Download Rheumatoid Arthritis and Osteoarthritis Treatment

Thank you for attending
Rheumatoid Arthritis and
Osteoarthritis Treatment
A CHAMPS webcast presented by
Dr. David Collier
on Thursday, November 3rd, 2005
SUPPLEMENTARY INFORMATION PACKET
I.
Presentation Slide Text (Notes Pages)
II.
Biography of Dr. David Collier
Pages 2-21
Page 22
III. Description of CHAMPS (Community Health
Association of Mountain/Plains States)
Page 22
IV. Description of the Arthritis Foundation
Page 22
RA and OA Treatment Webcast, November 3, 2005
PRESENTATION SLIDE TEXT (NOTES PAGES)
MANAGEMENT OF RHEUMATOID ARTHRITIS
RA: Observations
•
RA affects 1% of the adult population
•
>70% of patients develop joint damage or erosions within 2 years of the onset of disease
(chronic, polycyclic course)
•
>33% of patients are work disabled at 5 years
•
>50% of patients will be functional Class III or IV within 10 years of disease onset
•
If untreated, RA can result in joint destruction, deformity, disability, and premature death
RA: Challenges
•
Preconceived notions that RA is a disease of lesser significance (“it’s just arthritis”)
•
Lack of appreciation of the potentially severe prognosis (disability and early mortality) may delay
diagnosis, referral, and treatment
•
Delay in treatment may be due to lack of experience with prescribing and monitoring diseasemodifying antirheumatic drugs (DMARDs)
•
Primary care physicians are important members of the RA management team
•
Early recognition of the signs and symptoms of RA followed by expedited diagnosis and treatment
results in more favorable patient outcomes
ARA 1987 Criteria for RA (4 of 7 required)
•
Morning stiffness >1h, present for at least 6 wk
•
Swelling of 3 or more joint areas for at least 6 wk
•
Swelling of wrist, MCP, or PIP; >6wk
•
Symmetric joint swelling
•
Rheumatoid nodules
•
Serum rheumatoid factor (RF)
•
Hand radiographic changes: erosions
Criteria were not intended for the diagnosis of RA in the clinical setting, particularly early disease
Suspicion of an Inflammatory Arthritis
•
Spontaneous onset of 1 or more swollen joints
•
Morning stiffness lasting > 45 minutes
•
Diffuse joint pain and tenderness, particularly involving the MCPs and MTPs (forefoot pain can be
the first and only small joint complaint)
•
Marked fatigue
•
Onset in women in the first year postpartum
Screening Tool for Inflammatory Arthritis (RA) in Primary Care
•
Significant discomfort with squeezing the MCP and MTP joints
•
Presence of 3 or more swollen joints
•
More than 1 hour of morning stiffness
Emery P et al. Ann Rheum Dis 2002;61:290-297.
Anti-Cyclic Citrullinated Peptide Antibodies (Anti-CCP)
•
RF not very specific for RA
•
Autoantibodies reactive with synthetic peptides containing the unusual amino acid citrulline
(modified arginine residue) are specifically present in the sera of RA patients:
o Anti-CCP: sensitivity 56%, specificity 90%
o IgM RF: sensitivity 73%, specificity 82%
o RF and anti-CCP: sensitivity 48%, specificity 96%
•
The presence of RF with anti-CCP are associated with a higher probability of joint damage and
disability
Bas S et al. Rheumatology 2003;42:677-680.
RA: Poor Prognostic Indicators
•
Earlier age at onset
Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States
2
RA and OA Treatment Webcast, November 3, 2005
•
•
•
•
•
•
•
Polyarticular synovitis (>20 joints)
Rheumatoid nodules
High titer rheumatoid factor, possibly anti-CCP
Elevated ESR or CRP level
Erosions or cartilage loss on x-ray
HLA-DR4 or “shared epitope”
Extraarticular manifestations
Furst DE. Rheum Dis Clin North Am 1994;20:309-319.
RA: Extraarticular Manifestations
•
Rheumatoid nodules
•
Sjögren’s syndrome
•
Episcleritis or scleritis
•
Interstitial lung disease
•
Pericardial disease
•
Systemic vasculitis
•
Felty’s: RA, neutropenia, splenomegaly
RA: Important Lessons
•
Inflammation can be suppressed in early RA
•
When inflammation is suppressed, patients benefit
•
More therapy is not necessarily more toxic
•
Long-term benefits may be derived from early therapy
RA: Initial Treatment
•
NSAIDs: reduce joint pain and swelling; improve function (cost, GI tolerance, half-life, patient
preference)
•
Multidisciplinary care:
o Rheumatology consultation
o Physical and occupational therapy
o Podiatry
o Orthopaedics
•
Glucocorticoids ?
•
DMARDs: start within 2-3 months of diagnosis (shown to be the window of opportunity to prevent
more joint destruction and preserve function)
Lard LR et al. Am J Med 2001;111:446.
RA: Glucocorticoids
•
Local injection: limited to a few joints
•
Low-dose oral (<10 mg prednisone):
o “Bridge-therapy” until DMARD response (polyarticular synovitis)
o Control of disease despite NSAIDs and adequate trials of DMARDs
o Loss of independence or employment; flares; special events
o Elderly - lower threshold for use
o Toxicity (osteoporosis): dose and duration
•
Triamcinolone acetonide (Kenalog): 60 mg IM prn flare
An
•
•
•
•
•
•
•
•
Approach to Selecting DMARDs
Patient compliance and convenience
Cost of the DMARD and monitoring
Time until expected benefit
Potential for adverse reactions
Comorbid diseases
Response and toxicity to previous Rx
Severity and prognosis of the disease
Physician confidence in administering and monitoring the drug
An Approach to Selecting DMARDs
•
Milder RA with no or few “poor prognostic indicators” consider:
o Hydroxychloroquine (HCQ)
o Sulfasalazine (SSZ)
Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States
3
RA and OA Treatment Webcast, November 3, 2005
•
•
Severe RA with “poor prognostic indicators” consider:
o Methotrexate (MTX) with rapid dose escalation
o Combination DMARD therapy
o New DMARDs and Biologics
For women of childbearing age, effective contraception is required
Methotrexate (MTX)
•
Fast acting: response in 3-6 weeks
•
Not remitting: RA flares if drug d/ced
•
Dosage:
o Administer on a weekly basis, in one dose or cycled over 24 h
o 5.0 or 7.5 mg po or SC/IM weekly, escalate rapidly to 15 mg/wk within 4-6 weeks and
ideally to 20 mg/week by 8-12 weeks
o Oral absorption is variable: if ineffective without rise in the MCV, try SC route
MTX: Side Effects and Toxicity
•
Common:
o Stomatitis, GI intolerance: try folate 1-2 mg/day
o Myelosuppression: risks - use of antifolates, folate deficiency, renal insuff; use folate for
rising MCV or MCV >100
o Transient LFT abn: hold or reduce dose for levels >2-3 x nl
•
Uncommon:
o Hepatic fibrosis or cirrhosis (rare)
o Pneumonitis: 2-6%
o CNS reactions
o Accelerated nodulosis
o Fever, weight loss syndrome
o Cutaneous vasculitis
o Pneumocystis, fungal infections
o ? Lymphoma association
Methotrexate
•
Monitoring:
o Baseline CXR, hepatitis B and C serologies
o CBC, LFTs - 1 wk after 1st dose (idiosyncratic reaction)
o CBC, Plt, AST/ALT, Alb, Cr q 4-8 weeks
•
Contraindications / Precautions:
o Chronic renal insufficiency
o Significant pulmonary disease
o Alcohol abuse (no > few drinks/month), liver disease, obesity, diabetes
o Concomitant antifolate therapy
o Pregnancy and lactation
RA: Monitoring Activity and Treatment
•
Each visit:
o Degree of joint pain
o Duration of morning stiffness
o Severity of fatigue
o Active synovitis on exam by joint count
o Limitation of function
o Extraarticular manifestations
o Adverse drug reactions
o Health Assessment Questionnaire (HAQ) can be used to score the patient’s function
•
Periodically:
o Disease progression on PE: loss of motion, instability, malalignment, and/or deformity
o ESR or CRP elevation
o Progression of radiographic damage of involved joints (hands and feet) every 1 to 2 years
(joint exam may not adequately reflect disease activity or structural damage); x-ray,
possibly by ultrasound or portable MRI
Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States
4
RA and OA Treatment Webcast, November 3, 2005
RA: Active or Progressive Disease Despite Current Treatment
•
Rheumatology consultation
•
Local glucocorticoid injection
•
Change drug regimen:
o Increase DMARD dosage
o Change the DMARD
o Add a DMARD (combination therapy)
o Start or increase glucocorticoids (eval and treat secondary osteoporosis)
•
Physical / Occupational Therapy
•
Surgical options for mechanical symptoms
Refractory Rheumatoid Arthritis
•
Rheumatology consultation
•
Combination therapy: MTX/HCQ, MTX/SSZ, MTX/SSZ/HCQ, MTX/CSA, MTX/Leflunomide
•
Cyclosporine A (CSA)/Neoral: 2.5-4.0 mg/kg/day
•
Leflunomide (Arava)
•
Etanercept (Enbrel), Infliximab (Remicade), Adalimumab (Humira)
•
Anakinra (Kineret)
•
Mycophenolate (CellCept): 1000 mg bid
•
Cyclophosphamide, chorambucil
•
Investigational pharmacological or biological agents (anti-CD20, anti-CD40-L, CTLA4Ig)
ACR-20/-50/-70 Response Criteria
A 20%, 50%, or 70% improvement in:
•
Swollen joint count, AND
•
Tender joint count, AND
•
At least three of the following:
o Patient’s global assessment of disease activity
o Physician’s global assessment of disease activity
o Patient’s assessment of pain
o Acute-phase reactants (ESR or CRP)
o Patient’s assessment of disability (HAQ)
Efficacy of Triple Therapy in RA
(2 year study, 171 patients, disease duration 6.9 ± 6.8 years)
% Response
Response
%
90
80
70
60
50
40
MTX ++ SSZ
SSZ
78
P = 0.005
60
55
49
40
30
20
10
00
MTX ++ HCQ
HCQ
MTX ++ HCQ
HCQ ++ SSZ
SSZ
P = 0.05 P = 0.002
0.002
29
26
16
ACR-20
ACR-50
18
ACR-70
ACR-70
MTX
MTX 7.5-17.5
7.5-17.5 mg/wk,
mg/wk, HCQ 200 mg
mg bid,
bid, SSZ
SSZ 500-1000
500-1000 mg
mg bid.
bid.
O’Dell
O’Dell JR, et al.
al. Arthritis
Arthritis Rheum.
Rheum. 2002;46:1164–1170.
2002;46:1164–1170.
II.34
II.34
Newer Agents for the Treatment of RA
•
Leflunomide (Arava)
•
Anti-TNF agents:
o Etanercept (Enbrel), 1998
ƒ
Soluble TNF receptor
o Infliximab (Remicade), 2000
ƒ
Chimeric anti-TNF antibody
o Adalimumab (Humira), 2002
ƒ
Human anti-TNF antibody
•
Anti-IL-1 agent:
o Anakinra (Kineret), 2001
ƒ
Modified IL-1 receptor antagonist (IL-1Ra)
Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States
5
RA and OA Treatment Webcast, November 3, 2005
Leflunomide (Arava)
•
Mechanism of action:
o Prodrug: metabolite inhibits dihydroorate dehydrogenase required for pyrimidine
nucleotide synthesis
o Antiproliferative effects on T cells and anti-inflammatory effects
•
Onset of action:
o 4-12 wks, maximum effect by 4 months
•
Dosage:
o Loading dose: 100 mg qd x 3 (optional)
o Maintenance dose: 10-20 mg qd
•
Side Effects and Toxicity:
o Increased LFTs/: usually < 2x increase and reversible; >3x (7%) increase requires
discontinuation, dose reduction, cholestyramine if persistent
o Hepatic failure: rare reports
o Diarrhea (28%)
o Rash (15%), reversible alopecia (9%)
o Teratogenesis (Pregnancy Category X):
ƒ
Men or women who wish to have a child: stop leflunomide, cholestyramine 8
grams tid for 11 days, verify plasma (M1) levels < 0.02 mg/L by 2 separate tests
14 days apart (without cholestyramine - 2 yrs to eliminate drug)
o Bone marrow suppression/aplasia: rare
o Serious infection or lymphoma risk unknown
•
Monitoring:
o LFTs, CBC, Cr q 4 wks x 6 months, then q 4-8 wks; baseline hepatitis serologies
•
Contraindications / Precautions:
o Pregnancy and lactation
o Renal or hepatic insufficiency
o Severe uncontrolled infections or immunodeficiency
o No vaccinations with live virus
o Rifampin (40% ↑ M1 levels), MTX: possible hepatic toxicity
o ↑ NSAID and tolbutamide levels in vitro
Efficacy of Leflunomide in RA
Pathogenesis of Rheumatoid Arthritis
(6.3 years RA, 45% no prior DMARDs)
ACR-20 Responders Over Two Years*
% Responders
Responders
%
75
†† ‡‡
††
45
IFNγ
IFNγ and
and
HL A -DR
Methotrexate (n = 101)
other
other
cytokines
cytokines
Antigenpresenting
cells
Placebo (n = 36)
30
BB cell
cell or
or
macrophage
macrophage
15
Immune
Immune complexes
complexes
T cell
Leflunomide (n = 98)
60
Rheumatoid
Rheumatoid
factors
factors
BB cell
cell
Macrophage
TNF
IL-1
Synoviocytes
Synoviocytes
Pannus
Pannus
Chondrocytes
Chondrocytes
0
Osteoclast
Osteoclast
0
6
12
24
18
Month
ACR-20 = * 20% improvement in response rates over time in ITT population; †P <
0.001 vs placebo; ‡P = 0.317 vs methotrexate
For early withdrawals, the last observation carried forward (LOCF) is used.
Cohen et al. Arthritis Rheum. 2001;44:1984–1992.
Articular
cartilage
II.31
II.31
Characteristic
Infliximab
(REMICADE®®)
(mean duration of disease 13 years)
TNF MAb
TNF MAb
Construct
Recombinant
fusion protein
Chimeric MAb
Recombinant
human MAb
Half-life
4 days
8–10 days
10–20 days
Binding target
TNF/LTα
TNF
TNF
Administration
25 mg SC 2x week
or 50 mg
mg SC
SC once
once
weekly
3–10 mg/kg
IV
IV with
with MTX
MTX
Every 4–8 weeks
40 mg
SC
SC
Every other
week*
*Some
*Some patients
patients not
not taking
taking concomitant
concomitant MTX
MTX may
may derive
derive additional
additional benefit
benefit from
from
increasing
increasing the
the dosing
dosing frequency
frequency of
of adalimumab
adalimumab to
to 40
40 mg
mg every
every week
week
*
71
Etanercept
Etanercept 25
25 mg
mg ++ MTX
MTX (59)
Placebo + MTX (30)
70
% of Patients
sTNFR
VI.4
VI.4
Etanercept + MTX:
ACR Response Rates at 24 Weeks
Adalimumab
(HUMIRA™)
80
Class
Bone
Adapted from Arend WP, Dayer JM. Arthritis Rheum. 1990;33:305–315.
Evolution of TNF Blocking Therapies
Etanercept
(ENBREL®®)
Production of collagenase and
other neutral proteases
60
50
*
39
40
30
27
†
15
20
10
3
0
ACR-50
ACR-70
0
ACR-20
IV.3
IV.3
MTX 15-25 mg/week, *P < 0.001; †P < 0.05
Weinblatt ME, et al. N Engl J Med. 1999;340:253–259.
Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States
IV.8
IV.8
6
RA and OA Treatment Webcast, November 3, 2005
Etanercept in Early RA (12 months disease):
ACR Response Rates at Year 2
100
*†
MTX
MTX 20
20 mg
mg (217)
(217)
P = NS
59
60
Patients (%)
(%)
Patients
Etanercept 25 mg (154)
P = 0.005
72
80
% of Patients
TEMPO: ACR Response Rates at 52 Weeks
Etanercept + Methotrexate (disease duration 6.0 ± 5.0 yrs)
49
42
P = NS
40
24
ACR-20
ACR-50
48
43
40
30
ACR-70
IV.18
IV.18
24
19
Oral MTX
MTX (159)
Etanercept (170)
VII.24
VII.24
Klareskog L et al. Lancet 2004;363:675.
ARMADA
Patients Taking Concomitant MTX (16 ± 5 mg/week)
(disease duration 12 ± 9 years)
(duration of disease 9 years)
Placebo (88 patients)
Placebo (62 patients)
Adalimumab 40 mg EOW
80
Infliximab 3 mg/kg q8wk
(86 patients)
60
Responders (%)
(%)
Responders
Responders (%)
(%)
Responders
MTX + Etanercept (193)
Adalimumab: Rapid ACR-20 Response
Infliximab: Rapid ACR-20 Response
Patients Taking Concomitant MTX (median dose 15 mg/wk)
60
ACR-70
*‡
*‡
43
*P
*P << 0.01
0.01 for
for combination
combination vs
vs MTX;
MTX; †P
†P << 0.05
0.05 for
for combination
combination vs
vs etanercept;
etanercept;
‡P
‡P << 0.01
0.01 for
for combination
combination vs
vs etanercept
etanercept
Etanercept
Etanercept 25
25 mg
mg SC
SC twice/week;
twice/week; Average
Average dose
dose of
of MTX
MTX was
was 17.2
17.2 mg.
mg.
Analysis
Analysis using
using last
last observation
observation carried
carried forward
forward (LOCF)
(LOCF)
Genovese MC, et al. Arthritis Rheum. 2002;46:1443–1450.
80
*‡
69
76
75
0
0
ACR-20
ACR-50
85
20
10
29
20
ATTRACT
90
80
70
60
50
40
20
*
*
(67 patients)
*
*
*
*
*
*
40
*
20
0
0
0
2
6
10
14
22
18
0 1
26
5
Maini R, et al. Lancet. 1999;354:1932–1939.
VII.8
VII.8
20
24
Weinblatt ME, et al. Arthritis Rheum. 2003;48:35–45.
Osteoclast
Osteoclast
precursor
precursor
TT cell
cell
Total Sharp
TNF
3.5
JSN
Joint Erosion
3.2
M-CSF
M-CSF
Median
3.0
Change From
From Baseline
Baseline
Change
RANK
RANK
OPG
OPG
Bone-lining
Bone-lining cells
cells
VII.9
VII.9
Etanercept in Early RA:
Change in Sharp Scores At 2 Years
Effects of IL-1 and TNF on Bone Remodeling
RANKL
RANKL
15
*P
*P << 0.05
0.05 vs
vs placebo.
placebo.
Statistical
Statistical comparisons
comparisons were
were not
not performed
performed at
at these
these time
time points.
points.
IL-1 TNF
10
Weeks
Weeks
IL-1
Bone
Bone
Osteoclast
Osteoclast
MTX 20 mg
Etanercept 25 mg
2.5
1.9
2.0
*
1.3
1.5
1.3
1.0
†
0.7
*
0.7
0.5
0
Adapted from Gravallese EM, Goldring SR. Arthritis Rheum. 2000;43:2143–2151.
III.8
III.8
*P = 0.001; †P = NS
TEMPO: Change in TSS From Baseline at 52 Weeks
Infliximab + MTX (ATTRACT)
Etanercept + Methotrexate
Changes in Total Sharp Scores
14
Mean Change
Change From
From Baseline
Baseline
Mean
Change in
in TSS
TSS (m
(mean)
ean)
Change
3
2.8
2
1
*
0
(1.08, 4.51)‡‡
0.52
(-1.00,
(-1.00, -0.07)‡‡
(-0.10, 1.15)‡‡
-0.54
-1
Oral MTX
(n = 212)
Etanercept
25 mg BIW
(n = 212)
† **
Oral MTX +
Etanercept
(n = 219)
12.6
12.6
30 Weeks
12
54 Weeks
10
102 Weeks
8
6
77
4.8
4.8
4
P < 0.001
2
1.3 11
11 1.3
PP < 0.001
1.6
1.6
0.6
0.6
P < 0.001
P < 0.001
1.1
1.1
11
0.2
0.2
0
-0.5
-0.5
-2
TSS
TSS == Total
Total Sharp
Sharp Score;
Score; BIW
BIW == twice
twice per
per week.
week. Mean
Mean dose
dose of
of MTX
MTX was
was 17.2
17.2 mg/week.
mg/week.
*P
*P << 0.05
0.05 for
for etanercept
etanercept vs
vs MTX;
MTX; †P
†P << 0.01
0.01 for
for combination
combination vs
vs MTX;
MTX; **P
**P << 0.01
0.01 for
for combination
combination vs
vs etanercept;
etanercept;
‡(2-sided
‡(2-sided 95%
95% CI).
CI). One
One year
year values
values imputed
imputed by
by linear
linear extrapolation
extrapolation ifif needed.
needed.
Klareskog L et al. Lancet 2004;363:675.
IV.30
IV.30
Genovese MC, et al. Arthritis Rheum. 2002;46:1443–1450.
-0.3
-0.3 -0.7 -0.4
-0.7 -0.4
nn == 66
66 64
64 50
50
72
72 71
71 68
68
76
76 71
71 66
66
78
78 77
77 69
69
69
69 66
66 66
66
MTX
MTX Alone
Alone
33 mg/kg
mg/kg
q8w
q8w
33 mg/kg
mg/kg
q4w
q4w
10
10 mg/kg
mg/kg
q8w
q8w
10
10 mg/kg
mg/kg
q4w
q4w
MTX + Infliximab
VII.28
VII.28
P values are vs MTX alone
Lipsky PE, et al. Arthritis Rheum. 2000;43(suppl):S269.
Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States
IV.23
IV.23
7
RA and OA Treatment Webcast, November 3, 2005
Adalimumab: Mean Change in Joint Erosions
and Joint Space Narrowing in Patients
With Early RA (< 2 Years)
Placebo + MTX
Adalimumab
Adalimumab 40 mg
mg EOW + MTX
MTX
Joint Erosions
Joint Space Narrowing
2.6
2.6
3.0
3.0
2.5
2.5
Mean
ean Change
Change
M
Mean
ean Change
Change
M
3.0
3.0
2.0
2.0
1.5
1.5
1.0
1.0
0.2
0.2
0.5
0.5
00
2.2
2.2
2.5
2.5
2.0
2.0
1.5
1.5
1.0
1.0
0.2
0.2
0.5
0.5
00
52
52 Weeks
Weeks
52
52 Weeks
Weeks
EOW == every other week
VII.30
VII.30
Keystone E, et al. Ann Rheum Dis. 2003; 62(suppl 1):170.
Anakinra (Kineret)
•
Dosage:
o 100 mg daily subcutaneous injection: half-life 4-6 hours
o Predominantly cleared by the kidney: clearance ↓ in chronic renal insufficiency
•
Side Effects and Toxicity:
o Injection-site reactions: 71%; placebo 28%
o Serious infections: 2%; placebo <1%
o Use with TNF blocking agents not recommended: serious infections 7%; neutropenia 3%
o Rare hypersensitivity reactions
Anakinra + MTX: ACR Response Rates at Week 24*
(419 patients, had 6 months of prior MTX, 7.4 yrs of RA)
45
45
Anakinra
Anakinra 1.0
1.0 mg/kg
mg/kg SC
SC qd
qd + MTX
MTX
35
35
35
35
% of Patients
Placebo
Placebo ++ MTX
42
42
40
40
Anakinra
Anakinra 2.0
2.0 mg/kg
mg/kg SC
SC qd
qd + MTX
MTX
30
30
25
25
24
24
23
23
20
20
17
17
15
15
10
10
10
10
7
44
55
00
00
ACR-20
ACR-20
ACR-50
*Dose response; P = 0.003 vs placebo.
Cohen S, et al. Arthritis Rheum. 2002;46:614–624.
ACR-70
ACR-70
IV.6
IV.6
Anti-TNF Therapy: Adverse Effects
•
Injection site reactions, infusion reactions
•
Serious infections: d/c drug in the setting of an active infection
•
Atypical infections:
o Tuberculosis: need pre-treatment PPD and CXR
o Atypical mycobacterial infections
o Candidiasis
o Aspergillosis, Nocardiosis, Pneumocystis
o CMV, Cryptococcosis, Coccidioidomycosis
o Histoplasmosis: ? use in endemic areas
o Listeria: avoid unpasteurized milk products, heat ready-to-eat meats
•
Demyelinating disease
•
Neoplasia:
o Lymphoma: reported cases, difficult to ascertain increased drug risk over risk with RA
alone (SIR 2.5)
o Solid Tumors: limited data - risk unclear but does not appear to be increased, use with
caution with h/o malignancy
•
Cytopenias
•
Heart failure
•
Antibody production:
Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States
8
RA and OA Treatment Webcast, November 3, 2005
o
o
Non-neutralizing antibodies to the drug; incidence decreased with concomitant MTX
therapy
ANAs and anti-ds-DNA antibodies (10%-50%), rare cases of drug-induced lupus
Average Costs of DMARDs
Drug
Dose
AWP/ mos
AWP/ year
MTX
15mg/wk
$72
$936
Leflunomide
20mg/day
$422
$5,064
Etanercept
25mg twice weekly
$1,370
$16,440
Infliximab
300mg
infusion
Adalumimab
Anakinra
40mg qowk
100mg/day
$16,660
(8 doses)
$1,370
$1,303
RA: Health-Care Maintenance
•
Osteoporosis:
o Calcium / Vit D: 1500 mg /400-800 U/day
o Bisphosphonates
o DEXA scans
•
Cardiovascular disease: assess risk / modify
•
Smoking cessation
•
Infection risk (particularly pulmonary infections):
o Influenza vaccination yearly
o Pneumococcal vaccination: before MTX
$16,440
$15,636
ACR Treatment Algorithm
Establish diagnosis of RA early
R
R
hh
ee
uu
m
m
aa
tt
oo
ll
oo
gg
ii
ss
tt
PP
C
C
PP
Initiate therapy
Periodically assess disease activity
Adequate response
Inadequate response
Change/Add DMARDs
MTX naive
MTX
Other
mono
Combination
Suboptimal MTX response
Combination
Other
Biologics
mono Mono Combination
Multiple
Multiple DMARD
DMARD failure
failure
Adapted
Adapted from: ACR Subcommittee on RA Guidelines.
Arthritis
Arthritis Rheum. 2002;46:328–346.
Symptomatic
Symptomatic and/or
and/or structural
structural
joint
joint damage
damage
Rational Approach to DMARD Therapy in Severe RA
•
Start oral methotrexate (unless contraindicated) with rapid dose escalation, consider low-dose
steroid “bridge therapy”
•
Inadequate response: consider parenteral (sq) methotrexate
•
Inadequate response: MTX combination DMARD therapy [SSZ, HCQ, or leflunomide (risk of
hepatotoxicity)] or change to leflunomide
•
Inadequate response: add etanercept, infliximab, adalimumab, or anakinra
RA: Unanswered Questions
•
How do we select the best DMARD for each patient (identify predictors)?
•
Should we step-up or step-down initial DMARD therapy (combo rx)?
•
Is there a role for induction therapy with steroids and/or anti-TNF / anti-IL-1 agents?
TOPICS OF LECTURE
OSTEOARTHRITIS
•
Definition
•
Laboratory Tests
•
Risk Factors
•
Management of OA
OSTEOARTHRITIS
Definition:
Osteoarthritis is a heterogeneous disease representing a final common pathway of biochemical,
metabolic, physiologic, and pathologic changes characterized by loss of articular cartilage and
remodeling of subchondral and marginal bone.
Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States
9
II.10
II.10
RA and OA Treatment Webcast, November 3, 2005
OA: LABORATORY TESTS
No specific tests
Synovial fluid analysis
1. Type 1 fluid, 200-1500 WBC, 20-50% polys.
2. Normal viscosity, glucose
3. Negative Crystal Exam
Laboratory tests in secondary OA
Investigational: Cartilage degradation products in serum and joint fluid.
1. Hyaluronic acid, fragments of aggrecan
2. Type II collagen
3. Cartilage oligomeric protein (COMP)
OA: RADIOGRAPHIC FEATURES
•
Joint space narrowing
•
Bony sclerosis
•
Marginal osteophytes
•
Subchondral cysts
•
Altered shape of bone
•
Malalignment
o Nails the diagnosis.
Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States
10
RA and OA Treatment Webcast, November 3, 2005
OA: RISK FACTORS
•
Age: 75% of persons over age 70 have OA, uncommon under age 40.
•
Female sex
•
Obesity
•
Hereditary
•
Trauma
•
Neuromuscular dysfunction
•
Metabolic disorders
OA: Clinical Syndromes - Six Types
•
Primary generalized OA
•
Inflammatory/erosive small joint OA
•
Isolated nodule OA
•
Unifocal large joint OA
•
Multifocal large joint OA
•
Unifocal small joint OA
Management of OA
•
Establish the diagnosis of OA on the basis of history, physical and x-ray examinations
o 1. Knee pain with radiographic OA can be due to patellofemoral disease, ligament strain,
anserine bursitis, iliotibial band syndrome, referred from lumbosacral disease, etc.
o 2. Hip pain could be trochanteric, iliopsoas, and ischial bursitis, referred back pain,
sacroiliac disease, etc.
TWO APPROACHES TO THE MEDICAL MANAGEMENT
•
Practical Guidelines-ACR Osteoarthritis Guidelines of OA of the Knee, the American Pain Society
Guidelines to treat OA, or the EULAR 2003 Recommendations for Treating OA of the Knee
o Based on evidence and expert opinion
•
Pathophysiological approach to OA
WHAT IS IMPORTANT IN TREATING OSTEOARTHRITIS?
•
Biomechanical or Biochemical targets?
•
Primary Prevention?
o Reduction of risk factors
o 25% to 50% theoretically preventable by reducing obesity and repetitive activities.
•
Secondary Prevention?
o Interventions that prevent progression
o DMOADs
•
Tertiary Treatment?
o Treatment of consequences of OA
OA: FIT TREATMENT TO THE PATIENTS
•
Age
•
Comorbidity
•
Clinical Severity of OA
•
Individual preferences
•
Cost
Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States
11
RA and OA Treatment Webcast, November 3, 2005
OA: FIT TREATMENT TO THE PATIENT
•
What are you treating-pain or limited motion?
•
Discuss the patients concerns - clear up misconceptions
•
Discuss what you can and cannot do for the patient
•
Monthly telephone call to patient on stable treatment reduced joint pain
•
Arthritis self-management education programs(1)
(Self-help course of Arthritis Foundation)
1
Arthritis Rheum 2003; 48:2207-2213
OA: MODIFICATIONS
•
Weight loss if obese
•
Modify activities and occupations
•
Weight-bearing canes, braces and crutches
•
Assistive devices - door handles, toilet seat extenders, special chairs, etc.
•
Secondary fibromyalgia is common - correct sleep habits
OA: PHYSICAL THERAPY
•
Heat (ultrasound, heat packs, wet heat) or ice
•
Gait instruction
•
Massage
•
Balneaotherapy
•
TENS1
•
Exercise2
1
2
Clinical Rehabil 2002; 16:749-60
J Rheumatol 2002; 29:1737-45
OA: Exercise1,2
•
Prescribe progressive exercise to:
o Improve general health
o Modify possible risk-factors in disease progression
o Increase ROM and flexibility
o Increase endurance and strength
o Reduce fall risk
o Chondroprotective
1
2
Current Rheumatology Reports 2001; 3:520-523
J Rheumatol 2002; 29:1737-45
STRENGTHENING AND RECONDITIONING EXERCISE PROGRAM FOR OA
•
Physical and Reconditioning Exercise Program for OA
•
General program for muscle strengthening
o Warm up with ROM stretching
o Lift body part against gravity - 6 to 10 reps.
o Progressively increase resistance with weights or elastic bands
o Cool-down with ROM stretching
•
Progress to aerobic exercise program
ACR Osteoarthritis Guidelines
OA of the Knee
Nonpharmacologic Measures
Topical Therapy
Acetaminophen
NSAIDS, COX-2 Inhibitors
Nonselective NSAID
plus misoprostol or PPI in
high risk patients
Intraarticular
Therapy
(hyaluronan or
glucocorticoids)
Nonacetylated salicylates
Pure Analgesics
(tramadol or opioids)
ACR Subcommittee on OA Guidelines. Arthritis Rheum 2000; 43: 19051905-1915
Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States
12
RA and OA Treatment Webcast, November 3, 2005
PHARMACOLOGIC MANAGEMENT OF OA
•
Topical agents
•
Nonopioid analgesics
•
NSAIDs and COXIBs
•
Opioid analgesics
•
Nutraceuticals and alternative therapies
•
Intra-articular agents
•
Experimental
TOPICAL AGENTS IN OA
•
Counter irritants - Ben-Gay, Flexall 454, Icy-Hot, Mineral Ice, etc.
•
Capsaicin - containing topicals
o May paralyze C type pain fibers
o Two studies support use in OA
o Use daily, 4 times a day, for two weeks before benefit
o Compliance poor without full instruction
o Avoid contact with eyes
•
Topical NSAIDs – Aspercreme, diclofenac
•
Topical Glucosamine sulfate, chondroitin sulfate, and camphor
o
Recent blinded placebo controlled study showed improvement in knee OA in 4 weeks1
1
J Rheumatol 2003; 30:523
ACETAMINOPHEN
1. First-line pharmacological agent in the treatment of patients with OA
2. Low incidence of adverse events and low cost
3. Introduced in Europe in 1893 by von Mering
4. Rapidly and completely absorbed from GI tract
5. Peak plasma concentration in about 30 to 60 minutes
6. Plasma half-life is 2 hours
7. No specific precautions in the elderly
8. Metabolism altered by severe acute or chronic liver disease
9. Watch out for acetaminophen containing products
ACETAMINOPHEN
Mechanism of Action
•
Incompletely understood
•
Inhibitor of COX-3 in CNS
•
Does not inhibit neutrophile activation
•
In animal models inhibits substance P induced nociceptive response
CLINICAL TRIALS IN OSTEOARTHRITIS ACETAMINOPHEN
1. 1991 NEJM study by Bradley, Brandt, et.al.
– Randomized, double-blind, 4 week study with 184 patients with OA of knee
– 3 Groups - 2400mg or 1200mg of ibuprofen or 4,000mg APAP
– Outcome
Variable
(0-3)
HAQ Pain Score
Walking Pain Score
Rest Pain Score
Walking Distance
Score
APAP
4000mg
0.33
0.13
0.06
0.06
Ibuprofen
1200mg
0.30
0.31
0.33
0.01
Ibuprofen
2400mg
0.35
0.45
0.40
0.09
P value
0.93
0.10
0.05
0.77
OA: NSAIDs
•
Most widely prescribed drug class in country
•
1 in 7 Americans use NSAIDs, 17 million regular users, 50% over age 60.
•
111 million prescriptions annually. 3.9 billion dollars in annual costs.
Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States
13
RA and OA Treatment Webcast, November 3, 2005
•
Beneficial effects of NSAIDs
o Analgesia
o Antipyresis
o Anti-inflammatory
o Decreases platelet aggregation
New Theory: Mechanism of
Action of Nonspecific NSAIDs
Arachidonic Acid
COXCOX-1
“Constitutive”
Constitutive”
COXCOX-2
“Inducible”
Inducible”
Nonspecific
NSAIDs
Prostaglandins
Protection of Gastric
Mucosa
Prostaglandins
Hemostasis
Mediate Pain,
Inflammation, and Fever
Donnelly et al. Aliment Pharmacol Ther.
Ther. 1997;11:2271997;11:227-236.
Pairet et al. Fundam Clin Pharmacol.
Pharmacol. 1996:10:11996:10:1-15.
NSAIDs - CLASSIFICATION
•
COX-1 specific - low dose aspirin
•
COX nonspecific - Ibuprofen, Naproxen, Indomethacin, Sulindac, Piroxicam
•
COX-2 preferential - Etodolac, Diclofenac, Nabumetone, Meloxicam
•
COX-2 specific - Celecoxib, Rofecoxib, Valdecoxib
FACTORS AFFECTING THE CHOICE OF NSAIDs - THE DRUG
1. Efficacy
2. Tolerance / Safety
3. Dosage
4. Formulation
5. Cost
NSAIDs - EFFICACY
•
No important differences with any NSAID
•
Individual variations in response
•
No correlation between amount of cyclooxygenase inhibition or plasma levels and efficacy
•
COX-2 Specific Inhibitors: Celecoxib and formerly Rofecoxib, Valdecoxib
o Comparable to Ibuprofen, Naproxen and
Diclofenac
o Suppresses animal models of inflammation
o Indicated for OA, RA and Pain
TOXICITIES OF NSAIDS
•
Hypersensitivity
•
Gastrointestinal
•
Nephrotoxicity
•
Cardiotoxicity
•
Hepatotoxicity
•
Tinnitus / deafness
•
Central Nervous Systems
•
Cutaneous
HYPERSENSITIVITY REACTION AND THE COX-2s
HYPERSENSITIVITY
Aspirin Sensitivity
Normal Subjects
Chronic Rhinitis
Nasal Polyps
Asthma
Asthma w/ Nasal Polyps
Incidence
0.09%
1.4%
14-23%
3.8-28%
up to 78%
Celecoxib and Rofecoxib have generic NSAID warning
( J Allergy Clin Immunol 2001; 108:47)
Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States
14
RA and OA Treatment Webcast, November 3, 2005
FIVE MAIN CATEGORIES OF REACTIONS TO NSAIDs
Underlying
Reaction Mechanisms
Reaction Type Diseases
Cross-Reactions
Cox-1 Inhibition
Immunologic
Cross-reacting Asthma, polyps
respiratory
Sinusitis, rhinitis
Cross-reacting Chronic urticaria
urticaria
or none
Urticaria/
anaphylaxis
None
Aseptic Meningitis
None
Hypersensitivity
None
ASA/NSAIDs
ASA/NSAIDs
None
None
None
Yes
None
Yes
None
No
No
No
IgE mediated
DTH
DTH
Manifestation of NSAID-Induced Upper GI Toxicity
•
PUBs
o perforations
o ulcers
o bleeds
•
POBs
o perforations
o obstructions
o bleeds
•
Discomfort
o dyspepsia
o nausea
o abdominal pain
GASTROINTESTINAL
•
Gastritis, gastric ulcer, duodenal ulcers associated with NSAIDs
o Endoscopic erosions in 10-30% of patients on NSAIDS
o Ulcer complications 4%/year-most have no warning
•
Diarrhea-especially with meclomen
•
No protection from sucralfate and H-2 blockers
•
Protection from misoprostol and pump inhibitors
•
Poor PG inhibitors, such as sodium salicylate group (Disalcid, Trilisate) are easier on the stomach
•
Cox-2 inhibitors similar to placebo on stomach
Effects of ASA on
AntiAnti-inflammatory Drugs: SUCCESS Trial
UGI Safety
NSAIDs/
ASA
NSAIDS
Celecoxib/A
SA
Celecoxib
(N=348)
(N=4046)
(N=697)
(N=8103)
17.4
6.3
10
4.4
Ulcer
complication
1.6
0.8
0.8
0.1
Ulcer
complication/
Symptomatic
ulcers
6.3
1.8
2.3
0.9
UGI events/100 pt-yrs
Possible events
Events were upper GI ulcer complications (perforation, gastric obstruction, bleeding),
symptomatic upper GI ulcerations, or other GI events.
Addition of ASA to NSAIDs and coxibs increases adverse events
Singh et al. Available at: http://www.eular.org/eular2001/AbstractsOnline.cfm.
David H. Collier - 11/03/05
HIGH RISK PATIENTS FOR NSAID INDUCED ULCER
•
Older Age
•
Hx of PUD, GI BLEED
•
Prior NSAID - related GI Intolerance
•
Chronic Diseases (CAD, RA, COPD)
•
Smoking, Ethanol USE
•
Corticosteroids (> 10 mg)
Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States
15
RA and OA Treatment Webcast, November 3, 2005
•
•
Anticoagulant Therapy
Possibly H. Pylori Infection
CARDIOVASCULAR EFFECTS OF COX-2 INHIBITORS
Effects of NSAIDs on
Thromboxane and Prostacyclin
JAMA Article - August 22, 2001
Endothelial cell
Platelet
COX-1
Nonspecific
NSAIDs/ASA
COX-1
Coxibs
COX-2
Thromboxane (Tx) A2
Prostacyclin (PGI2)
Vasoconstrictor
Promotes platelet aggregation
Vasodilator
Inhibitor of platelet aggregation
Hemostasis
Thrombosis
David H. Collier - 11/03/05
McAdam et al. Proc Natl Acad Sci USA. 1999;96:272.
Celecoxib Long-term Arthritis Safety Study
Vioxx® Gastrointestinal Outcomes Research Trial
VIGOR Trial
Design
CLASS Trial
• Randomized, double-blind
• RA patients
Design
• Randomized, double-blind
• OA/RA patients
• Conduct based on clinical
practice norms
• Minimum 6 months’ exposure
Treatments
• Celecoxib 400 mg BID
• Diclofenac 75 mg BID
• Ibuprofen 800 mg TID
• Median follow-up: 9.0 months
Treatments • Rofecoxib 50 mg QD
• Naproxen 500 mg BID
• Low-dose aspirin excluded
• Antacids and OTC H2-receptor antagonists
allowed
• Acetaminophen, non-NSAID analgesics,
glucocorticoids, and DMARDs allowed
Sample size
• 8,076 patients (4,047 rofecoxib; 4,029
naproxen)David H. Collier - 11/03/05
Thromboembolic CV Adverse Events:
VIGOR and CLASS Studies
VIGOR
Q
R
Silverstein, et al. JAMA. 2000;284:1247–1255.
David H. Collier - 11/03/05
Risk of Cardiovascular Events Associated With Selective COX2 Inhibitors
(JAMA. 2001;286:954-959)
CLASS
J
P
Rofecoxib 50 mg qd (n=4047)
Naproxen 500 mg bid (n=4029)
R
R
R
R
R
R
R
RR
R
1.5
R
R
R
R
R
R RR R
RR
R
P
RR
1.0
RR
PP
RR
R
PP
R RR
R
p < 0.05
PPP
R
P
R
0.5
R P PP
R
R
PP
RR
R
P
RP
RP
P
R
R
PP
P
0 PR P
0 40 80 120 160 200 240 280 320 360
2.0
Celecoxib 400 mg bid (n=3987)
NSAIDs (n=3981)
2.5
% of Patients
2.5
% of Patients
Sample size • 8,000 patients (4,000 celecoxib;
2,000 per NSAID); intent-to-treat analysis
2.0
J
JP
PJ
PP J
JPPJ
J
1.5
J P P
JJ P
JJ P
PPJ
P
JJ
PJJP
P
J
J
1.0
PP
P
JJ
P
P
JJ
PP JJ
PJ J
p = 0.973
P
J
PP
JJ
P
0.5
J
PJ
P
PPJ J
PJPJ
P
JJ
J
P
J
P
JPP
JP
0 JPPJ J
0
0
40 80 120 160 200 240 280 320 360
Days
Days
White et al. Am J Cardiol;2002:89:425Cardiol;2002:89:425-430
www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_6_cardio.doc
David H. Collier - 11/03/05
Relative Risk of APTC End Point:
Pooled Analysis
Decreased risk on
rofecoxib
Increased risk on
rofecoxib
NSAIDs and Risk of Cardiovascular Thrombotic Events
No Increased Risk with Celecoxib: All Patients
Rofecoxib
vs placebo
0.84 (0.51, 1.38)
Pt-years = 3867
Celecoxib vs
placebo
Rofecoxib
vs non-naproxen
NSAIDs
0.79 (0.40, 1.55)
Pt-years = 2918
Celecoxib vs
non-naproxen
NSAIDs
Rofecoxib
vs naproxen
1.69 (1.07, 2.69)
Pt-years = 8364
0.2
0.5
1.0
2.0
5.0
Relative risk of rofecoxib to comparator
David H. Collier - 11/03/05
Konstam et al. Circulation. 2001;104:2280.
Increased risk on
celecoxib
Decreased risk on celecoxib
0.85 (0.23, 3.15)
Pt-years=700
1.06 (0.70, 1.61)
Pt-years=4,969
0.93 (0.32, 2.69)
Pt-years=2,422
Celecoxib vs
naproxen
0.0
0.2
0.5
Triangles represent relative risk,
David
and size of triangles represents patient-years of exposure.
Bars indicate 95% CI.
1.0
2.0
H. Collier - 11/03/05
5.0
White WB et al. ACR 2002.
Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States
16
RA and OA Treatment Webcast, November 3, 2005
Cardiovascular Problems with NSAIDS
•
APPROVe study-Vioxx vs placebo in patients with colonic polyp history
o 2,600 pts, 25 mgs Vioxx, after 18 months
o 45 pts CV events Vioxx, 25 pts CV events placebo
•
Adenoma Prevention Trial with Celecoxib or APC trial-NIH
o >2,000 pts, 400 mg, 800 mg Celebrex, > 33 month
o CV events, placebo-6, 400mg-15, 800mg-20
•
Prevention of Spontaneous Adenomatous Polyps or PreSAP trial-Pfizer
o >1,500 pts, 400mg, >33 months
o 400mgs (n=993) 16 events (1.7%, Placebo (n=628)11 events (1.8%)
•
Alzheimer’s Disease Anti-inflammatory Prevention Trial (Adapt)
o Naprosyn more CV events, Celebrex and placebo the same.
FDA Kaiser Permanente Collaboration
•
Objectives
o Determine if risk of AMI and SCD is increased with NSAID or COXIB use
o Compare risk of AMI and SCD between COXIBS: celecoxib and rofecoxib
•
Study Population
o California memebership of Kaiser Permanente (KP)
o All patients age 18-84 treated with coxib or NSAIDs from 1/1/1999 through 12/31/2001
(N = 1.4 million)
•
Methods
o Nested case-control study within this NSAID-exposed study cohort
o Cases: All study cohort members with AMI or SCD during the study period
o N=8,199 acute cardiac events (6,675 AMI: 1,524 SCD)
o Controls: Risk-set matched 4:1 on event date, age, gender and health plan region
AMI=acute myocardial infarction; SCD=sudden cardiac death
Graham et al. Presented at ISPE 2004
Case-control Observational Study
Risk of AMI and SCD With Current Use of
COXCOX-2 Selective and NSNS-NSAIDs
P<0.01
Adjusted† Odds Ratio (95% CI)
3.5
3.15
(1.14-8.75)
3.0
2.5
P=0.06
P=0.01
2.0
1.5
1.0
1.18
(1.04-1.35)
1.09
1.00
0.86
(0.99-1.21)
(reference) (0.69-1.07)
*
P<0.01
1.29
(0.93-1.79)
1.16
(1.04-1.30)
P=0.005
1.33
(1.09-1.63)
1.69
(0.97-2.93)
0.5
0.0
Control
Celecoxib
(remote use)
Ibuprofen
Naproxen Rofecoxib
≤25 mg
Rofecoxib
>25 mg
Other Indomethacin Diclofenac
NSAIDs
AMI=acute myocardial infarction; SCD=sudden cardiac death.
*P=0.04 compared with celecoxib.
†Adjusted for age, gender, health plan region, medical history, smoking, and medication use.
Adapted from Graham et al. Lancet. 2005;365:475-81.
Platelet and Cardiovascular Effects of COX-2 Specific Inhibitors
•
COX-2 specific inhibitors spare platelets
•
COX-2 specific inhibitors do NOT decrease cardiovascular risk
o If have cardiovascular risk, do not use COXIBs
o Celebrex behaves differently than Vioxx or Bextra
•
Patients with cardiovascular risk need
low-dose aspirin (≥ 81 mg/d) – use traditional NSAIDs with PPI
•
All NSAIDs possibly could increase CV risk
RENAL EFFECTS OF COX-2 INHIBITORS
Intrarenal Functional Role of COX-2 vs COX-1
•
COX-2 appears to be a dominant contributor to sodium chloride and water homeostasis.
•
COX-1 appears to have a more dominant role in the maintenance of glomerular filtration rate.
•
Nonetheless, functions of both COX enzymes appear to overlap.
Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States
17
RA and OA Treatment Webcast, November 3, 2005
Renal Syndromes Related to Use of Conventional NSAIDs
Fluid and electrolyte abnormalities
• Sodium chloride and water retention with edema formation (typically ≥ 5%)
• Hyperkalemia
Hypertension
• Interaction with antihypertensive drugs and diuretics
Congestive heart failure
• Fluid retention and interaction with diuretic drug treatment
Acute renal failure
• Hemodynamically mediated during decreased renal perfusion
Nephrotic syndrome
• Minimal change glomerulonephritis and interstitial nephritis
Papillary necrosis
• Acute (usually single-drug pathogenesis)
• Chronic (usually multi- drug pathogenesis)
HIGH RISK PATIENTS FOR RENAL TOXICITIES
•
Older Age
•
ASHD
•
Renal Insufficiency
•
Renal hypoperfusion states: CHF, Cirrhosis, diuretics, hypovolemia, nephrotic syndrome
•
Risk factors for hyperkalemia: diabetes, renal insufficiency, ACE inhibitors, beta blockers,
potassium sparing diuretics
NSAIDs
•
Dosage - single and twice-a-day regimens have more compliance
•
Formulation
o Enteric coated - Ecotrin, Easprin, Diclofenac
o Liquid - Ibuprofen, Naproxen,Trilisate
o Slow release - Indocin SR, Voltaren XR, Naprelan, Oruvail
o Injectable – Ketorolac (soon to see Paracoxib)
•
Cost - use generic NSAIDs first if patient not at risk
o COX-2 inhibitors more costly than traditional NSAID
o Traditional NSAIDS plus H+ pump inhibitor may be less costly as pump inhibitors go
generic.
NSAIDs - COX-2 Inhibitors
•
Drug interactions
o Can be used with warfarin
o Increases methotrexate levels slightly
o Have potential interactions with diuretics and ACE inhibitors, increase drug levels of
lithium
o Celecoxib contraindicated in sulfa allergic
•
COX-2 inhibitors are not “super” aspirin but are a safer aspirin
NONOPIOID ANALGESICS IN OA
•
Tramadol (Ultram)1
•
Tramadol and Acetaminophen (Ultracet)2
o Affects U-1 opioid and serotonin pathways
o Non ulcerogenic
o May be added to NSAIDs, acetaminophen
o Both forms studied in OA and found beneficial
o Side effects: Nausea, vomiting, dizziness, drowsiness, rash, constipation and may lower
seizure threshold
1
2
J Rheumatol 2002;29:2196-9
Clin Ther 2002; 24:282-97
OPIOID ANALGESICS FOR OA
•
Use after most other medical interventions tried
•
Document decrease in pain level (VAS) and increase in function
•
Follow routinely-watch for addictive behavior
Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States
18
RA and OA Treatment Webcast, November 3, 2005
•
•
•
Contract your patients
o State objectives for determining treatment success
o You are exclusive supplier of drug
o Can get urine-tox screen at any time
Codeine, propoxyphene, hydrocodone, oxycodone, and long acting morphine all studied in OA
o Only oxycodone and long acting morphine shown statistically better in blinded study than
acetaminophen
o Anticipate and prevent constipation
o Watch for CNS effects in elderly
o Long-acting oxycodone may have fewer CNS side effects
Morphine and fentanyl patches for severe pain interfering with daily activity and sleep
NUTRACENTICALS IN OA
•
Glucosamine and chondroitin sulfate marked in US as nutritional supplements for arthritis
•
Popularized by Jason Theodasakis, MD in two books, “The Arthritis Cure” and “Maximizing the
Arthritis Cure”
•
www.Theo.com
NUTRACEUTICALS IN OA - SUMMARY
•
Glucosamine and chondroitin sulfate are orally absorbed and preferentially distributed to the joints
•
Have analgesic effect in OA
•
Onset of analgesia slower than NSAIDs
•
Some evidence for “chondroprotection”
•
Very safe. Dose of glucosamine is 500 mg TID, Chondroctin Sulfate 400 mg TID. If respond in
two months may decrease dose.
INTRA-ARTICULAR AGENTS
•
Corticosteroids1
o Two year, double-blinded study of every 3 months injection of steroid or placebo
o Significant pain relief
o No difference in joint space width
•
Hyaluronate
•
IL-Ira (Kineret)2
o 14 patients injected with150mg of IL-1ra
o Dramatic improvement in pain at one month
o No side effects
1
2
Arthritis Rheum 2003; 48:370-77
ACR Annual Scientific Meeting - Late Breaking Abstract - 10/28/03
HYALURONAN OR VISCOSUPPLEMENTATION IN OA
•
Hyaluronic acid (HA) is polysaccharide made up of N-acetyl glucosamine and glucoronic acid and is
core protein of proteoglycans
•
Exhibits elastic and viscous properties - slow movement HA is viscous, fast movement HA is elastic
•
When injected HA disappears from joint in less than a week
•
HA induces the formation of endogenous HA
•
HA has anti-inflammatory effects
•
Human and animal studies show prolonged analgesia after a series of HA injections
Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States
19
RA and OA Treatment Webcast, November 3, 2005
Overall Response to
Hylan G-F 20 Viscosupplementation
Much Better
35.0%
HA
MW 700,000
hylan G-F 20
hylan A MW 6 million
Better
42.2%
Worse or
Much Worse
1.3%
David H. Collier - 11/03/05
Same
21.4%
Reference: Lussier A, Cividino AA, McFarlane CA, et al. Viscosupplementation with hylan for the
treatment of osteoarthritis: findings from clinical practice in Canada. J Rheumatol.
1996;23(9):1579-1585.
David H. Collier - 11/03/05
CAVEATS ABOUT HYALURONAN IN OA
•
The cross linked product (Synvisc) has been reported to be associated with rare post injection
flares
•
About 2.7% of patients develop local adverse reactions
•
Crystalline induced flares have been described post injection
•
Both products are isolated from rooster comb. Patients who are allergic to chickens or eggs
should not receive therapy
•
No studies of repeated series of injections reported
•
Cost of therapy is $500-$800 (HA product, visit, injection) and is reserved for those who failed
conventional therapy
•
Only approved for use in knee but studied in shoulder and ankle
SURGICAL INTERVENTIONS IN OA
•
Tidal joint irrigation
•
Arthroscopic examination
•
Reparative
•
Reconstructive
•
Joint Replacement
Complimentary and Alternative Therapy in Patients with OA
•
Use of Alternative Therapy is Common in OA1
o 4 Ethnic groups studied for use of alternative therapy (AT)
o 83% of all patients used AT
ƒ
African-Americans – 85%
ƒ
Asian – 87%
ƒ
Caucasian – 79%
ƒ
Hispanic –81%
o Dietary changes were the most common AT
1
Arthritis & Rheum 2003; 48(9Supp):S488
ALTERNATIVE THERAPIES IN OA
•
Leech therapy1
•
S-adenosylmethionine (SAMe)2
•
Ginger extract3
•
Avocado/Soybean Unsaponifialbles4
•
Acupuncture5,8
•
Electromagnetic Fields6
•
Magnets7
1
Ann Intern Med 2003; 193:724-730
J Fam Pract 2002; 51: 425-30
3
Arthritis Rheum 2001; 44:2531-8
4
Arthritis Care & Research 2002; 47:50-8
5
Acupuncture Med 2002; 2019-21 & BMC Complement
Altern Med 2002;2:3
6
Cochrane Database Syst Rev 2002; 1:CD003523
7
Curr Med Res Opin 2001; 17:190-6 & Altern Ther Health Med 2002; 8:50-5
8
Arthritis & Rheum 2004;50(9supp);S644
2
Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States
20
RA and OA Treatment Webcast, November 3, 2005
Pulsed Electrical Stimulation (Bionicare Device) in Knee OA1
•
Pulsed Electrical Stimulation (PES) is a low frequency, low amplitude, voltage source, Monphasic,
spiked signal to the knee via skin surface electrodes.
•
Use for 6 or more hours per day
•
Showed mild but statistically significant improvement in physician’s global evaluation, patient’s
evaluation of pain, and patient’s evaluation of function of the treated knee.1
•
Mild skin reactions (thought to be to the gel) in 24%
•
The main author of the study was Thomas Zizic
J Rheumatol 1995;22:1757-61
OA: MANAGEMENT SUMMARY
•
First be sure the pain is joint related
•
Discuss disease and concerns of patient
•
Initial treatment
o Modifications - weight loss, modify activities and occupations, assistive equipment
o Strengthening and reconditioning program
o Topical agents and local heat or ice
o Acetaminophen
OA: MANAGEMENT SUMMARY
•
Second-line approach
o NSAIDs
o Nutraceuticals - glycosamine and chondroitin sulfate
o Intra-articular agents or lavage
ƒ
Steroids
ƒ
Hyaluronan
o Tramadol or Opioids
o Alternative Therapies
•
Third-line
o Arthroscopy
o Osteotomy
o Total joint replacement
ADDITIONAL NOTES:
Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States
21
RA and OA Treatment Webcast, November 3, 2005
Biography of Dr. David Collier
Dr. David H. Collier is the Chief of the Division of Rheumatology at Denver Health
Medical Center, and a Professor of Medicine at University of Colorado Health Sciences
Center. He received a Bachelor of Science degree from California Institute of
Technology in Pasadena, California, and his MD from the Washington University
School of Medicine in St. Louis Missouri. Since his graduation, Dr. Collier has been a
prolific researcher, writer, and presenter. He received an Excellence in Teaching
Award from the Medical Student Council at the University of Colorado Health
Sciences Center in 1998, received the 6th Annual Faculty Outstanding Clinician Award
of the Year in 2000 by the Denver Health and Hospital Medical Staff, and was given
the Rocky Mountain Chapter of the Arthritis Foundation Physician of the Year Award
in 2005. Dr. Collier currently serves on the Board of Directors for the Rocky
Mountain Chapter of the Arthritis Foundation, and acts as Chairman of their Patient
Advocacy Committee.
Description of CHAMPS
CHAMPS, the Community Health Association of Mountain/Plains States, is a nonprofit organization dedicated to providing a coordinating structure of service to nonprofit primary health care programs whose primary purpose is to serve the
medically indigent and medically underserved of Region VIII (CO, MT, ND, SD, UT,
and WY). CHAMPS also serves the Region VIII State Primary Care Associations that
assist those nonprofit primary health care programs. Currently, CHAMPS programs
and services focus on education and training, collaboration and networking, policy
and funding communications, and the collection and dissemination of regional data
for Region VIII Community Health Centers and Primary Care Associations.
For more information, please visit www.champsonline.org or call (303) 861-5165.
Description of the Arthritis Foundation
The Arthritis Foundation exists to help clinicians help their patients. The Arthritis
Foundation supports research, and offers a wide variety of classes, presentations,
and free lectures to provide information and instruction that can help people with
arthritis take control and ensure high quality of life. The mission of the Arthritis
Foundation is to improve lives through leadership in the prevention, control, and
cure of arthritis and related diseases. The Foundation is the only organization in
the country committed solely to helping find a cure for this disease which is the
leading cause of disability in the US, and to making life easier for those who are
faced with the challenges of arthritis. The Rocky Mountain chapter, located in
Denver, Colorado, serves the more than 1 million people with arthritis in Colorado,
Wyoming, and Montana.
For more information, please visit www.arthritis.org or call 1-800-475-6447.
Presented by Dr. David Collier; Sponsored by Community Health Association of Mountain/Plains States
22