra-articular disease
rheumatoid nodule

34. Methotrexate - toxicity
accelerated rheumatoid nodulosis
susceptibility to infection
induction of malignant disease

35. Leflunomide (Arava®) immunomodulatory drug
inhibits pyrimidine synthesis
retards progression of RA erosions
loading dose first three days (100 mg)
once daily therapy thereafter (20 mg)

36. Leflunomide (Arava®) common side effects diarrhea, nausea alopecia
rash, toxic epidermal necrolysis
hepatic toxicity
contraindicated in pregnancy

37. Biologic Response Modifiers
Drug therapy of RA
Biologic Response Modifiers
Reginald D Sanders, MD

38. Biologic response modifiers
targeted therapy for rheumatoid arthritis
result of better understanding of disease processes
parenteral administration (IV or SQ)
akin to chemotherapy

39. Cytokines mediate immune functions produced by activated immune cells
actions
enhance immune response or
inhibit immune response
anticytokine therapy in RA?

40. Tumor necrosis factor alpha
produced by macrophages (cytokine)
stimulates synovial cells to produce collagenases
found in increased amounts in RA synovium
must attach to cell receptor to work

41. TNF inhibition - approaches
cell surface receptor antagonists
soluble receptor antagonists
antibodies to cytokines
antibodies to cytokine receptors

42. Inhibitors of TNF alpha
etanercept (Enbrel®)
infliximab (Remicade®)
adalimumab (Humira®)
inhibits TNF alpha activity

43. Etanercept (Enbrel®) biologic modifier
recombinant human tumor necrosis factor receptor fusion protein
binds & inactivates soluble TNF
subcutaneously, once or twice a week
retards erosive disease

44. Etanercept (Enbrel®) soluble TNF receptor fusion protein
-S-S-
extracellular human TNF-receptor p75 monomer
human IgG1 Fc domain
soluble TNF receptor fusion protein

45. Soluble TNF receptor binding
synovial cell
macrophage

46. Etanercept (Enbrel®) low incidence of side effects
may truly help fatigue
marked improvement in RA symptoms
used in combination with methotrexate

47. Etanercept - side effects
local injection site reactions
headache
increased risk of infections
increased risk of autoimmune disease?
increased risk of malignancy?

48. Infliximab (Remicade®)
chimeric anti-TNF monoclonal antibody
human IgG1
mouse binding sites for TNF
Clinical trials with infliximab provided the first direct evidence that TNF inhibitors might be useful therapeutic agents for patients with RA
Human anti-chimeric antibody (HACA) responses to infliximab have been noted in many patients; this antibody response may be diminished by concomitant treatment with low dose methotrexate

49. Infliximab binds TNF alpha

50. Infliximab (Remicade®)
chimeric monoclonal antibody
binds to human TNF alpha
retards erosive disease
best when used with methotrexate
intravenous dosing (q 6-8 weeks)

51. Infliximab - side effects
activation of latent tuberculosis
activation of latent histoplasmosis
increased risk of other infections
increased risk of demyelinating disease?
increased risk of malignancy?

52. Adalimumab (Humira®)
fully human recombinant anti-TNF alpha monoclonal antibody
subcutaneous every 2 weeks
side effects similar to other TNF inhibitors

53. TNF inhibition - approaches
cell surface receptor antagonists
soluble receptor antagonists
antibodies to cytokines
antibodies to cytokine receptors

54. T-cells – role in RA large number T cells in RA joints
T cells from RA joints can transfer disease to immunodeficient mice
depletion of pathogenic T cells prevent collagen-induced arthritis in mice

55. Activated T-cells – role in RA
release chemical mediators that stimulate activity of other immune cells
other immune cells release second set of mediators that induce inflammation & joint damage

56. Abatacept (Orencia®) selective T-cell co-stimulation modulator
soluble fusion protein (CTLA-4 antigen + Fc of human IgG1)

57. Fusion Protein (CTLA4 + Fc Fragment)
Abatacept (Orencia®)
Fusion Protein (CTLA4 + Fc Fragment)

58. Abatacept (Orencia®) selective T-cell co-stimulation modulator
soluble fusion protein (CTLA-4 antigen + Fc of human IgG1)
binds to CD80 & CD86
blocks interaction with CD28
attenuates T-cell activation

59. Co-stimulatory modulation
Antigen Presentation Generates Signal #1

60. Co-stimulatory modulation
CD28 Costimulation Provides Signal #2

61. Co-stimulatory modulation
Without Abatacept
With Abatacept

62. Abatacept - indications
reduce signs & symptoms of RA
slow progression of structural damage
improve physical function
used if inadequate response to methotrexate and/or TNF inhibitors
not used with TNF inhibitors

63. Abatacept – adverse events
infections
malignancy?
infusion reactions (headaches, dizziness, hypertension)

64. B-cells – role in RA

65. B-cells – role in RA

66. Rituximab (Rituxan®) monoclonal antibody B-cell lymphoma therapy
binds to & depletes C-20+ cells

67. Rituximab – CD20 targeting

68. Biologic modifiers etanercept anti-TNF adalimumab anti-TNF
infliximab anti-TNF
abatacept T-cell directed
rituximab B-cell directed

69. Biologic modifier naming
etanercept cept
abatacept cept
adalimumab mab
infliximab mab
rituximab mab

70. RA – changing approaches
earlier use of remittive drugs in patients at risk for erosive disease
majority of joint damage within 5 years
typical patient has severe functional impairment within 2 years
at 10 years 40% of patients disabled

71. Erosive RA - risk factors
female sex
synovitis resistant to therapy
positive rheumatoid factor
high sedimentation rate
polyarthritis
elderly onset of disease

72. RA - new approaches
earlier use of remittive drugs in patients at risk for erosive disease
combination of remittive drugs

73. RA - new approaches
earlier use of remittive drugs in patients at risk for erosive disease
combination of remittive drugs
targeted therapy (biologic response modifiers)

74. Therapeutic wheel of fortune?
NSAID
methotrexate
leflunomide
sulfasalazine
antimalarial
combination
biologics
gold

75. RA - choosing a remittive agent
Mild RA hydroxychloroquine sulfasalazine
Moderate RA hydroxychloroquine sulfasalazine methotrexate
Severe RA
methotrexate azathioprine leflunomide biologic modifiers combinations

76. Toxicity - NSAIDs vs DMARDs
lowest toxicity with salsalate
DMARDs comparable to most toxic NSAIDs
hydroxychloroquine very safe DMARD

77. Drug therapy of RA
Case Presentation

78. Therapy - current choices
NSAIDs
“disease-modifying” anti-rheumatic drugs
corticosteroids
“biologic agents”
no “cure”, only “control”
limitations

79. Case presentation - therapy
NSAID
low dose prednisone
methotrexate
biologic
weeks 0-3
weeks 4-16
weeks 17+

80. LSU Clinical Pharmacology
Drug Therapy of Rheumatoid Arthritis
Reginald D Sanders, MD