Transcript Benefits and risks of treatment of Spondyloarthropathies

Medications used in the treatment
of Spondyloarthropathies
David S. Hallegua MD
Assistant Professor of Medicine
Cedars-Sinai Medical Center/UCLA school
of Medicine
Board Member, Spondylitis Association of
America
Definition
• The spondyloarthropathies are a group of diseases
that share clinical manifestations, genetic
predisposition and disease complications
• They share unique disease causing mechanisms
that can be treated with specific drugs that target
these pathways in the body
• The severity of illness varies widely among
affected individuals and treatment can be tailored
to disease severity
Ankylosing Spondylitis and related spondyloarthritis
Arthritis
Juvenile
Associated with
Inflammatory Spondyloarthritis
Bowel
Ankylosing
Psoriatic
Arthritis
Spondylitis
Acute
Anterior
Uveitis
Undifferentiated
Spondyloarthritis
Reactive
arthritis
Disease Mechanisms in AS and related
illnesses
• Considerable body of evidence pointing to
inflammation as a cause for symptoms
• Inflammation leads to excessive activation of bone
remodeling cells causing bone erosions and
osteoporosis
• New bone formation can lead to fusion of joints
and calcification of ligaments in the spine. The
Dkk protein and Wnt pathways have been
implicated in AS
Dichotomy of Th17 and Treg Subsets
Treg cell
CTLA-4
Self Ag +
TGFb
IL-10
FoxP3
GITR
TGFb
TGFb
PROTECTION
Naive
T-cell
IL-23R
Self Ag +
TGFb + IL-6
IL-23
(survival)
RORgt
IL-17
INFLAMMATION
IL-22
Th17 cell
MMP
CTLA4 = cytotoxic T lymphocyte-associated antigen 4; GITR = glucocorticoid-induced TNF receptor-related protein; MMP = matrix
metalloproteinase; TGF = transforming growth factor.
Tesmer L, et al. Presented at: American College of Rheumatology; November 10-15, 2006; Washington, D.C. Abstract 297; FuruzawaCarballeda J, et al. Autoimmun Rev. 2007;6:169–175; Bettelli E, et al. Nature. 2006;441:235–238; Ivanov II, et al. Cell. 2006;26:1121;
Bacchetta R, et al. J Allergy Clin Immunol. 2007;120:227–235.
Synovitis Promotes Bone Erosion and
osteoporosis via RANKL and TNF
Activated
Macrophages
TNF
TNF
RANK
Osteoclast
Precursors
Activated
T cells
RANK L
Activated
Synoviocytes
TNF
RANK L
TNF
RANK
TNF
TNF
BONE
RANK = receptor activator of nuclear factor-κB; RANKL = RANK ligand.
Gravallese EM, et al. Arthritis Res. 2001;3:6–12; Zwerina J, et al. Arthritis Rheum. 2004;50:277–290.
Activated
Osteoclasts
Organ Involvement in
Spondyloarthropathies
•
•
•
•
•
•
Peripheral arthritis
Spinal involvement
Skin and mucous membranes
Gastrointestinal involvement
Cardiovascular involvement
Pulmonary manifestations
Assessment Tools in AS
•
BASDAI (Bath AS Disease Activity Index)
– 4 Questions on fatigue, pain in neck, back, and hip, pain in other joints, and discomfort in areas
tender to touch or pressure
– 2 Questions on duration and severity of morning stiffness (scores are averaged)
•
BASMI (Bath AS Metrology Index)
–
•
Used to define clinically significant changes in spinal movement
ASAS (Assessment in AS) 20, 40,* 50, 70
– Improvement of ≥ 20%, 40%, 50%, or 70% and absolute improvement of ≥ 10 units in ≥ 3
domains:
• Patient global assessment, back pain, inflammation (mean of both BASDAI stiffness scores),
and function (BASFI)
•
– No deterioration: ≥ 20% worsening or worsening of ≥ 10 units (scale of 0-100) in any domain
ASAS 5/6 (Assessment in AS 5/6)
– ASAS-20 plus 2 additional criteria:
• Spinal mobility (BASMI)
• C-reactive protein (CRP)
– ≥ 20% Improvement in 5 of 6 domains
– No deterioration in any domain
*ASAS-40 is the recommended criteria for evaluating potential disease-modifying agents.
Axial symptoms and signs of AS
Axial symptoms and signs of AS
X-ray showing characteristic squaring of vertebra and
syndesmophytes
Dactylitis
Enthesitis
Treatment for Spondyloarthritis
Peripheral Spondyloarthritis
(± axial disease; ± psoriasis)
Early DMARDs if
synovitis, joint damage
NSAIDs ±
IA corticosteroids
GR
Monitor
NR/PR
GR
2 DMARDs individually or in combination
SSZ, LEF, MTX, cyclosporine
Monitor
NR/PR
Active joint disease?
(≥ 3 TJC & ≥ 3 SJC)
Alternative TNF antagonists followed
by other biologics if continued failure
If YES
NR/PR
TNF antagonists
ACR-50 response?
PASI-75 response?
GR
Monitor
IA = intra-articular; LEF = leflunomide; GR = good response; NR/PR = no response or poor response; PASI-75 = Psoriasis Area and Severity Index
(75% response); PsA = psoriatic arthritis; PsARC = Psoriatic Arthritis Response Criteria; SJC = swollen joint count; SSZ = sulfasalazine;
TJC = tender joint count. Adapted with permission from Kyle S, et al. Rheumatology. 2005;44:390–397. By permission of Oxford University Press.
Non-steroidal anti-inflammatory drugs
• Most of the NSAID’s have FDA approval for AS
• Commonly used non-selective NSAID’s include
diclofenac, ibuprofen, naproxen, indomethacin,
enteric coated aspirin, sulindac,
• Appear to help relieve adequate amount of pain
and stiffness in 50% of AS patients treated
• Limited by stomach toxicity and loss of efficacy
over time
Do NSAIDs Modify Disease Progression?
• 215 patients with AS were randomized to celecoxib 200
mg bid continuous (C) or on demand (OD)
• Structural changes assessed by using the modified Stokes
Ankylosing Spondylitis Spine Score (SASSS)
• At 2 years, 76 C patients had complete radiographs
compared to 74 OD patients
• Mean +/- SD scores for progression was 0.4 +/- 1.7 in the
C group and 1.5 +/- 2.5 in the OD group (p=0.002)
• More studies need to performed before any firm
conclusions can be drawn
Wanders A et al. Arthritis Rheum. 2005;52 (6):1756-65
Upper Gastrointestinal Toxicity From Conventional NSAIDs
GI Adverse Effects Associated
With Conventional NSAIDs
• Upper GI intolerance
– Dyspepsia
– Nausea
– Abdominal pain
• Asymptomatic ulcers
• Symptomatic ulcers
• Ulcer complications
– Bleeding
– Perforation
– Gastric outlet obstruction
Arthritis Care: An Increasing Burden on Healthcare Resources
Mortality From NSAID-Induced GI Complications*
Versus Other Diseases in United States
Number of Deaths
Per Year
25,000
20,197
20,000
16,685
16,500
15,000
10,503
10,000
5,338
5,000
4,441
1,437
0
Leukemia1
HIV1
NSAIDs Multiple Asthma1 Cervical Hodgkin’s
myeloma1
GI2
cancer1 disease1
Cause of Death
*Data from 1997
1. National Center for Health Statistics, 1998; 2. Singh, Triadafilopoulos. J Rheumatol.
1999;26(suppl 56):18–24.
Upper Gastrointestinal Toxicity From Conventional NSAIDs
Strategies for Preventing NSAID-Induced GI
Injury
• Use COX-2 specific inhibitor or non-NSAID analgesic1
• Prescribe lowest effective dose of NSAID
• Administer additional therapy
– Misoprostol2,3
– High-dose H2-receptor antagonist4
– Proton pump inhibitor5,6
• Avoid concomitant anticoagulant or corticosteroid use7,8
1. Wolfe, et al. N Engl J Med. 1999;340:1888–1899; 2. Graham, et al. Ann Intern Med. 1993;119:257–262;
3. Raskin, et al. Ann Intern Med. 1995;123:344–350; 4. Taha, et al. N Engl J Med. 1998;334:1435–1439;
5. Cullen, et al. Aliment Pharmacol Ther. 1998;12:135–140; 6. Hawkey, et al. N Engl J Med. 1998;338:727–734; 7.
Silverstein, et al. Ann Intern Med. 1995;123:241–249; 8. Shorr, et al. Arch Intern Med. 1993;153:1665–1670.
COX-2 Specific Inhibitors: Reducing the Incidence of Upper GI Ulcers
Patients With Ulcers  3 mm (%)
Cumulative Gastric/Duodenal Endoscopic
Ulcer Incidence With Rofecoxib Treatment*
50
45
40
35
30
25
20
15
10
5
0
46.4
Placebo
(n = 340)
Rofecoxib
25 mg/d
(n = 373)
28.5
9.7
Rofecoxib
50 mg/d
(n = 360)
Week 24
Ibuprofen
2,400 mg/d
(n = 354)
†
†
†
7.3
†
4.7
8.1
13.5
**
Week 12
*Life-table estimate, intent-to-treat population
No statistically significant difference between rofecoxib and placebo
†P < 0.001 vs ibuprofen; **placebo group not assessed at week 24
Hawkey, et al. Arthritis Rheum. 2000;43:370–377.
Celecoxib Long-term Arthritis Safety Study
Ulcer Complication and Symptomatic Ulcer
Rates- All Patients
P = 0.02
Annualized Incidence (%)
4
3.54
3
Celecoxib 400 mg BID
P = 0.09
2.08
2
1.45
1
0.76
0
Complications
Complications and
Symptomatic Ulcers
Silverstein, et al. JAMA. 2000;284:1247–1255.
Conventional NSAIDs
Cardiovascular Effects of COX-2 Specific Inhibitors: CLASS Trial
Cardiovascular Adverse Events in CLASS Trial
% of Patients
Celecoxib
All Patients
MI
CVA
Non-Aspirin Users
MI
CVA
NSAIDs
0.3
0.1
0.3
0.3
< 0.1
< 0.1
0.1
0.2
Celecoxib vs NSAIDs: P = NS for all comparisons
MI = myocardial infarction; CVA = cerebrovascular accident
Silverstein, et al. JAMA. 2000;284:1247–1255.
Cardiovascular Effects of COX-2 Specific Inhibitors: VIGOR Trial
Mortality and Cardiovascular Events in VIGOR Trial
Outcome
Death
Rofecoxib
(n = 4,047)
0.5%
Naproxen Difference
(n = 4,029) (95% CI)
0.4%
0.1
(-0.15 to 0.49)
CV death
0.2%
0.2%
0.0
(-0.21 to 0.21)
MI
0.4%*
0.1%
0.3
(0.07 to 0.57)
Ischemic CVA
0.2%
0.2%
0.0
(-0.17 to 0.27)
*P < 0.05 vs naproxen
CV = cardiovascular; MI = myocardial infarction; CVA = cerebrovascular accident
Bombardier, et al. N Engl J Med. 2000;343:1520–1528.
Renal and Related Cardiovascular Effects of Conventional NSAIDs
Conventional NSAIDs: Effects in Hypertension
Findings From Two Meta-analyses1,2
• Conventional NSAID-induced blood pressure
elevations occur in treated hypertensive patients (4–6
mm Hg)1,2
• Normotensive patients are minimally influenced
• Greatest effects seen in patients taking:
– ACE inhibitors
– Beta blockers, vasodilators
ACE = angiotensin converting enzyme
1. Pope, et al. Arch Intern Med. 1993;153:477–484.
2. Johnson, et al. Ann Intern Med. 1994;121:289–300.
Renal and Related Cardiovascular Effects of COX-2 Specific Inhibitors
6-Week Trial in Treated Hypertensive
Patients With OA
Incidence of Edema*
P = 0.014
9.5
% of Patients
10
8
6
4.9
4
2
0
Celecoxib
200 mg QD
(n = 411)
*Assessed by clinical criteria
Whelton, et al. Am J Ther. 2001;8:85–95.
Rofecoxib
25 mg QD
(n = 399)
Renal and Related Cardiovascular Effects of COX-2 Specific Inhibitors
Mean SBP Changes From
Baseline (mm Hg)
6-Week Trial in Treated Hypertensive
Patients With OA
Mean Systolic Blood Pressure (SBP)
3
*
†
‡
2.58
2.61
2.11
2
Rofecoxib 25 mg QD
1
Celecoxib 200 mg QD
0
-1
0.32
0.15
1
2
0.47
3
Week
*P = 0.014; †P = 0.006; ‡P = 0.007
Adapted from Whelton, et al. Am J Ther. 2001;8:85–95.
4
5
6
Renal and Related Cardiovascular Effects of COX-2 Specific Inhibitors
Risks for Poor Renal and Related
Cardiovascular Outcomes in Users of Conventional
NSAIDs or COX-2 Specific Inhibitors
• Caution and appropriate monitoring when used in:
– Heart disease
– Pre-existing renal impairment
– Liver disease
– Advanced age
• Avoid use when serum creatinine  2.5 mg/dL (220 mol/L)
• In elderly hypertensive patients, monitor and treat new onset
of edema and/or destabilization of BP control
• In “at risk” individuals (eg, elderly, patients with heart
disease), monitor for onset of CHF and treat appropriately
Other therapies for AS
• Corticosteroid injections help temporarily with
peripheral arthritis, enthesitis
• White willow bark
• Yarrow extracts
• Acupuncture, massage therapy, spa therapy
• Physical therapy, Tai Chi, stretching exercises
• Opiates such as a fentanyl patch provides relief of
pain
Other oral disease controlling therapy in SpA
1.Sulfasalazine Effective in doses > 2 gm/day in controlling
peripheral arthritis. Rashes, liver inflammation,
sperm count, diarrhea
2. Methotrexate Effective in doses of > 7.5mg/week in
3.Thalidomide
4. Leflunomide
controlling peripheral arthritis. Low blood
counts, liver inflammation, hair loss
Effective at doses of 200 mg/day in reducing
symptoms of AS. Nerve damage, blood clots,
fetal deformities
Preliminary evidence of efficacy in peripheral
arthritis at 20 mg/day. Liver inflammation,
diarrhea, nerve damage
1.Clegg DO et al Arthritis Rheum. 1999;42(11):2325-9. 2.Gonzalez-Lopez L J Rheum.2004;31(8):1568-74
3. Wei JC J Rheum. 2003 Dec;30(12):2627-31
4..Haibel H et al. Ann Rheum Dis. 2005;64(1):124-6
Pamidronate in AS
• 84 AS patients randomized to 60 mg or 10 mg
monthly for 6 months
• Primary outcome variable – 50% decrease in
BASDAI
• 40% of the 60 mg group achieved the primary
outcome variable
• No change in ESR/CRP seen and no major sideeffects were noted. Occasional bone pain
• MRI of lumbar spine showed decrease in edema
Maksymowych WP et al. Arthritis Rheum 2002. 46:766-773
TNF Antagonists in Psoriatic Arthritis
ACR and PASI Results at Week 24
Patients, %
ACR-20
ACR-50
PASI-50
ACR-70
100
100
80
80
60
40
57
39
37
20
42
27
23
60
60
41
47
39
40
23
20
9
0
Adalimumab1
Etanercept2,3
Infliximab4
40 mg EOW
(N = 151)
25 mg BIW
(N = 101)
5 mg/kg
(N = 100)
PASI-90
75
75
59
54
50
PASI-75
0
6
Adalimumab1
40 mg EOW
(N = 69)
Etanercept2,3
25 mg BIW
(N = 66)
ACR = American College of Rheumatology response; BIW = twice weekly; EOW = every other week.
1. Mease PJ, et al. Arthritis Rheum. 2005;52:3279–3289; 2. Mease PJ, et al. Arthritis Rheum. 2004;50:2264–2272;
3. Enbrel® (etanercept) package insert. Immunex Corporation; Thousand Oaks, CA; 2006; 4. Antoni C, et al.
Ann Rheum Dis. 2005;64:1150–1157.
Infliximab4
5 mg/kg
(N = 83)
Radiographic Progression in Patients With PsA
Receiving Etanercept for 2 Years
Placebo → Etanercept (n = 70)
JSN Score
Erosion Score
Total Sharp Score
Mean Change From Baseline
Etanercept → Etanercept (n = 71)
1.2
1.2
1.2
0.8
0.8
0.8
0.4
0.4
0.4
0
0
–0.4
–0.4
ETN OL
–0.8
–0.4
ETN OL
ETN OL
–0.8
0
0
–0.8
5 10 15 20 25
0 5 10 15 20 25
0
Time From Randomization, Months
ETN = etanercept; JSN = Joint Space Narrowing; OL = open label; PsA = psoriatic arthritis.
Adapted with permission from Mease PJ, et al. J Rheumatol. 2006;33:712–721.
5
10 15 20
ATLAS
Adalimumab: Enthesitis Scores (MASES)
Placebo (n = 106)
(baseline mean = 6.7)
Adalimumab (n = 205)
(baseline mean = 6.4)
Mean Change in MASES‡
Week 12
Week 24
0
-1
-2
-1.3
-1.6
-3
-2.7
-4
Score range: 0–13 for pain
*P = 0.018 vs placebo; †P = 0.005 vs placebo.
‡Mean change from baseline.
MASES = Maastricht AS Enthesitis Score.
van der Heijde D, et al. Arthritis Rheum. 2006;54;2136–2146.
*
-3.2
†
Etanercept: Sustained Efficacy
for up to 72 Weeks
Double-Blind
Etanercept
25 mg BIW
Responders, %
100
Open-Label
Etanercept
25 mg BIW
75
50
ASAS-20
ASAS-40
ASAS 5/6
25
0
0
n = 139
12
24
n = 129
36
48
Week
60
72
84
96
n = 105
ASAS = Assessments in Ankylosing Spondylitis group; BIW = twice weekly.
Davis JC, et al. Ann Rheum Dis. 2005;64:1557–1562. Adapted with permission from BMJ Publishing Group.
RAPID 2
Certolizumab Pegol Plus Methotrexate
ACR
Response
Rates
at
Week
24
70
ACR-20
60
ACR-50
57
ACR-70
50
Patients, %
*
*
57
40
*
33
*
32
30
†
16
20
10
†
11
9
3
1
0
Placebo
(n = 130)
Certolizumab Pegol
200 mg q 2 wk
(n = 252)
*P < 0.001 vs placebo; †P ≤ 0.006 vs placebo.
Smolen J, et al. Ann Rheum Dis. 2007;66(suppl 1):187. Abstract THU0202.
Certolizumab Pegol
400 mg q 2 wk
(n = 252)
90
Golimumab in Ankylosing Spondylitis
ASAS Response Rates at Week 14
ASAS 20
80
Patients, %
70
ASAS 40
60.3
59.4
54.3
60
50
43.5
40
30
20
21.8
15.4
10
0
Placebo
(n = 78)
Golimumab
50 mg q 4 wk
(n = 138)
Golimumab
100 mg q 4 wk
(n = 140)
P < 0.001 vs placebo.
Inman R, et al. Arthritis Rheum. 2008 Nov;58(11):3402-12.
Efficacy of TNF Antagonists in AS:
BASDAI-50 Response Rates
Better Response if Treated Early
Patients, %
80
73
58
60
40
31
20
0
< 10 years
(n = 37)
11–20 years
(n = 33)
> 20 years
(n = 29)
Rudwaleit M, et al. Ann Rheum Dis. 2004;63:665–670. Used with permission from BMJ Publishing Group.
RHAPSODY
100
80
Switching to Adalimumab From Etanercept
or Infliximab
ASAS Response Rates at Week 12
No Prior ETN or IFX (n = 877)
Prior ETN or IFX (n = 309)
80
Patients, %
67
63
60
60
46
43
40
20
0
ASAS-20
ASAS-40
ASAS 5/6
ASAS = Assessments in Ankylosing Spondylitis group; ETN = etanercept; IFX = infliximab.
Burmester G, et al. Presented at: American College of Rheumatology annual meeting; November 6-11, 2007;
Boston, Massachusetts, USA. Abstract 945.
Do TNF blockers modify progression of
spinal bone fusion?
• All TNF blockers decrease bone marrow edema on
Gad or fat suppressed MRI
• 41 patients with AS (Group 1) with complete x-ray
sets from an extension trial of infliximab 5 mg/kg for 2
years compared to 41 patients from GESPIC (Group 2)
• Group 1 patients were older, had a longer disease
duration and more radiographic damage at baseline.
• Mean mSASSS change was 0.4 (+/-2.7) (Group 1) and
0.7 (+/-3.4) (Group 2) (p=n.s.).
Baraliakos X et al Ann Rheum Dis. 2005 Mar 18
Uveitis
Monoclonal TNF Antagonists May Be More Effective
Than Etanercept in Preventing Uveitis Flares in AS
Flares/100
Patient-years
n
Before
AntiTNF
With
AntiTNF
P
All anti-TNF
46
51.8
21.4
0.03
Etanercept
13
54.6
58.5
0.92
Monoclonals
33
50.6
6.8
0.001
Infliximab
25
47.4
9.0
0.008
Adalimumab
8
60.5
0.0
0.04
Guignard S, et al. Ann Rheum Dis. 2006;65:1631–1634.
Images used from the collection of JT Rosenbaum, MD.
Psoriasis rash, skin and nail changes
PASI Scoring and PASI Response Levels
Region
Area
Involvement
Severity
0.1
Multiply each
area factor
by
involvement
score (0–6)
Multiply each
area factor
by
sum of severity
scores (0–4)
for redness, scale,
and thickness
0.2
0.3
0.4
Baseline
PASI-50
PASI-75
PASI Score
Total PASI score
is the sum of
involvement and
severity scores
for each
body region
PASI-90
PASI
Response
PASI = Psoriasis Area and Severity Index.
Fredricksson T, et al. Dermatologica. 1978;157:238–244.
100
Psoriasis: Response to TNF Antagonists
at Weeks 24 to 26
PASI-75
Patients, %
80
PASI-90
PGA "Clear or Almost Clear"
79
78
70
65
60
60
59
64
56
55
49
44
39
40
33
ETN2
50 mg BIW
(N = 164)
IFX3
3 mg/kg
q 8 wk
(N = 149)
20
20
0
30
ADA1
40 mg EOW
(N = 814)
ETN2
25 mg BIW
(N = 162)
IFX3
5 mg/kg
q 8 wk
(N = 150)
ADA = adalimumab; ETN = etanercept; IFX = infliximab; EOW = every other week; BIW = twice weekly; PGA = Physician’s Global Assessment.
1, Menter A, et al. J Am Acad Dermatol. 2008;58:106–115. Epub 2007 Oct 23; 2. Leonardi CL, et al. N Engl J Med ,2003;349:2014–2022;
3. Menter A, et al. J Am Acad Dermatol. 2007;56:31.e1–e15.
Health-Related Economic Consequences of
not Treating Severe RA With a TNF Antagonist
• Analysis of RA patients from a single UK district
• All met BSR/NICE guidelines for TNF antagonist eligibility
• Some patients did not receive TNF antagonists due to budget
shortfalls
• Healthcare utilization: On
cost/1000
patient-months
TNF Antagonist
Not on TNF Antagonist
(n = 56)
Outpatient visits
Nurse Calls
ER visits
Hospitalisations
Total costs
$737
$338
$1052
$27,720
$29,848
(n = 36)
$50,440
$586
$3206
$290,070
$344,302
Conclusion: failure to treat active RA results in additional costs
Beevor C, et al. Ann Rheum Dis. 2007;66(suppl II):163. Abstract THU0128.
Use of TNF Antagonists and the Risk for
Cardiovascular Events and Death
Cardiovascular Events
2.5
2.5
Dixon
Suissa
Solomon
1.5
2.0
Ratio
Ratio
2.0
All-Cause Mortality
1.0
1.5
1.0
Carmona
0.5
Greenberg
0.0
0.5 Michaud
Jacobsson
0.0
Data expressed as standardized mortality ratios, hazard ratios, and incidence rate ratios.
Dixon W, et al. Arthritis Rheum. 2006;54(9 suppl). Abstract 681; Suissa S, et al. Arthritis Rheum. 2006;55:531–
536; Greenberg J, et al. Arthritis Rheum. 2006;54(9 suppl). Abstract 917; Solomon DH, et al. Arthritis Rheum.
2006;54:3790–3798; Michaud K, Wolfe F. Ann Rheum Dis. 2005;64(suppl III):87; Jacobsson L, et al. Arthritis
Rheum. 2006;54(9 suppl). Abstract 729; Carmona L, et al. Ann Rheum Dis. 2007;66:880–885.
Safety Considerations With TNF Antagonists
• Serious infections
– Do not initiate in patients with active infections
– Patients with RA are at higher risk than the general population
– Monitor closely and consider discontinuing if a serious infection develops
• Opportunistic infections and TB
– Include histoplasmosis, listeriosis, pulmonary aspergillosis, Pneumocystis
carinii pneumonia
– Patients should be screened for latent TB with a TST prior to use and
re-evaluated on a yearly basis
• Lymphoma
– Patients with RA are at higher risk for lymphoma than the general
population, AS patients may be similar to RA
– Risk for lymphoma may be increased in children receiving TNF antagonists
TB = tuberculosis; TST = tuberculin skin test.
Hochberg MC, et al. Semin Arthritis Rheum. 2005;34:819–836; Keystone E, et al. J Rheumatol. 2005;32:8–12;
Schiff MH, et al. Ann Rheum Dis. 2006;65:889–894; Scott DL, Kingsley GH. N Engl J Med. 2006;355:704–712.
Safety Considerations With TNF Antagonists
• Administration reactions
• Live vaccines are contraindicated
– Including MMR, varicella, Herpes zoster, yellow fever, and intranasal
influenza mist vaccines
• Demyelinating disorders
– Rare; includes exacerbation of MS, optic neuritis, Guillain-Barré syndrome
• Hematologic abnormalities
– Rare; includes cytopenia and pancytopenia (including aplastic anemia)
• CHF
– Rare with adalimumab and etanercept
– Infliximab is contraindicated in patients with NYHA class III & IV CHF
• Autoantibodies, SLE, lupus-like syndrome and new onset psoriasis
– Rare; symptoms include cutaneous lesions, photosensitivity, and
pleural/pericardial serositis, new onset psoriasis
CHF = congestive heart failure; MMR = measles/mumps/rubella; MS = multiple sclerosis; NYHA = New York Heart Association;
SLE = systemic lupus erythematosus.
Hochberg MC, et al. Semin Arthritis Rheum. 2005;34:819–836; Keystone E, et al. J Rheumatol. 2005;32:8–12;
Schiff MH, et al. Ann Rheum Dis. 2006;65:889–894; Scott DL, Kingsley GH. N Engl J Med. 2006;355:704–712.
CORRONA
Significant Risk Factors Associated
With Infections in Patients With RA
• 5596 Patients with RA (6817 PY)
• 3012 Receiving TNF antagonists (54%; 2722 PY)
• ADA: 12%; ETN: 40%; IFX: 48%
Variable
Adjusted RR (95% CI)
TNF blocker
ACR functional class > 2
Erosion
Diabetes
Lung disease
Smoking
1.16 (1.06, 1.28)
1.32 (1.19, 1.48)
1.16 (1.04, 1.28)
1.27 (1.08, 1.50)
1.37 (1.18, 1.58)
1.63 (1.46, 1.83)
ADA = adalimumab; CI = confidence interval; ETN = etanercept; IFX = infliximab; PY = patient-years; RR =
relative risk.
Maury E, et al. Arthritis Rheum. 2005;52:S547. Abstract 1453.
TNF Antagonists Increase the Risk of Hospitalization
for Bacterial Infections in Patients With RA
• Health organization database cohort of RA patients:
– TNF antagonist: N = 2393 (3894 PY)
– MTX: N = 2933 (4846 PY)
• Claims review of all patients with a history of RA who were hospitalized for
infection: 1998–2003; 187 charts
• Chart review of all bacterial infection diagnoses by nurses and
2 blinded infectious disease specialists
Conclusions:
• RR for infection: 1.9 (1.3–2.8) for anti-TNF agent vs MTX
– Number to treat: 143 patients had to receive anti-TNF agents for 1 increased
infection
– Pneumonia: 1/3 of cases
• RR for infection: 4.2 (2.0–8.8) within the first 6 months of therapy
RR = relative risk; PY = patient-years.
Curtis JR, et al. Arthritis Rheum. 2007;56:1125–1133.
ARTIS
•
•
TNF Antagonist Treatment and
the Risk of Hospitalization for Infection
Swedish RA database
– 6410 Biologic-treated patients
• 1998–2006
• IFX 64%, ETN 40%, ADA 13%
– 46,937 Hospitalized patients
• 1964–2004
434 Hospitalizations for infection
– 5.3 per PY with TNF antagonists
Conclusions:
• Increase of 30% in hospitalization in
patients receiving TNF antagonists
• No increase in mortality
• Risk decreases with duration of
treatment (RR = 0.82 after 2 years)
RR
Adjusted for Age, Sex, Propensity
All
Infections
1.31 (1.18–1.46)
Respiratory
1.20 (1.02–1.46)
Sepsis
1.11 (0.85–1.45)
Articular
1.63 (1.15–2.31)
GI
0.81 (0.57–1.16)
Cutaneous
0.88 (0.61–1.28)
ADA = adalimumab; ETN = etanercept; IFX = infliximab; PY = patient-years; RR = relative risk.
Adapted from Askling J, et al. Ann Rheum Dis, 2007;66:1339–1344 .
BSRBR
TNF Antagonists and the Risk of
Serious Postoperative Infections
On/Off at Time of
Surgery
On
SPOI
AOR
(CI)
Off
49 (3.0%) 15 (3.5%)
On/Off for 28 d
Before Surgery
On 28 d
Off 28 d
59 (3.4%)
5 (1.4%)
1.00
1.15
1.00
0.38
(Ref)
(0.62–2.12)
(Ref)
(0.38–0.93)
• Treatment with TNF antagonists or DMARDs resulted in the same risk for
SPOI (OR not significant)
• Patients on or off TNF antagonists had same low risk of SPOI
• Patients off TNF antagonists > 28 days had a 60% reduction in SPOI
• Data support discontinuation of TNF antagonists ≥ 4 weeks before surgery
AOR = adjusted odds ratio; OR = odds ratio; Ref = referent; SPOI = serious postoperative infections.
Dixon W, et al. Ann Rheum Dis. 2007;66(suppl II):118. Abstract OP0215; Dixon W, et al. Data presented at:
European League Against Rheumatism Annual Meeting; Barcelona, Spain; June 13-16, 2007.
TB Rates Prescreening and Postscreening
in Clinical Trials With Adalimumab
Events per 100 PY
2.0
Prior to TST
Prescreening
1.5
After Introduction of TST
Postscreening
1.31
Combined 0.27
1.0
0.5
0.33
0.08
0.0
No. of cases
Exposure (PY)
Europe
Europe
7
534
23
7058
North America
4
4914
*Through April 15, 2005. Data from RA clinical trials with adalimumab, including open-label extension
studies and phase IV studies.
PY = patient years; TB = tuberculosis.
Adapted with permission from Schiff MH, et al. Ann Rheum Dis. 2006;65:889–894. Used with permission
from BMJ Publishing Group.
Infliximab and Opportunistic Infections
Postmarketing Reports
Adverse Event
Pneumocystis carinii pneumonia
Histoplasmosis
Atypical mycobacteria
Listeriosis
CMV infections
Aspergillosis
Systemic candidiasis
Coccidioidomycosis
Cryptococcus
Nocardia
Toxoplasmosis
Blastomycosis
CMV = cytomegalovirus; PY = patient-years.
FDA Periodic Safety Update Report 10; August 2004.
Reports per 100 PY
0.07
0.06
0.06
0.05
0.04
0.04
0.03
0.03
0.02
0.02
0.01
0.00
Risk of Malignancy in Patients
Receiving Biologic DMARDs
Cases
Odds Ratio
(95% Confidence
Interval)
All
537
1.0 (0.8–1.2)
Breast
102
0.9 (0.5–1.3)
Colon
37
0.8 (0.3–1.7)
Lung
112
1.1 (0.7–1.8)
Lymphoma
45
1.0 (0.5–2.0)
Melanoma
32
2.3 (0.9–5.4)*
Skin (nonmelanoma)
623
1.5 (1.2-1.8)†
Cancer
*P = 0.07; †P < 0.001.
Wolfe F, Michaud K. Arthritis Rheum. 2007;56:2886–2895.
ARTIS
Cancer Rates in RA Patients
Treated With TNF Antagonists
Relative Risk (all Primaries) by Time Since Start of Treatment1
Cancer Site
< 1 Year
1–3 Years
> 3 Years
All sites
0.98 (0.75–1.27)
0.88 (0.70–1.11)
0.99 (0.76–1.27)
Lung
1.11 (0.56–2.19)
1.15 (0.65–2.03)
1.62 (0.94–2.77)
Breast
0.72 (0.26–1.96)
0.65 (0.28–1.51)
0.50 (0.20–1.24)
NMSC
2.06 (1.00–4.23)
1.57 (0.84–2.92)
1.15 (0.50–2.63)
• Overall, no increased occurrence of cancer in patients receiving TNF antagonists1
• Signals suggestive of an increased risk for certain cancer types1 are consistent with
results from other studies
– Lung (COPD trial of infliximab)2
– Solid malignancies (Wegener’s granulomatosis etanercept study)3
– Melanoma and nonmelanoma skin cancer4
– Lymphoma and Leukemia in children⁵
COPD = chronic obstructive pulmonary disease; NMSC = nonmelanoma skin cancer.
1. Askling J, et al. Data presented at: EULAR; June 13–16, 2007; Barcelona, Spain. Abstract OP0013; 2. Rennard SI, et al. Am J
Respir Crit Med. 2007;175;926–934; 3. WGET Research Group. N Engl J Med. 2005;352:351–361; 4. Wolfe F, Michaud K. Arthritis
Rheum. 2007;56:2886–2895; 5. Watson KD, et al. Ann Rheum Dis. 2006;65(suppl III):512. Abstract SAT0202.
The Effect of Previous Cancer on the Risk of
Recurrent Cancer With TNF Antagonists
CA
Status
N
CA
(n)
Rate per
1000 PY
10.0
8.0
4.0
2.0
No prior CA
1819
27
14.1
Prior CA
58
1
18.2
IRR
DMARD
1.0
0.4
0.2
Anti-TNF Agents
No prior CA
9844
158
8.4
Prior CA
154
6
20.5
0.1
No Prior
CA
DMARD
Prior
CA
No Prior
CA
Prior
CA
TNF Antagonist
• The overall risk of cancer was not significantly different between patients receiving
DMARDs and patients receiving TNF antagonists (IRR = 0.7; 95% CI: 0.4, 1.2)
• The risk of recurrent cancer was not increased in patients receiving DMARDs
(IRR = 1.2, 95% CI: 0.2, 8.9) but was significantly increased with respect to lymphoid
malignancies in patients receiving TNF antagonists (IRR = 2.5; 95% CI: 1.2, 5.8)
CA = cancer; CI = confidence interval; IRR = incidence risk ratio; PY = patient-years.
Watson K, et al. Ann Rheum Dis. 2006;65(suppl III):512. Abstract SAT0202.
Future Direction of Spondyloarthritis
Research
•Improve understanding of risk of infectious and
neoplastic risks of treatments
•Increase in the therapeutic arsenal to control the
illness
•Prevention of fusion of the spine and the joints