Optimization treatment AS and RA by Samy Slimani

Raising the bar in the treatment of AS and RA - What is new in efficacy and safety? AFLAR 2011 5th May 2011, Algeria

Dr. Xenofon Baraliakos Rheumazentrum Ruhrgebiet Ruhr-University Bochum Germany

Raising the bar in the treatment of AS and RA - What is new in efficacy and safety? Topics of the presentation •Ankylosing spondylitis,Spondyloarthritis •Rheumatoid arthritis •Safety of biologics

SpA: Common clinical characteristics Spine Sacroiliitis, Spondylitis

Eyes

Arthritis

Uveitis

Enthesitis, Dactylitis

Skin Psoriasis

Urinary systems Reactive SpA

Bowel Inflamm. bowel disease Reactive SpA

Spondyloarthritides (SpA) Main Manifestations 1. Axial involvement/spinal inflammation 2. Peripheral arthritis/enthesitis

Axial SpA

3. Organ involvement

SpA Subtypes 1.

Ankylosing spondylitis (AS)

2. 3. 4. 5.

Undifferentiated SpA Psoriatic SpA Reactive SpA SpA associated with chronic inflammatory bowel diseases

The radiographic cut-off between AS and uSpA according to the modified New York Criteria

Sacroiliitis

Grade 0 â&#x20AC;&#x201C; 2 unilaterally Undifferentiated Spondyloarthritis

Grade 2 bilateral â&#x20AC;&#x201C; Grad 4 Ankylosing Spondylitis

Mean delay for diagnosis in AS: 9 years 100% 80%

Erkrankungsalter

60% Alter bei der Diagnose

40%

920 m채nnliche 476 weibliche Patienten

20%

Male Female

v 20

Age in Years Feldtkeller E, Curr Opin Rheumatol 2000

Mean delay for diagnosis in AS: 9 years 100% 80%

Erkrankungsalter

60% Alter bei der Diagnose

40%

920 m채nnliche 476 weibliche Patienten

20%

Male Female

Age in Years Feldtkeller E, Curr Opin Rheumatol 2000

Clinical situation • Male, 28 years old • LBP since some years • Symptomatic therapy • One episode of uveitis 5 yrs ago • Positive family history with AS • HLA-B27 positive • CRP 2.8 mg/dl

Clinical situation

Clinical situation 6 years earlier

Timepoint of diagnosis

ASAS Classification Criteria for Axial Spondyloarthritis (SpA) In patients with ≥3 months back pain and age at onset <45 years Sacroiliitis on imaging* plus

HLA-B27 OR

plus

≥1 SpA feature# #

SpA features • inflammatory back pain • arthritis • enthesitis (heel) • uveitis • dactylitis • psoriasis • Crohn‘s/colitis • good response to NSAIDs • family history for SpA • HLA-B27 • elevated CRP

Rudwaleit M et al. Ann Rheum Dis 2009;68:777-783 (with permission)

≥2 other SpA features# *Sacroiliitis on imaging • •

active (acute) inflammation on MRI highly suggestive of sacroiliitis associated with SpA definite radiographic sacroiliitis according to mod NY criteria

n=649 patients with back pain; Sensitivity: 82.9%, Specificity: 84.4% Imaging alone: Sensitivity: 66.2%, Specificity: 97.3%

ASAS/EULAR Recommendations for the Management of Ankylosing Spondylitis

Education, exercise, physical therapy, rehabilitation, patient associations, self help groups

NSAIDs Peripheral disease

Axial disease

Sulfasalazine Local corticosteroids

TNF Blockers

Zochling J et al. Ann Rheum Dis 2006;65:442-52 (with permission)

A n a l g e s i c s

S u r g e r y

Efficacy of NSAIDs for the Treatment of Patients with Ankylosing Spondylitis

AS (n=69)

Mechanical Back Pain (n=768)

1. Amor B et al. Rev Rheum Engl Ed 1995;62:10-5 2. van der Heijde D et al. Arthritis Rheum 2005;52:1205-15

Etoricoxib 90/120 mg (n=195)

Placebo (n=93)

Conventional DMARDs Are Largely Not Effective for the Treatment of Patients with AS Sulfasalazine1

Leflunomide2

Methotrexate3

2 g/day

20 mg/day

20 mg/week sc

P=0.03

1. Braun J et al. Ann Rheum Dis 2006;65:1147-53 2. Haibel H et al. Ann Rheum Dis 2005;64:296-8 3. Haibel H et al. Arthritis Rheum 2006;54:678-81

ASAS 40 Response after 24 Weeks of Treatment of AS Patients with TNFÎą Blocking Agents* *Different studies, no head to head comparison

60 50

44 39

30 20 12

10 0 Infliximab1 Placebo

Etanercept2 Placebo

Adalimumab3 Placebo

Golimumab4 Placebo

1. van der Heijde D et al. Arthritis Rheum 2005;52:582-91 2. Davis JC et al Ann Rheum Dis 2005;64:1557-62 3. van der Heijde D et al. Arthritis Rheum 2006;54:2136-46 4. Inman RD et al. Arthritis Rheum 2008;58:3402-12 and Braun J et al. Ann Rheum Dis 2008;67(Suppl II):58

Anti-TNFÎą therapy in patients with AS Results after 6 years % patients

Etanercept

week of treatment

Baraliakos X, EULAR 2009

SF-36 in AS and RA during anti-TNF Îą treatment

n = 253 patients with RA and AS receiving Infliximab and Etanercept

ANCOVA

Standardised response mean Heiberg M, Arthritis Rheum 2005

Treatment of active AS with abataceptan open label 24-week study • ABA 10mg/kg i.v.; n=30 • 15 pts anti-TNF naive; Primary endpoint: ASAS40 • 15 pts non-responders to anti-TNF; Primary endpoint: ASAS20 TNF-blocker-naive patients (n=15)

TNF-blocker failure patients (n=15)

All patients (n=30)

ASAS20

26.7%

20.0%

23%

ASAS40

13.3%

ASAS part. remission

6.7%

BASDAI20

33.3%

20.0%

27%

BASDAI50

6.7%

3% Song I-H et al, EULAR 2010; OP0029

Treatment of active AS with Rituximab TNFa-blocker-naive patients, n=10, 24 weeks follow-up Differenc Assessment Baseline Week 24 % change e

p-value

BASDAI (0-10)

5.7 (SD 1.59)

3.7 (SD 2.04)

2.0

34.9%

0.047

Patient global (0-10)

6.3 (SD 2.16)

4.1 (SD 2.73)

2.2

34.9%

0.057

Patient pain (0-10)

7.3 (SD 1.95)

4.4 (SD 2.84)

2.9

39.7%

0.021

CRP (ref 6mg/l)

24.6 (SD 32.7)

19.1 (SD 26.7)

5.6

22.5%

0.017

ASAS 20 (TNF

50%

ASAS 40

40%

ASAS part. Remission

30%

BASDAI 50

50%

Song IH et al, Ann Rheum Dis 2009;68 (Suppl III):74

No effect of NSAIDs on MRI lesions in AS

Jarrett SJ, Ann Rheum Dis 2008

MRI of the SIJs after anti-TNF treatment Etanercept 2x25mg/wk

Baseline

after 6 weeks

after 24 weeks

Rudwaleit M, Ann Rheum Dis. 2005

Spinal MRI during anti-TNF therapy Etanercept 2x25mg/wk

baseline

48 weeks

Baraliakos X, Arthritis Rheum. 2005

Spinal inflammation and new bone formation are associated in AS (n=39)

6.5 % syndesmophytes developed from inflammation L2

L2 L3

p = 0.006 OR: 3.3 (95% CI: 1.5 – 7.4)

2.1 %

syndesmophytes developed without inflammation STIR MRI – inflammation at baseline

Syndesmophyte formation – after 2 years of anti-TNF Baraliakos X, Arthritis Res Ther. 2008

No significant decrease of radiographic progression under anti-TNFa treatment

0,91

0,80 0,95

0,80

1,00

All studies: p = n.s.

0,90

vdHeijde D, Arthritis Rheum 2008 vdHeijde D, Arthritis Rheum 2008 3 vdHeijde D, Arthritis Rheum 2009 1 2

Clinical presentation in established (RX) and early (non-RX) AS is similar Established AS (n=81)

HLA-B27 +

Non-radiographic AS (n=81) 84%

Inflamm. back pain +

87.7%

84%

Heel enthesitis

22.2%

13.6%

Dactylitis

8.6%

4.9%

Pos. family history

27.2%

21%

Oligo-arthritis

21%

16%

Uveitis

7.4%

14.8%

Psoriasis

11.1%

7.4%

IBD

2.5%

4.9%

Prev. Reactive Art.

4.9%

87.7%

Brandt J, EULAR 2007

Axial Spondyloarthritis

Non-radiographic stage

Radiographic stage Modified New York Criteria 1984

Back pain Sacroiliitis on MRI

Back pain

Radiographic sacroiliitis

Syndesmophytes

Time (years)

Rudwaleit M et al. Arthritis Rheum 2005;52:1000-8 (with permission)

Anti-TNF in patients with non-radiographic SpA ESTHER study: RCT (1 year), disease duration <5 years

ETA

SSZ Song I.-H., ARD 2011

Improvement of MRI inflammation after 48 weeks % of improvement of inflammation

All p<0.05

* only patients with inflammation at baseline Song IH, ARD 2011

Comparison of clinical and imaging outcomes Status at week 48

ASAS Rem.

MRI-

ASAS Rem and MRI -

ETA ITT-population, LOCF (last observation carried forward)

ASAS Rem. MRI-

ASAS Rem and MRI -

SSZ Song IH, ARD 2011

Better treatment response to anti-TNF if treated earlier BASDAI 50%

< 10 years (n=37)

11-20 years (n=33)

>20 years (n=29)

AS patients (n=99) under anti-TNF treatment Rudwaleit M, Ann Rheum Dis. 2004

Better treatment response to anti-TNF if treated earlier • The AS Study Comparing ENbrel with SSZ Dosed Weekly (ASCEND) • 379 AS Patients ETN 50mg/wk vs. SSZ daily for 16 weeks BL variables predicting BASDAI response at 16 wks with ETN vs. SSZ ( P -value) Swollen joints < 3

< 0.0001

Age < 40 years

< 0.0001

CRP < ULN

0.0019

BASMI < 3

0.0020

HLA-B27 positive

0.0025

BASFI < 55

0.0028

Pain/stiffness duration < 5 yrs

0.0053

• Patients with AS who were younger, had fewer years of pain/stiffness, or did not have polyarthritis responded better to either therapy • Younger patients had a significantly better response with ETNvd than SSZ.EULAR 2010 Horst-Bruinsma,

Short Term Response Predicts Long-Term Outcome and Discontinuation in Patients with AS treated with TNF Blockers

Probability of response

OR=1.27, 95%CI: 1.0 – 1.6, p=0.06 OR=1.85, 95%CI: 1.2 – 6.0, p=0.002 OR=2.73, 95%CI: 1.2 – 6.0, p=0.012

Baraliakos X et al, EULAR 2010, FRI0358

Higher rates of radiographic progression in patients with radiographischen damage

mSASSS change

all patients (n=116)

Baraliakos X, Ann Rheum Dis 2007

Higher rates of radiographic progression in patients with radiographischen damage

p <0.05 mSASSS change

No Syndesmophytes at baseline (n=59)

all patients (n=116)

Syndesmophytes at baseline (n=59)

Baraliakos X, Ann Rheum Dis 2007

Concept of Spondyloarthritides (SpA)

Reactive arthritis Early non-radiographic axial SpA

Psoriatic Arthritis

Ankylosing Spondylitis

Arthritis with inflammatory bowel disease Undifferentiated SpA

Predominant Axial SpA

Predominant Peripheral SpA

ASAS Classification Criteria for Peripheral Spondyloarthritis (SpA)

Arthritis or enthesitis or dactylitis plus ≥ 1 SpA feature • • • • • •

≥ 2 other SpA features

uveitis psoriasis Crohn‘s/colitis preceding infection HLA-B27 sacroiliitis on imaging

• • • • •

arthritis enthesitis dactylitis inflammatory back pain (ever) family history for SpA

Sensitivity: 75.0%, Specificity: 82.2%; n=266

Rudwaleit M et al. Ann Rheum Dis 2009 in press

ENT vs. SSZ: Efficacy on axial involvement in nonradiographic SpA

ESTHER study: RCT (1 year), disease duration <5 years

p (BL vs. W24)= 0.672 p (BL vs. W48)= 0.027

Song I.-H., ARD 2011

Enthesitis before anti-TNF

Enthesitis after 48 weeks of anti-TNF

STIR

Therapeutic Goals in RA: Reversal • Reverse signs and symptoms of inflammation – Joint swelling, tenderness, pain, stiffness (“disease activity“) – Laboratory abnormalities (APR, anemia, etc) • Halt progression of damage (“reverse“ damage progression) – Halt progression of erosions, joint space narrowing (“damage“), bony appositition and fusion - Reverse all damage - healing? • Normalize physical function and quality of life (“reverse“ disability)

Current Populations • Early disease – DMARD-naive • Need “first line“ therapy • Long-standing disease – Attaining desired state with MTX/other synthetic DMARDs/biological DMARDs • Do not need change of first line therapy – Active disease despite MTX/syntehtic DMARDSs / (AS: NSAIDs) • Need a “second line“ of therapy – Active disease despite TNF-blockers/other biologicals • Need a “third line“ of therapy

ACR20:50:70 70:50:30 60:40:20

60:40:20

50:25:10

Smolen et al, Lancet, 2007

Profound responses are achieved in ~20% on MTX, ~20% on first biological and ~10% on subsequent biological agents

% Patients

How many Patients Respond Very Well (ACR70) to Current Algorithms Using MTX and Biologicals?

100 90 80 70 60 50 40 30 20 10 0

More therapies are needed!

MTX

1st Biological Responder

2nd Biological

3rd Biological

Nonresponder

Assuming 20% responders to MTX, 20% in anti-TNF-naive and 10% responders in anti-TNF-experienced patients

Combination of Methotrexate and Etanercept in Active Early Rheumatoid Arthritis (COMET)

Patients with early RA (≥3 months and ≤2 years) Randomization (N=542) *Randomization occurred only once and was blinded for both Year 1 and Year 22

ETN + MTX

(n=111)

(n=274)

ETN

(n=111)

ETN + MTX

MTX

(n=90)

(n=268)

MTX

(n=99)

Period 1 N=542

52 wk

Period 2 N=411

104 wk

1. Emery P, et al. Lancet. 2008;372:375-382. 47 2. Emery P, et al. Arthritis Rheum. 2010;62:674-682.

Demographics and Baseline Disease Characteristics EM/EM (n = 108)

M/EM (n = 88)

EM/E (n = 108)

M/M (n = 94)

Demographic Characteristics, mITT Population (at Year-1 Baseline) Age, mean years (SD) Female, n (%) Caucasian/White, n (%)

52.4 (14.3)

55.6 (13.1)

52.2 (14.6)

53.2 (12.5)

78 (72)

52 (59)

82 (76)

77 (82)

94 (87.0)

78 (88.6)

95 (88.0)

83 (88.3)

Disease Characteristics, mITT Population (at Year-2 Baseline) Disease duration, months (SD)

8.4 (5.7)

9.0 (6.0)

9.1 (5.6)

8.7 (5.4)

DAS28

2.7 (1.2)

3.3 (1.4)

2.6 (1.2)

3.4 (1.4)

Swollen joint count, 0–68 possible joints (SD)

2.7 (6.1)

3.9 (6.4)

1.5 (3.0)

3.1 (4.4)

Tender joint count, 0–71 possible joints (SD)

3.9 (7.3)

6.4 (10.2)

3.7 (7.9)

6.1 (7.9)

Health Assessment Questionnaire, 0–3 range (SD)

0.6 (0.6)

0.7 (0.7)

0.6 (0.7)

0.8 (0.7)

15.8 (12.4)

22.5 (15.9)

15.3 (12.8)

22.7 (17.8)

6.0 (5.0)

10.0 (13.8)

7.6 (13.9)

10.5 (14.6)

Erythrocyte sedimentation rate, mm/hr (SD) C-reactive protein, mg/L

DAS28 Remission during year 1

Etanercept + MTX (n=265)

79% more likely to achieve remission with combination therapy

(DAS28: <2.6; LOCF)

Emery P, et al. Lancet. 2008 49

DAS28 Remission (DAS28 <2.6) at Week 104 (LOCF)

% of Subjects Achieving Clinical Remission (LOCF)

P=0.002 P=0路003

100 80

40 20 0 EM/EM (n=108)

M/EM

EM/E

(n=88)

(n=108)

M/M (n=94)

EULAR Good or Moderate Response at Week 104 (LOCF) % of Subjects Achieving EULAR Good/Moderate Response (LOCF)

P=0.004

100

98.1

95.5

92.6

M/EM

EM/E

M/M

(n=88)

(n=108)

(n=94)

87.2

80 60 40 20 0 EM/EM (n=107)

Nearly 3 Times Less Likely to Stop Working in Combination arm vs MTX Alone

% patients who stopped work at least once in 1 year

Modified ITT population

30 25

MTX (n=100) ETN + MTX (n=105)

24%

20 15 10

5 0 Week 52 Emery P, Lancet. 2008 5252

Radiographic progression: Mean Change in mTSS Over 2 Years

Mean change in mTSS

ETN+MTX/ETN+MTX (n=111) ETN+MTX/ETN (n=111)

MTX/ETN+MTX (n=90) MTX/MTX (n=99)

5 4 3 2

† P <0.001 ETN+MTX/ETN+MTX vs. MTX/ETN+MTX ‡

P <0.001 ETN+MTX/ETN+MTX vs. MTX/MTX

† ‡

104

Time (Weeks)

Modified ITT population (LOCF) Annualized change from baseline

Emery P, Arthritis Rheum. 2010

Safety Summary for Weeks 52 to 104 EM/EM (n = 111)

M/EM (n =90)

EM/E (n = 111)

M/M (n = 99)

91 (82.0)

71 (78.9)

89 (80.2)

79 (79.8)

Discontinuation due to adverse event

3 (2.7)

7 (7.8)

5 (4.5)

9 (9.1)

Serious adverse event

8 (7.2)

11 (12.2)

10 (9.0)

12 (12.1)

Death*

1* (1.0)

Malignancy†

5 (5.6)

1 (0.9)

3 (3.0)

1 (0.9)

1 (1.1)

2 (1.8)

2 (2.0)

Any treatment-emergent adverse event

Serious infection

*1 subject in M group died during year 2 due to pneumonia and adenocarcinoma of the lungs with metastasis. † 7 non-skin–related malignant diseases were reported: 4 cases in the M/EM group; 1 case in the EM/E group; and 2 cases in the M/M group. 2 cases of basal-cell cancer were reported in the M/EM and M/M groups. 54

Patients (%)

The use of biologics is (still) increasing

Corticosteroids Âą NSAIDs

MTX-Monotherapy

Other DMARD-Monotherapies

MTX + other DMARD

Other DMARDs-Combination

Biologic-Monotherapy

MTX + Biologic

Biologics (all)

Yazici Y., Bull NY Hosp Jt Dis 2008;

Rationale for longitudinal observational studies / registries New drug

Clinical practice

RCT

Clinical practice

European registries Country

Name of Registry

Details

Sweden

ARTIS1

• Nationwide but organised on regional basis • No concurrently recruited controls; utilises other RA cohorts for reference

BSRBR2

• National registry powered to detect 2-fold increase in lymphoma in comparison to a DMARD-treated cohort

Germany

RABBIT3

• National registry to describe long-term effectiveness • Comparison with conventional DMARDs from national database

France

RATIO4

• Enhanced pharmacovigilance programme • Includes reports from hospitals that may prescribe TNFi or manage patients with opportunistic infections or lymphomas

Spain

BIOBADASER5

• National database of RA patients on biologic response modifier therapy

Norway

NOR-DMARD6

• Registry based on DMARD (including TNFi) prescriptions

Denmark

DANBIO7

• Biologics registry

Czech Rep

ATTRA8

• Biologics registry

Netherlands

DREAM9 (and others)

• Observational registry of TNF starters

Italy

GISEA10-11, LOHREN12

• Italian multicentre registry

Switzerland

SCQM13

• Longitudinal observational population based cohort study

Greece

HRBT14

• Biologics registry

• STURE (Stockholm) • SSATG (Southern Sweden)

1. Askling J, et al. Ann Rheum Dis 2006;65:707–12. 2. Hyrich KL, et al. Rheumatology 2008;47:1441–3. 3. Listing J, et al. Arthritis Res Ther 2006;8:R66. 4. Tubach F, et al. Joint Bone Spine 2005;72:456–60. 5. Gomez-Reino JJ, et al. Arthritis Rheum 2003;48:2122–7. 6. Kvien TK, Clin Exp Rheumatol 2005;23(5 Suppl 39):S188–94. 7. Hetland ML. Clin Exp Rheumatol 2005;23(5 Suppl 39):S205-7. 8. Tegzova D, et al. Ann Rheum Dis 2006;65(Suppl II):505. 9. Kievit W, et al. Ann Rheum Dis 2007;66:1473–8..10. Mancarella L, J Rheumatol 2007;34:1670–3. 11. Iannone F, et al. Ann Rheum Dis 2007;66:249–52. 12. Marchesoni A, et al. Ann N Y Acad Sci 2009;1173:837-46. 13. du Pan SM, et al. Arthritis Rheum 2009;61:560–8. 14. Flouri I, et al. Ann Rheum Dis 2009;68(Suppl3):430.

Safety aspects Infections

Lymphoma Solid tumors

Heart diseases

Mortality Pregnancy

Swedish (ARTIS) Register: Hospitalizations due to infections under anti-TNF treatment •

44 496 RA patients included between 1999 and 2003 – 2692 patients in ARTIS Register received a TNF Inhibitor for the first time • Incidence of infections was 5.4/100 patient-years (n=261) RR * for Hospitalization due to infection during first ant-TNF treatment

RR* since treatment start, depending on infection type

Adjusted RR (95% CI)

Year 1

Year 3

Respiratory

1.24

0.68

Pneumonia

1.11

0.59

Gastrointestinal

1.03

0.94

Skin/Soft tissue

0.57

0.82

0.8

Joints

1.26

1.42

0.6 0.5 0.4

Sepsis

1.07

0.62

4 3 2

1.43

1.15 0.82

Year 1

Year 2

Year 3

Small increase in risk of hospitalization due to infection disappears with increasing treatment duration Askling J, Ann Rheum Dis 2007

US-Registry: Severe bacterial infections under treatment in older RA patients 6 Anti-TNFÎą (n= 469)

Steroids (n= 10.617)

DMARDs (n=654)*

4 3 2 1 0

Pneumonia

Bacteri- Osteo- All bact. aemia myelitis infections

Pneumonia

Bacteri- Osteo- All bakt. aemia myelitis infections

Pneumonia

Bakteri- Osteo- All bact. aemia myelitis infcetions

Patients > 65 years (mean age 76.5 y.) Prospective study, 1995 â&#x20AC;&#x201C; 2003 Steroids: RR: 2.1 as compared to MTX Reference: Patients with MTX; * Patients with Azathioprine, Cyclosporine, Leflunomide Schneeweiss, Arthritis Rheum 2007

Expected rates of serious infections per 100 patient years

DAS28 = 4.3 FFbH = 67% of full function (~HAQ = 1.3)

Listing et al., ACR 2009 No. 1956

Tuberculosis DMARD

Anti-TNF (total)

ETA

INF

ADA

3232

10,712

5521

3718

4857

Patient years

7345

28,447

12,744

8069

7634

TB incidence

27 (+13)

95 (63-138)

39 (13-92)

136 (68-244 )

144 (72-258)

Referent

3.1 (1.0-9.5)

4.2 (1.4-12.4)

Rate / 100,000 (95% CI) IRR (adj. for age, gender, year of inclusion)

13/40 Reactivations occured after withdrawal of therapy 25/40 (62%) of the cases where extrapulmonary, 11 disseminating

Dixon W, ARD 2009

RATIO: TB risk factors – multivariate analysis TB cases and controls (68 cases and 136 controls) OR [95% CI]

P value

1.69 [1.20 – 2.38]

0.003

Born in a tuberculosis endemic area • No • Yes

1 10.35 [2.40 – 44.55]

0.002

Last anti-TNF received • Etanercept • Adalimumab • Infliximab

1 17.08 [3.62 – 80.59] 13.29 [2.56 – 69.04]

Age (increase of 10 years)

Tubach F, et al. Arthritis Rheum. 2009:60:1884–1894.

<0.001 0.002

Tubach F, Joint Bone Spine 2005

Tuberculosis

Systematische Untersuchung: Effectivity of Screening recommendations: Tuberkulose

BIOBADASER: 34 Pat. with TB in 7,825 py (= 0.4 per 100py) ď&#x192; 83% decrease after initiation of screening, similar to EMECAR rate

Before Screening

After Screening

1,0 IRR vs. Popul.

5,0

10,0

IRR vs. RA Cohort

15,0

20,0

25,0

Carmona et al, Arthritis Rheum 2005

Algorithm for TB Screening: European Recommendations New patient TB Screening Tests (Pat. history + Skin test, INF- Îł + Lung x-ray) Evaluate test results

Test negative

Start anti-TNF

Test positive and normal x-ray

Test positive and active TB

Start with treatment of latent TB

Treat TB

Start anti-TNF

Risk for viral infections Only a few data on risk for latent viral infections

Example: Herpes zoster

RABBIT: Risk of Herpes Zoster

Anti-TNF

Controls

6.112

4.291

Incidence rate (/1000 py)

10.1

5.6

Multiderm.+ ophth. zoster

Incidence rate (/1000 py)

2.5

0.9

Patient years Herpes zoster (total)

Strangfeld et al. JAMA 2009

RABBIT: Risk of Herpes Zoster

Etanercept

Infliximab/ Adalimumab

Anti-TNF total

Controls

2588

3524

6112

4291

Herpes zoster (total)

Incidence rate (/1000 py)

8.9

11.1

10.1

5.6

Multiderm.+ ophth. zoster

Incidence rate (/1000 py)

0.8

3.7

2.5

0.9

Patient years

Strangfeld et al. JAMA 2009

Safety aspects Infections

Lymphoma Solid tumors

Heart diseases

Mortality Pregnancy

Cardiovascular disease and risk factors in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis

â&#x20AC;˘ RA = 28,208; PsA = 3,066; AS = 1 843 â&#x20AC;˘ IHD: ischemic heart disease; PVD: peripheral vascular disease; CHF: congestive heart failure CVD: cerebrovascular disease; NIDDM: non-insulin dependent diabetes mellitus

Han C et al. J Rheumatol 2006

Heart disease Hazard Ratios (HR) for worsening of heart insufficiency multivariate Coxregression analsis

95% CI

Age (per 10 years)

1.6

0.6 – 4.3

0.39

Male vs. Female

5.8

1.5 – 22.1

0.01

Glucocorticoids >=10 mg vs. < 10 mg

3.3

1.0 – 11.2

0.055

1.14

0.3 – 4.5

0.84

Anti-TNF Therapy vs. conventional DMARDs

Listing et al, Arthritis Rheum 2008

Incidence of verified MI ’s in anti-TNFα responders vs. non-responders N

Pt years

MI events

Rate of MI (1000 pt years)

Non-responders

1638

1815

9.4 (5.5 – 15.0)

Responders

5877

9886

3.5 (2.5 – 4.9)

Incidence rate ratio’s of verified MI’s in anti-TNFα responders vs. anti-TNFα non-responders

Non responders

Dixon WG, Arthritis Rheum. 2007

Safety aspects Infections

Lymphoma Solid tumors

Heart diseases

Mortality Pregnancy

Lymphoma Data from Swedish registry (ARTIS) Comparison of

6.604 RA patients exposed to biologics

(67.743 patients in the registry) with 471.024 persons from normal population (data from cancer and death registry available) 26 Lymphomata = 96 /100.000 patient years Anti-TNF exposed vs. normal population: RR = 2.72 Anti-TNF exposed vs. naive (RA): RR = 1.35 Increase of risk only in the first year of approval: 1998-2001: RR=1,62

2002-2006: RR=0,9 Askling J, ARD 2009

Lymphoma in RA patients exposed to anti-TNF Relative Risk for lymphoma in Swedish RA patients Stratified per year of treatment start with anti-TNF, anti-TNF vs. TNF-naive 3,5 3 2,5 2

1,61

1,5

1,14

0,55

0,5 0

1999-2001

2002-2003

2004-2006 Askling J, ARD, 2009

Lymphoma in RA patients exposed to anti-TNF

Years of diagnosis prior to anti-TNF treatment Baecklund E, A&R 2006

Solid tumors in RABBIT Cancer cases in patients without history of cancer

Anti TNF

Anakinra

DMARDs

3.651

247

1.684

Patient years

8.558

690

3.561

Incidence of cancer

Incidence rate / 1.000 py

5.1

7.2

8.4

Strangfeld A, Arthritis Res Ther 2010

Danish DANBIO: 4 years drug survival

Drug survival (unadjusted)

(n = 2935 RA patients)

adalimumab

1.0

etanercept

0.8 0.6

56%

0.4 0.2

P<0.0001

63%

44%

infliximab

0.0 24

120

Months

Hetland ML, Arthritis Rheumatism 2010

% patients remaining on therapy

Swedish STURE: Survival on anti-TNF therapy in RA

# pts on each anti-TNF - ETN = 559, INF = 906, ADA = 143

There was no difference in drug survival when patients started anti-TNFs after 2003

Van Vollenhoven et al. ARD 2006;65(Suppl II):511

Conclusions Efficacy in AS/SpA and RA •Early diagnosis is possible due to new classification criteria •Anti-TNF treatment is efficacious and safe in long term •Early treatment predicts better outcomes and less dropouts Safety •Registries provide information about safety which cannot be obtained from RCTs •Patients under anti-TNF with different rates of infection risk (Tbc, infections, zoster) •Some analyses indicate a difference between etanercept and monoclonal antibodies in risk of Tbc and zoster infections •Late treatment onset is associated with higher safety issues