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

AcuteAnteriorUveitis

Psoriatic Arthritis

Reactive arthritis

Undifferentiated Spondyloarthritis

ArthritisAssociated with Inflammatory

Bowel

JuvenileSpondyloarthritis

Ankylosing Spondylitis and related spondyloarthritis

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

FoxP3

Treg cell

Self Ag + TGF

IL-10

TGFPROTECTION

IL-17

IL-22

MMP

INFLAMMATIONSelf Ag + TGF + IL-6

IL-23 (survival)

IL-23R

CTLA-4

TGFGITR

Naive T-cell

RORt

Th17 cell

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; Furuzawa-Carballeda 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.

Dichotomy of Th17 and Treg Subsets

Activated Osteoclasts

Osteoclast Precursors

RANKRANK

C

ytokines

TNF

ActivatedT cells

Activated Synoviocytes

ActivatedMacrophages

TNF TNF

BONEBONE

RANKRANK

RANK LRANK L

TNFTNF

TNF

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.

RA

NK

LR

AN

K L

Synovitis Promotes Bone Erosion and osteoporosis via RANKL and TNF

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 SpondyloarthritisPeripheral Spondyloarthritis(± axial disease; ± psoriasis)

NSAIDs ± IA corticosteroids

Early DMARDs if synovitis, joint damage

MonitorGR

2 DMARDs individually or in combinationSSZ, LEF, MTX, cyclosporine

MonitorGR

NR/PR

Active joint disease?(≥ 3 TJC & ≥ 3 SJC)

If YES

TNF antagonistsACR-50 response?PASI-75 response?

GRMonitor

NR/PR

Alternative TNF antagonists followed by other biologics if continued failure

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.

NR/PR

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

GI Adverse Effects Associated With 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

• Upper GI intolerance– Dyspepsia– Nausea– Abdominal pain

• Asymptomatic ulcers

• Symptomatic ulcers

• Ulcer complications– Bleeding – Perforation– Gastric outlet obstruction

Upper Gastrointestinal Toxicity From Conventional NSAIDsUpper Gastrointestinal Toxicity From Conventional NSAIDs

Mortality From NSAID-Induced GI Complications* Versus Other Diseases in United States

Mortality From NSAID-Induced GI Complications* Versus Other Diseases in United States

*Data from 19971. National Center for Health Statistics, 1998; 2. Singh, Triadafilopoulos. J Rheumatol. 1999;26(suppl 56):18–24.

*Data from 19971. National Center for Health Statistics, 1998; 2. Singh, Triadafilopoulos. J Rheumatol. 1999;26(suppl 56):18–24.

20,19720,197

16,68516,685 16,50016,500

10,50310,503

5,3385,338 4,4414,441

1,4371,437

00

5,0005,000

10,00010,000

15,00015,000

20,00020,000

25,00025,000

Leukemia1Leukemia1 HIV1HIV1 NSAIDs GI2

NSAIDs GI2

Multiplemyeloma1

Multiplemyeloma1

Asthma1Asthma1 Cervicalcancer1

Cervicalcancer1

Hodgkin’sdisease1

Hodgkin’sdisease1

Nu

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of

De

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s

Pe

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P

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Cause of DeathCause of Death

Arthritis Care: An Increasing Burden on Healthcare ResourcesArthritis Care: An Increasing Burden on Healthcare Resources

Strategies for Preventing NSAID-Induced GI Injury

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

• 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.

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.

Upper Gastrointestinal Toxicity From Conventional NSAIDsUpper Gastrointestinal Toxicity From Conventional NSAIDs

Placebo (n = 340)

Rofecoxib25 mg/d (n = 373)

Rofecoxib50 mg/d(n = 360)

Ibuprofen2,400 mg/d(n = 354)

Placebo (n = 340)

Rofecoxib25 mg/d (n = 373)

Rofecoxib50 mg/d(n = 360)

Ibuprofen2,400 mg/d(n = 354)

*Life-table estimate, intent-to-treat populationNo statistically significant difference between rofecoxib and placebo†P < 0.001 vs ibuprofen; **placebo group not assessed at week 24Hawkey, et al. Arthritis Rheum. 2000;43:370–377.

*Life-table estimate, intent-to-treat populationNo statistically significant difference between rofecoxib and placebo†P < 0.001 vs ibuprofen; **placebo group not assessed at week 24Hawkey, et al. Arthritis Rheum. 2000;43:370–377.

Cumulative Gastric/Duodenal Endoscopic Ulcer Incidence With Rofecoxib Treatment*Cumulative Gastric/Duodenal Endoscopic Ulcer Incidence With Rofecoxib Treatment*

7.37.3 †

4.7

†

4.7

†

9.7

†

9.7†

8.1

†

8.1

†

13.5

†

13.5

28.528.5

46.446.4

0055

1010151520202525

303035354040

45455050

Week 12Week 12 Week 24Week 24

Pat

ien

ts W

ith

Ulc

ers

3

mm

(%

)P

atie

nts

Wit

h U

lcer

s

3 m

m (

%)

COX-2 Specific Inhibitors: Reducing the Incidence of Upper GI UlcersCOX-2 Specific Inhibitors: Reducing the Incidence of Upper GI Ulcers

****

Celecoxib Long-term Arthritis Safety StudyCelecoxib Long-term Arthritis Safety Study

Ulcer Complication and Symptomatic Ulcer

Rates- All Patients

Ulcer Complication and Symptomatic Ulcer

Rates- All Patients

Silverstein, et al. JAMA. 2000;284:1247–1255.Silverstein, et al. JAMA. 2000;284:1247–1255.

Celecoxib 400 mg BID

Conventional NSAIDs

Celecoxib 400 mg BID

Conventional NSAIDs

An

nu

aliz

ed I

nci

den

ce (

%)

An

nu

aliz

ed I

nci

den

ce (

%)

00

11

22

33

44

ComplicationsComplications Complications andSymptomatic UlcersComplications and

Symptomatic Ulcers

P = 0.09P = 0.09

P = 0.02P = 0.02

0.760.76

1.451.45

2.082.08

3.543.54

Celecoxib NSAIDsCelecoxib NSAIDs

All Patients

MI 0.30.3

CVA 0.10.3

Non-Aspirin Users

MI < 0.10.1

CVA < 0.10.2

All Patients

MI 0.30.3

CVA 0.10.3

Non-Aspirin Users

MI < 0.10.1

CVA < 0.10.2

Cardiovascular Adverse Events in CLASS TrialCardiovascular Adverse Events in CLASS Trial

Cardiovascular Effects of COX-2 Specific Inhibitors: CLASS TrialCardiovascular Effects of COX-2 Specific Inhibitors: CLASS Trial

Celecoxib vs NSAIDs: P = NS for all comparisonsMI = myocardial infarction; CVA = cerebrovascular accidentSilverstein, et al. JAMA. 2000;284:1247–1255.

Celecoxib vs NSAIDs: P = NS for all comparisonsMI = myocardial infarction; CVA = cerebrovascular accidentSilverstein, et al. JAMA. 2000;284:1247–1255.

% of Patients% of Patients

Mortality and Cardiovascular Events in VIGOR TrialMortality and Cardiovascular Events in VIGOR Trial

*P < 0.05 vs naproxenCV = cardiovascular; MI = myocardial infarction; CVA = cerebrovascular accidentBombardier, et al. N Engl J Med. 2000;343:1520–1528.

*P < 0.05 vs naproxenCV = cardiovascular; MI = myocardial infarction; CVA = cerebrovascular accidentBombardier, et al. N Engl J Med. 2000;343:1520–1528.

Rofecoxib NaproxenDifferenceOutcome (n = 4,047) (n = 4,029)(95% CI)

Death 0.5% 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)

Rofecoxib NaproxenDifferenceOutcome (n = 4,047) (n = 4,029)(95% CI)

Death 0.5% 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)

Cardiovascular Effects of COX-2 Specific Inhibitors: VIGOR TrialCardiovascular Effects of COX-2 Specific Inhibitors: VIGOR Trial

ACE = angiotensin converting enzyme1. Pope, et al. Arch Intern Med. 1993;153:477–484.2. Johnson, et al. Ann Intern Med. 1994;121:289–300.

ACE = angiotensin converting enzyme1. Pope, et al. Arch Intern Med. 1993;153:477–484.2. Johnson, et al. Ann Intern Med. 1994;121:289–300.

Conventional NSAIDs: Effects in Hypertension

Findings From Two Meta-analyses1,2

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

• 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

Renal and Related Cardiovascular Effects of Conventional NSAIDsRenal and Related Cardiovascular Effects of Conventional NSAIDs

Incidence of Edema*Incidence of Edema*

Renal and Related Cardiovascular Effects of COX-2 Specific InhibitorsRenal and Related Cardiovascular Effects of COX-2 Specific Inhibitors

*Assessed by clinical criteriaWhelton, et al. Am J Ther. 2001;8:85–95.*Assessed by clinical criteriaWhelton, et al. Am J Ther. 2001;8:85–95.

P = 0.014P = 0.014

9.59.5

00

22

44

66

88

1010

Celecoxib 200 mg QD

(n = 411)

Celecoxib 200 mg QD

(n = 411)

Rofecoxib 25 mg QD(n = 399)

Rofecoxib 25 mg QD(n = 399)

% o

f P

atie

nts

% o

f P

atie

nts

4.94.9

6-Week Trial in Treated Hypertensive Patients With OA

6-Week Trial in Treated Hypertensive Patients With OA

Renal and Related Cardiovascular Effects of COX-2 Specific InhibitorsRenal and Related Cardiovascular Effects of COX-2 Specific Inhibitors

*P = 0.014; †P = 0.006; ‡P = 0.007Adapted from Whelton, et al. Am J Ther. 2001;8:85–95.*P = 0.014; †P = 0.006; ‡P = 0.007Adapted from Whelton, et al. Am J Ther. 2001;8:85–95.

Mean Systolic Blood Pressure (SBP)Mean Systolic Blood Pressure (SBP)

Rofecoxib 25 mg QD

Celecoxib 200 mg QD

Rofecoxib 25 mg QD

Celecoxib 200 mg QD

-1-1

00

11

22

33

11 22 33 44 55 66WeekWeek

Me

an

SB

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Fro

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Me

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*2.11*

2.11

†

2.58

†

2.58

‡

2.61

‡

2.61

-0.32

-0.32

-0.15

-0.15

-0.47

-0.47

6-Week Trial in Treated Hypertensive Patients With OA

6-Week Trial in Treated Hypertensive Patients With OA

Risks for Poor Renal and Related Cardiovascular Outcomes in Users of Conventional

NSAIDs or COX-2 Specific Inhibitors

Renal and Related Cardiovascular Effects of COX-2 Specific InhibitorsRenal and Related Cardiovascular Effects of 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

• 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 controlling peripheral arthritis. Low blood counts, liver inflammation, hair loss

3.Thalidomide Effective at doses of 200 mg/day in reducing symptoms of AS. Nerve damage, blood clots, fetal deformities

4. Leflunomide 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 side-effects 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 ArthritisACR and PASI Results at Week 24

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.

40 mg EOW(N = 151)

Adalimumab1

25 mg BIW(N = 101)

Etanercept2,3 Infliximab4

5 mg/kg(N = 100)

Pat

ien

ts,

%

40 mg EOW(N = 69)

Adalimumab1

25 mg BIW(N = 66)

Etanercept2,3 Infliximab4

5 mg/kg(N = 83)

75

47

75

59

23

60

42

6

39

0

20

40

60

80

100

PASI-50 PASI-75 PASI-90

5750 54

39 37 41

23

9

27

0

20

40

60

80

100ACR-20 ACR-50 ACR-70

1.2

0.8

0.4

0

–0.8

–0.4

1.2

0.8

0.4

0

–0.8

–0.4

1.2

0.8

0.4

0

–0.8

–0.4

Mea

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Time From Randomization, Months

5 15 250 10 20 5 15 250 10 20 5 150 10 20

Total Sharp Score Erosion Score JSN Score

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.

Etanercept → Etanercept (n = 71)Placebo → Etanercept (n = 70)

ETN OL ETN OL ETN OL

Radiographic Progression in Patients With PsA Receiving Etanercept for 2 Years

Week 12 Week 24

Adalimumab (n = 205) (baseline mean = 6.4)

Placebo (n = 106)(baseline mean = 6.7)

Mea

n C

han

ge

in M

AS

ES

‡

-1.3-1.6

-2.7

* -3.2†

-4

-3

-2

-1

0

*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.

ATLAS

Score range: 0–13 for pain

Adalimumab: Enthesitis Scores (MASES)

Etanercept: Sustained Efficacy for up to 72 Weeks

Res

po

nd

ers,

%

n = 139 n = 129 n = 105

0

25

50

75

100

0 12 24 36 48 60 72 84 96Week

ASAS-20ASAS-40ASAS 5/6

Double-BlindEtanercept 25 mg BIW

Open-Label Etanercept 25 mg BIW

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.

                                                                                                                        

                                          

Certolizumab Pegol Plus MethotrexateACR Response Rates at Week 24

Placebo(n = 130)

Certolizumab Pegol200 mg q 2 wk

(n = 252)

Certolizumab Pegol400 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.

119

57 57

31

32 33

16

*

*

*

*

††

RAPID 2

0

10

20

30

40

50

60

70

Pat

ien

ts,

%

ACR-20

ACR-50

ACR-70

Golimumab in Ankylosing SpondylitisASAS Response Rates at Week 14

Placebo(n = 78)

Golimumab50 mg q 4 wk

(n = 138)

Golimumab100 mg q 4 wk

(n = 140)P < 0.001 vs placebo. Inman R, et al. Arthritis Rheum. 2008 Nov;58(11):3402-12.

21.8

59.460.3

15.4

43.5

54.3

ASAS 20 ASAS 40

0

10

20

30

40

50

60

70

80

90

Pat

ien

ts,

%

Efficacy of TNF Antagonists in AS: BASDAI-50 Response Rates

Better Response if Treated Early

Rudwaleit M, et al. Ann Rheum Dis. 2004;63:665–670. Used with permission from BMJ Publishing Group.

73

58

31

0

20

40

60

80

< 10 years 11–20 years > 20 years

Pat

ien

ts,

%

(n = 37) (n = 33) (n = 29)

Switching to Adalimumab From Etanerceptor Infliximab

ASAS Response Rates at Week 12

0

20

40

60

80

100

ASAS-20 ASAS-40 ASAS 5/6

Pat

ien

ts,

%

No Prior ETN or IFX (n = 877)

Prior ETN or IFX (n = 309)

RHAPSODY

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.

80

6067

46

63

43

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

n

Flares/100

Patient-years

P

Before Anti-TNF

With Anti-TNF

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

Monoclonal TNF Antagonists May Be More Effective Than Etanercept in Preventing Uveitis Flares in AS

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

PASI = Psoriasis Area and Severity Index.Fredricksson T, et al. Dermatologica. 1978;157:238–244.

Baseline PASI-50 PASI-75 PASI-90

Total PASI scoreis the sum of involvement andseverity scores for each body region

Region Area Involvement Severity

0.4

0.2

0.3

0.1 Multiply eacharea factor

byinvolvementscore (0–6)

Multiply eacharea factor

bysum of severity

scores (0–4) for redness, scale,

and thickness

PASI Response

PASI Score

Psoriasis: Response to TNF Antagonists at Weeks 24 to 26

0

20

40

60

80

100

Pat

ien

ts,

%

PASI-75 PASI-90 PGA "Clear or Almost Clear"

ADA1

40 mg EOW(N = 814)

ETN2

25 mg BIW(N = 162)

ETN2

50 mg BIW(N = 164)

IFX3

3 mg/kg q 8 wk

(N = 149)

IFX3

5 mg/kg q 8 wk

(N = 150)

70

49

60

44

20

39

59

30

55

65

33

64

78

56

79

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: cost/1000 patient-months On TNF Antagonist (n = 56)

Not on TNF Antagonist

(n = 36)

Outpatient visits

$737 $50,440

Nurse Calls $338 $586ER visits $1052 $3206Hospitalisations $27,720 $290,070Total costs $29,848 $344,302Conclusion: failure to treat active RA results in additional costs

Beevor C, et al. Ann Rheum Dis. 2007;66(suppl II):163. Abstract THU0128.

Greenberg

SolomonSuissa

Dixon

0.0

0.5

1.0

1.5

2.0

2.5

MichaudJacobsson

Carmona

0.0

0.5

1.0

1.5

2.0

2.5

Cardiovascular Events All-Cause Mortality

Use of TNF Antagonists and the Risk for Cardiovascular Events and Death

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.

Rat

io

Rat

io

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

• 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

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.

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

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 1.16 (1.06, 1.28)ACR functional class > 2 1.32 (1.19, 1.48)Erosion 1.16 (1.04, 1.28)Diabetes 1.27 (1.08, 1.50)Lung disease 1.37 (1.18, 1.58)Smoking 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.

CORRONA

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.

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

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)

ARTIS

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)

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 .

TNF Antagonists and the Risk of Serious Postoperative Infections

On/Off at Time of Surgery

On/Off for 28 d Before Surgery

On Off On 28 d Off 28 d

SPOI 49 (3.0%) 15 (3.5%) 59 (3.4%) 5 (1.4%)

AOR(CI)

1.00(Ref)

1.15 (0.62–2.12)

1.00(Ref)

0.38 (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

BSRBR

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.

0.0

0.5

1.0

1.5

2.0

Europe North AmericaEurope

Eve

nts

per

100

PY

Prior to TSTPrescreening

After Introduction of TSTPostscreening

No. of cases 7

534

23 4

7058 4914Exposure (PY)

*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.

0.330.08

1.31

Combined 0.27

TB Rates Prescreening and Postscreening in Clinical Trials With Adalimumab

Adverse Event Reports per 100 PY Pneumocystis carinii pneumonia 0.07Histoplasmosis 0.06Atypical mycobacteria 0.06Listeriosis 0.05CMV infections 0.04Aspergillosis 0.04Systemic candidiasis 0.03Coccidioidomycosis 0.03Cryptococcus 0.02Nocardia 0.02Toxoplasmosis 0.01Blastomycosis 0.00

CMV = cytomegalovirus; PY = patient-years.FDA Periodic Safety Update Report 10; August 2004.

Infliximab and Opportunistic Infections Postmarketing Reports

Risk of Malignancy in Patients

Receiving Biologic DMARDs

Cancer 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)†

*P = 0.07; †P < 0.001.Wolfe F, Michaud K. Arthritis Rheum. 2007;56:2886–2895.

Cancer Rates in RA Patients Treated With TNF Antagonists

• 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

Cancer Site

Relative Risk (all Primaries) by Time Since Start of Treatment1

< 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)

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.

ARTIS

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.

IRR

0.1

0.2

1.0

2.0

4.0

DMARD TNF Antagonist

0.4

No PriorCA

PriorCA

No PriorCA

PriorCA

8.0CAStatus N

CA(n)

Rate per1000 PY

DMARD

No prior CA 1819 27 14.1

Prior CA 58 1 18.2

Anti-TNF Agents

No prior CA 9844 158 8.4

Prior CA 154 6 20.5

• 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)

The Effect of Previous Cancer on the Risk of Recurrent Cancer With TNF Antagonists

10.0

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