Anti TNFAnti TNF-- αα in Rheumatoid Arthritis in Rheumatoid Arthritis

safety data from the LORHEN registrysafety data from the LORHEN registry

Carlomaurizio MontecuccoCattedra ed Unità Operativa di Reumatologia

Università degli Studi di Pavia

Fondazione IRCCS Policlinico San Matteo, Pavia

Interpretation of Studies

• Randomised controlled phase III trials

– comparison of two treatments (usually active drug vs. placebo)

in a selected, relatively small, population, over a short period of

time, and usually funded and managed by drug companies

• Observational studies• Observational studies

– “real life” studies in large cohorts of unselected patients over

longer periods and usually less dependent of drug companies

– long term safety and efficacy of a drug in everyday practice

– survival on treatment: good indicator of a drug performance

(combination of safety, efficacy, and other real life factors)

Studied Population

• Patients from the Lorhen database

– RA (ARA criteria), active, refractory to traditional DMARDs and

treated with at least one dose of anti-TNF-α

• Follow-up between 6 and 36 months

•• Discontinuations within the first 6 months also included

in the data analysis (intention-to treat-approach)

• Only the first course of therapy (switches not included)

Etanercept N=249 (22,4%)

Adalimumab N=332 (29,8%)

Lorhen Register N=1114

No follow-up N=50

Efficacy analisys

N=1010

Patients excluded from the analysis

N=5

LOmbardy RHEumatology Network

Infliximab N=533 (47,8%)

Discontinuation or AE

N=54

Safety analyses N=1064

6 months

Number of the patients fulfilling

the minimum criteria for the analysis

N=1005

Caporali R et al. Autoimm Rev 2008

Demographics

All pts

1064

Infliximab

519 (48.8%)

Adalimum.

303 (28.5%)

Etanerc.

242 (22.7%)

p

Age (years) 55.84±12.96 55.72±12.07 56.07±13.11 55.81±14.57 ns

Females 885 (83.2%) 423 (81.5%) 258 (85.1%) 204 (84.3%) ns

Males 179 (16.8%) 96 (18.5%) 45 (14.9%) 38 (15.7%) nsMales 179 (16.8%) 96 (18.5%) 45 (14.9%) 38 (15.7%) ns

Disease dur.

(yrs)

9.44±7.29 9.28±7.00 9.56±7.90 9.63±7.11 ns

DAS28 5.90±0.97 6.01±0.94 5.68±0.96 5.93±1.02 .000

DI-HAQ 1.46±0.61 1.61±0.61 1.25±0.54 1.41±0.63 .000

Demographics

All pts

1064

Infliximab

519 (48.8%)

Adalimum.

303 (28.5%)

Etanerc.

242 (22.7%) p

RF positive 810 (76.1%) 417 (80.3%) 214 (70.6%) 179 (74.0%) .001

Comorbidity 657 (61.7%) 316 (60.9%) 179 (59.1%) 162 (66.9%) ns

Func. class III 317 (29.0%) 186 (35.8%) 63 (20.8%) 68 (28.1%) .000

Methotrexate 899 (84.5%) 499 (96.1%) 226 (74.6%) 174 (71.9%) .000

Corticosteroid 896 (84.2%) 459 (80.7%) 233 (76.9%) 204 (84.3%) .000

Survival on Treatment

Favalli EG et al Ann NY Acad Sci 2009

Survival on TreatmentTreatment discontinuation

0,7

0,8

0,9

1,0

Sur

viva

l

0,4

0,5

0,6

0,7

0 6 12 18 24 30 36 Months

Sur

viva

l

Any cause

Inefficacy

Adverse event

Other

At riskTotal events

10640

924120

746218

585 294

482331

353374

247405

Discontinuations: Timinig

• Mean time on therapy at discontinuation:

all patients: 13.01±9.78 months

inefficacy group: 14.07±9.97 monthsinefficacy group: 14.07±9.97 months

adverse event group: 12.26±10.17 months

Discontinuations: Adverse Events

Adverse eventAll patients

194 (18.2%)

Infliximab

106 (20.4%)

Adalimumab

60 (19.8%)

Etanercept

28 (11.6%)

Serious infection 73 (6.9%) 42 (8.1%) 20 (6.6%) 11 (4.5%)

Malignancy 18 (1.7%) 6 (1.2%) 8 (2.6%) 4 (1.7%)

Skin or infusion Skin or infusion

reaction58 (5.5%) 48 (9.2%) 8 (2.8%) 2 (0.8%)

Death 13 (1.2%) 3 (0.6%) 5 (1.7%) 5 (2.1%)

Other 32 (3.0%) 6 (1.2%) 19 (6.3%) 7 (2.9%)

Percentages are referred to all patients of that specific group

Deaths

Cause of death DrugPatient’s age

at death (yrs)

Days on

therapy

Suggested

relation to

therapy

Myocardial infarction etanercept 74.0 5 none

Heart failure adalimumab 48.2 30 likely

Aortic aneurysm

ruptureetanercept 73.0 197 none

ruptureetanercept 73.0 197 none

Stroke infliximab 61.9 314 unlikely

Myocardial infarction infliximab 68.9 363 unlikely

Atlo-epistrofic surgery adalimumab 65.5 380 none

Stroke adalimumab 76.5 536 unlikely

Deaths

Cause of death DrugPatient’s age

at death (yrs)

Days on

therapy

Suggested

relation to

therapy

Myocardial infarction etanercept 77.6 578 unlikely

Pancreatic cancer adalimumab 68.7 587 unlikely

Septicaemia infliximab 65.0 873 certainSepticaemia infliximab 65.0 873 certain

Aortic aneurysm

ruptureetanercept 70.5 909 unlikely

Septicaemia adalimumab 77.8 921 certain

Post-infective

cerebritisetanercept 57.0 980 likely

Risk of Discontinuation

All causes Adverse events

AHR (95% CI) p

AHR (95% CI) p

AgeFor 10 yrs more

1.07 (0.98-1.17) .150

1.20 (1.05-1.37) .009

1.04 1.25 Sex Male

1.04 (0.78-1.39) .777

1.25 (0.83-1.88) .287

Dis. dur. <5 years 1 1

5-10 yrs0.97

(0.74-1.28) .8461.07

(0.72-1.61) .736

>10 years0.82

(0.62-1-08) .1621.00

(0.67-1.50) .991

Risk of DiscontinuationAll causes Adverse events

AHR (95% CI) p

AHR (95% CI) p

N. previousDMARDs

2 1 1

31.39

(1.07-1.81) .0130.74

(0.49-1.13) .164

≥≥≥≥41.62

(1.22-2.14) .0011.31

(0.90-1.90) .163(1.22-2.14) (0.90-1.90)Corticost. No 1 1

≤≤≤≤5 mg/day1.03

(0.76-1.40) .8371.07

(0.67-1.70) .775

>5 mg/day1.57

(1.09-2.26) .0152.13

(1.26-3.60) .005

MTXYes

0.53(0.38-0.75) .000

0.68 (0.42-1.10) .113

Comorb.Yes

0.80(0.64-1.01) .055

0.69 (0.50-0-97) .032

Risk of Discontinuation

All causes Adverse events

AHR (95% CI) p

AHR (95% CI) p

N. tender joints

For 1 joint more

1.04 (1.01-1.07) .013

1.04 (0.99-1.09) .096

N. swoll. joints

For 1 joint more

1.01 (0.98-1.03) .555

0.99 (0.96-1.03) .692joints more (0.98-1.03) (0.96-1.03)

DI-HAQ For 0.3 points more

0.99 (0.92-1.06) .745

1.08(0.97-1.20) .147

DAS28 For 0.6 points more

0.84 (0.71-0.99) .033

0.82 (0.64-1.04) .095

ESR (mm/h) For 10 points more

1.14 (1.07-1.21) .000

1.12 (1.02-1.23) .017

Factors Associated with Discontinuation

• Age: adverse events

• N. DMARDs ≥4: inefficacy

• Steroid >5 mg/day: adverse events

• No MTX: inefficacy• No MTX: inefficacy

• Absence of comorbidity: adverse events

• ESR (10 points): inefficacy + adv. events

Discontinuations: Adverse Events

Adverse eventAll patients194 (18.2%)

Serious infection 73 (6.9%)

Malignancy 18 (1.7%)Malignancy 18 (1.7%)

Skin or infusion reaction

58 (5.5%)

Death 13 (1.2%)

Other 32 (3.0%)

DMARDS and infections in RA

• Increased risk in RA vs non-RA (RR 1.33) Doran MF et al Arthritis Rheum 2002

• Factors associated with higher risk– Age– Extraarticular disease– Extraarticular disease– Rheumatoid factor– ESR– Cyclophosphamide– Corticosteroids

• MTX not associated with a significant risk

Caporali R et al Autoimm Rev 2008

SERIOUS INFECTIONS IN LORHEN STUDY

Favalli EG et al. Autoimm Rev 2009

Incidence rate of serious infections during

anti-TNF treatment for RA in real life

(x1000 pts/year)

• LORHEN1 35.9

• BSRBR2 53.2

• French study3 105 (34 before anti-TNF)

1) Favalli EG et al. Autoimm Rev 2009

2) Dixon W et al. Arthritis Rheum 2006

3) Salliot C et al Rhematology 2007

TB reactivation during TNF blockade

MONITORNET 9 cases / 8787 p-y

LORHEN 5 cases / 2069 p-y

Discontinuations: Adverse Events

Adverse eventAll patients194 (18.2%)

Serious infection 73 (6.9%)

Malignancy 18 (1.7%)Malignancy 18 (1.7%)

Skin or infusion reaction

58 (5.5%)

Death 13 (1.2%)

Other 32 (3.0%)

The background rates of malignancy in RA

Symmons D PM, Silman AJ. Arthritis Rheum2004

N°of cases

p-y N°/1000 p-y

NHLLORHEN

4 2069 1.93

MONITORNET 6 8787

Crude incidence rate of malignancies in

two Italian registries

MONITORNET 6 8787 0.69

OTHER MALIGNANCIES

LORHEN 14 2069 6.76

MONITORNET 24 8787 2.73

Cancer type Observed Expected SIR (95% CI)

Lymphomas^ 4 0.80 4.98 (1.34-12.74)

Hematologic* 5 1.23 4.07 (1.31-9.49)SIRs of cancer in RA

a)

Cancer type Observed Expected SIR (95% CI)

Lymphomas^ 4 0.67 5.99 (1.61-15.35)

Hematologic* 5 1.23 4.08 (1.32-9.53)

Solid** 13 17.99 0.72 (0.38-1.24)

Overall 18 19.22 0.94 (0.55-1.48)

Solid** 13 15.33 0.85 (0.45-1.45)

Overall 18 16.56 1.09 (0.64-1.72)

SIRs of cancer in RA

patients treated with

TNF blockers in

comparison with

general population

living in Milan (a) and

Varese (b).

b)

Evaluation of risk of cancer in RA patients included in the LORHEN study.

Results of a multivariate analysis.

10

100

AH

R a

nd 9

5% C

I

0,1

1

Age Male No* 0-5 mg >5 mg No* MTX

AH

R a

nd 9

5% C

I

Corticosteroids DMARDs association

Safety according to age

Discontinuation rate for AEs in pts >65 years old vs younger pts

Hazard Ratio=1.49

1,0

0,9

0,8

0,7

0,6

0,5

0,4

65+ yrs<65 yrs

Age

Severe adverse event

SO

PR

AV

VIE

NZ

A C

UM

ULA

TIV

A

18<age<65(n= 771)

Age ≥65(n=293)

p

Total discontinuations 282/771 (36.6%)

123/293 (42%)

0,043

Due to AEs 130/771 (16.9%)

64/293 (21.8%)

0,017

Due to inefficacy 129/771 (16.7%)

51/293 (17.4%)

0,591

Due to other causes 23/771 (3%)

8/293 (2.7%)

0,932

Severe infections (10%) p=0.0042

Malignancies (3,7%) p=0.004

3630241812600,4

Filippini M et al Clin Rev Allergy Immunol. 2009

Conclusions• In an Italian cohort of more than 1000 patients

with long-standing RA refractory to traditional DMARDs, the 3-year expected survival rate on anti-TNF therapy was about 53%

• Adverse events and inefficacy were equally responsible for drug discontinuation, although during the first year they were more frequently responsible for drug discontinuation, although during the first year they were more frequently due to adverse events

• Serious infection was the most frequent adverse event responsible for drug discontinuation, followed by infusion or skin reaction

Conclusions

• Etanercept showed the best retention rate but the design of the study did not allow a comparison of the three drugs

• Increasing age, corticosteroid dose >5 • Increasing age, corticosteroid dose >5 mg/day and absence of comorbidity were associated with a significantly higher risk of therapy discontinuations because of adverse events

Conclusions

• Can we do better?– concomitant MTX (or other DMARD ?) in all

cases

– corticosteroid dose as low as possible

– anti-TNF as second line agent

– optimization of infusion procedures

– infection alert: correct TB screening, close follow-up and monitoring