The Biologic therapies

Dr. R MUSA

SPR rheumatology

TNF Antagonists: licensed indications and future use

Confirmed in Trials Crohn’s disease Rheumatoid arthritis

Spondyloarthropathies Psoriatic arthritis Psoriasis Ankylosing spondylitis Reactive arthritis

Juvenile RA Adult Still’s disease

Under Investigation Vasculitis: Wegener’s disease, giant

cell arteritis Scleroderma Graft-versus-host disease Inflammatory myositis Interstitial lung disease Sjogren’s syndrome Inflammatory eye and ear disease Asthma Hepatitis Sarcoidosis Behcet’s disease Pyoderma gangrenosum

Cush J. Rheumatology. 2003. In press.

Cytokine Signaling Pathways & TNF

Adapted from Choy EHS, Panayi GS. N Engl J Med. 2001;344:907-916.Copyright © 2001 Massachusetts Medical Society. All rights reserved.

TNF-IL-1IL-6

IFN-IL-12

IL-4IL-10

Macrophage

RF

IL-4IL-6IL-10Plasma

cell

B cell

Interferon-

Th0

Th2

Synovium

OPGL

CD4 + T cell

CD69 CD11

CD11CD69

Osteoclast FibroblastChondrocyte

Production of metalloproteinases andother effector molecules

Migration of polymorphonuclear cells

Erosion of bone and cartilage

TNF secretedby macrophage

Biologic therapy AnakinraInfliximabEtanerce

ptAdalimuma

b

HumanChimericHumanRecombinantconstruct

Type I IL-1RTNF-TNF-Primary binding target

4–6 hours8–10 days4.3 daysHalf-life

Human

TNF-

10–13.6 days

IL-1RaTNF- mAbsTNFR construct

Class TNF- mAb

100 mg/d sc3–10 mg/kg4–8 wk iv

+ MTX

25 mg sc2x/wk

Administration

40 mg sc eow

Adapted with permission from Choy EHS, Panayi GS. N Engl J Med. 2001;344:907-916.Copyright © 2001 Massachusetts Medical Society. All rights reserved.

Inhibition of Cytokines

Inflammatory cytokine

Normal interaction Neutralization of cytokines

Receptor blockadeActivation of

anti-inflammatory pathways

Cytokine receptor

Soluble receptor

Monoclonal antibody

Monoclonal antibody

Receptor antagonist

Anti-inflammatorycytokineSuppression ofinflammatorycytokines

No signal

No signal

Inflammatory signals

PRE-INFUSION 2 WEEKS POST

POST-GD SE T1

Baseline

2 weeks

One year

SACROILIAC JOINT INFLAMMATION

Baeten et al Arthritis Rheum 2001

the effect of 3 infusions infliximab on the synovium evaluated between baseline on the left and at 12 weeks on the right

BASELINE

2 DAYS

2 WEEKS

SPINAL INFLAMMATION

TB and Anti-TNFRecommendations

Purified protein derivative (PPD) and chest x-ray (CXR) in all patients on biologics

PPD 0.1 mL is neither 100% sensitive or 100% specific, because there are as many as 25% false negatives

Sensitivity varies with cutoff 5 vs 10 vs 15 Low cutoff for those at high risk Treatment with isoniazid (INH) for 9 months for

all PPD > 5 mm Delay anti-TNF therapy if possible, avoid

infliximab

Antibody Formation With TNF Inhibitors

Etanercept Infliximab Adalimumab

< 5% (non-neutralizing)

10% (HACA) 5% neutralizing (Range 1% on MTX; 12% on monotherapy)

•Monoclonal antibodies appear to form neutralizing antibodies in a portion of the population, regardless of whether they are human- or mouse-based

•This may affect long-term efficacy

Infliximab in Crohn’s Disease Influence of Immunogenicity on Duration of Clinical Response (N=125)

Baert F, et al. Baert F, et al. N Engl J Med.N Engl J Med. 2003;348:601-608. 2003;348:601-608.

6565

38.538.5

00 1010 2020 3030 4040 5050 6060 7070

Days of Clinical Days of Clinical ResponseResponse

Patients With Infusion

Reactions*

Patients Without Infusion

Reactions

*Infliximab antibodies detected (61%); cumulative incidence of infusion *Infliximab antibodies detected (61%); cumulative incidence of infusion rxs (27%).rxs (27%).

PP<0.0<0.00101

The incidence of lymphomas is increased in RA, but. The apparent increase in lymphomas in patients treated with TNF inhibitors may be due to confounding by indication — that is, that patients with severe disease who are (historically) most likely to develop lymphomas are also the ones most likely to receive TNF inhibitors.

TNF-alpha plays an important role in tumor surveillance, particularly lymphoma. Because of this, Using TNF-alpha blocking agents in the treatment of rheumatoid arthritis (RA) may increase the risk of developing malignancies. Clinical trials of TNF inhibitors have not identified an increase in tumor (including lymphoma) risk, but are limited by short observation intervals and small cohorts. Here,

Geborek et al Bladstrom, Jacobsson 2003

Lymphoma With TNF Antagonists

Lymphoma With TNF Antagonists

5.4(2.6–10.0)

6.4(1.7–16.3)

2.313.47(1.59–6.59)

SIR Lymphoma (95% conf interval)

18 mo(2.0–42.0)

10-19 mo(6.4)

21 mo(0.1–4.6)

Mean Time to Onset (range)

1/91/33/6Hodgkin's/Non-Hodgkin's†

10469Total No.

2468(4870)

1298(2458)

3389(8336)

Treated/Exposure Pt-No. Pt-Yr

AdalimumabInfliximabEtanercept

† Majority diffuse large B cell

SIR=standardized incidence ratio

Spondyloarthropathy family of disorders

Inflammatory condition primarily affecting the spine which have in common the presence of sacroilitis, the presence of the HLA B27 gene and characteristic extra-articular manifestation. example:

Ankylosing spondylitis

Psoriatic arthritis

Reactive arthritis

Reiter syndrome

Enteropathic arthritis (IBD associated arthritis)

Undifferentiated Spondyloarthropathy

Ankylosing Spondylitis

Common inflammatory disease of the spine Spinal deformity and disability

Progressive with symptoms beginning in the 2nd or 3rd and continuing into the 5th and 6th decade

Prior to the advent of biologics no effective treatments

Extra-axial features of AS Peripheral joints (30% of patients)

Enthesopathy (up to 98%) enthesitis inflammation at the site of insertion of ligaments and tendons on to

bone this often progress to ossification periosteal new bone formation common site involved are Achilles tendon insertion can be quit painful.

Extra-articular manifestations Bowel (60% asymptomatic colitis), UC, Crohn disease Cardiac (10%) Aortitis (ascending aorta),AVR, MVR, AV Block Renal –Amylodosis, IgA nephropathy Lung Apical lung fibrosis(colonize aspergi), limited chest expansion Eye uveitis (20 – 30%) higher if HLA27+ 84%

Fever, weight loss, general fatigue, morning stiffness, improve symptoms with activities

Important diagnostic issues…. Which diagnostic criteria to use?

modified New York criteria

vs

European Spondyloarthropathy Study Group criteria Delay in diagnosis AS does not occur after the age of 40’

Normal SI - SE T1 Fused SI - SE T1

Sacroilitis by MRI

Modified new York criteria 1984(Van der Linden)

Radiological criterion sacroilitis, Grade=/>2 bilat / Grade3/4 unilat

Clinical criterion (2 out of the following 3)

1-Low back pain and stiffness for >3months improve with exercise but not rest

2-Limitation of motion of lumber spine in both the sagital and frontal planes

3-Limitation of chest expansion relative to normal value for age and sex

Instruments for assessment of AS 1-BASFI=Bath Ankylosing Spondylitis Functional Index

Used to evaluate functional ability BASFI is scored as follows: 8 VAS regarding function scored:

Easy 0 1 2 3 4 5 6 7 8 9 10 Impossible 2 questions regarding ability to cope with daily life scored:

Easy 0 1 2 3 4 5 6 7 8 9 10 ImpossiblePlease indicate your level of ability with each of the following activities during the last week. (An aid is a piece of equipment which helps you perform an action or movement) 1. Putting on your socks or tights without help or aids (e.g. sock aid). easy impossible 2. Bending forward from the wait to pick up a pen from the floor without an aid. easy impossible 3. Reaching up to a high shelf without help or aids (e.g. helping hand). easy impossible 4. Getting up out of an armless dining room chair without using your hands or any other help. easy impossible 5. Getting up off the floor without help from lying on your back. easy impossible 6. Standing unsupported for 10 minutes without discomfort. easy impossible 7. Climbing 12-15 steps without using a handrail or walking aid. One foot at each step. easy impossible 8. Looking over our shoulder without turning your body. easy impossible 9. Doing physically demanding activities (e.g. physiotherapy exercises, gardening or sports). easy impossible 10. Doing a full days activities, whether it be at home or at work. easy impossible

1 2 3 4 6 7 8 9 10 5 0

1 2 3 4 6 7 8 9 10 5 0

1 2 3 4 6 7 8 9 10 5 0

1 2 3 4 6 7 8 9 10 5 0

1 2 3 4 6 7 8 9 10 5 0

1 2 3 4 6 7 8 9 10 5 0

1 2 3 4 6 7 8 9 10 5 0

1 2 3 4 6 7 8 9 10 5 0

1 2 3 4 6 7 8 9 10 5 0

1 2 3 4 6 7 8 9 10 5 0

2-BASDAI=Bath Ankylosing Spondylitis Disease Activity Index

Please tick the box that indicates your answer to each question. All questions refer to last week. 1. How would you describe the overall level of fatigue/tiredness you have experienced? none very severe 2. How would you describe the overall level of AS neck, back or hip pain you have had? none very severe 3. How would you describe the overall level of pain/swelling in the joints other than neck, back or hips you have had? (ie: peripheral joints) none very severe 4. How would you describe the overall level of discomfort you have had from any areas tender to touch or pressure? none very severe 5. How would you describe the overall level of mourning stiffness you have had from the time you wake up? none very severe 6. How long does your morning stiffness last from the time you wake up? 0 hr 1 hr 2 or

more hours

1 2 3 4 6 7 8 9 10 5 0

1 2 3 4 6 7 8 9 10 5 0

1 2 3 4 6 7 9 10 5 0

1 2 3 4 6 7 8 9 10 5 0

1 2 3 4 6 7 8 9 10 5 0

1 2 3 4 6 7 8 9 10 5 0

3-Global Assessment: PtGA

1. Please tick a box to indicate the effect your disease has had on your well-being over the last week. none very severe 2. Please indicate the effect your disease has had on your well-being over the last six months. none very severe

1 2 3 4 6 7 8 9 10 5 0

1 2 3 4 6 7 8 9 10 5 0

Source: Jones, SD., Steiner, A., Garrett, SL., and Calin A.. The Bath Ankylosing Spondylitis Patient Global Score (BAS-G). British Journal of Rheumatology 1996;35:66-71.

4-BASMI:SPINAL MOBILITY

Lateral bending Intermalleolar distance Occiput to wall Modified schober index

life impact of AS

Suffer pain and disability

Socio-economic impact because onset at early age

Unemployment (>50%) and high insurance

50% develop hip arthritis at early age and require Hip replacement which more often require reoperation due

to heterotopic ossification of the hip prosthesis

Mortality higher 1.5 than general population due to

Cardiac valvular disease

Amyloidosis

Osteoporosis occurs early in disease increase fracture

Annual health cost of one patient=6720$

Conventional therapy for AS

Aim: relieve pain and stiffness

Regular physiotherapy

Hydrotherapy

NSAIDs(improvement within 24 hours if there is failure to response

Probability of suffering from AS is as low as 3%)

long term use do not alters structural progression of the disease

(use mainly as symptomatic relieve of pain and stiffness)

Risk of GI upset use Naprxone / Use COX2 inhibitor ?celebrex

support in the NASS and OPD rheumatology clinic NOTES:Treatment of peripheral and axial disease are different

May be spontaneous remission later in life

Rationale for TNF blockade

TNF- in AS Over-expression of TNF in mouse model produces

AS like disease

Abundant TNF- mRna in Sacroiliac joint biopsy specimens from inflamed sacroiliac joints

Good therapeutic effect in other autoimmune disease, IBD, RA 60% AS patients have sub clinical colitis

Bollow M, Braun J. Ann Rheum Dis. 2000.

Sacroiliac Biopsy In Ankylosing Spondylitis

TNF mRNA In Sacroiliac Biopsy In AS

Inflamed sacroiliac joint of a young, female patient with AS

3 years disease duration

In situ hybridization

Braun J et al. Arthritis Rheum. 1995.

BSR Guideline on Eligability for anti TNF therapy (the same as ASAS Consensus) ASsessments in AS working group

Initiation of therapy 1-Ankylosing Spondylitis patient satisfies modified New York

criteria 2-Failed conventional therapy (2 or > NSAID each taken sequentially at

maximum tolerated dose for 4 weeks 3-Active disease for at least 4 weeks

BASDAI =/> 4 and Physician global (specialist) yes/no

Refractory disease

Failed at least 2 NSAIDS at max tolerated doses during 3 month period and I/A steroids/SSZ if indicated

ASAS workshop, Berlin January 2003

Contraindication Pregnancy or breast feeding Active significant infection Septic arthritis of prosthetic joint within last 12/12 or

indefinitely if joint remain in site Precautions TB and positive PPD test Congestive heart failure (NYHA grade ¾) Demyelination

adverse events Major: Reactivation of TB, shingle, Sepsis, anaphylactic shock

Minor: Injection site reactions, infusion reactions, autoantibodies formation and lupus, Abnormal liver function tests

BSR definition of response to treatment (the same as ASAS consensus guidelines)

Response Time of evaluation at 6-12 weeks BASDAI >50% improvement and absolute

improvement >2 units and Physician global assessment of response to treatment

Infusions every 6-8 weeks patient pain and patient global assessment, spinal

mobility, CRP and BASDAI assessed in follow up on all patients

NASS

Welcome to NASSNorwich.co.uk

The Norwich Branch of The National Ankylosing

Spondylitis Society (NASS).

Run by Patients for Patients.

We offer Support, Advice, and Exercise

Sessions with Professional Supervision

www.spondylitis.ca

Biologic Audit Rheumatology DepartmentWatford G Hospital

Dr R MUSA

Dr A Hayee

Margaret Brown

Total of 22 Patients currently on biologic therapy for Rheumatology indication at WGH

23 rheumatoid arthritis patients (11) adalimumab (Humira) (3) infliximab (Remicade) (5) Etanercept (Enbrel) Six RhA Patients their therapy suspended (11) Patients waiting to start near further 2 RhA Patients have switch between more than one biologic

therapy one still on therapy and one suspended 3 Ankylosing spondylitis Patients – 3 Etanercept (Enbrel)

Aims of the Audit to evaluate the current practice of Biologic therapy at Rheumatology Department for RhA & AS.

Age & sex distributionOn therapy -13 female all Rheumatoid arthritis patients

9 male six Rheumatoid arthritis and three AS

All the six suspended patients are female

Age range RhA(35 - 80) and AS(22 - 69)

Age distribuation of patients on biologic therapy Blue RhA and Brown AS patients

0

50

100

1 3 5 7 9

11

13

number of cases

ag

e Series1

Series2

Data available on 15 patients with Rh A

DAS28 value pre (blue1) & post (brown2) anti TNF therapy

0

2

4

6

8

101 3 5 7 9 11

13

Patients

DA

S28 v

alu

e

(th

era

py s

tart

wit

h

DA

S>

5.1

)

Series1

Series2

Data available on 15 patients with Rh A

ESR value pre (blue1) & Post (Brown2) anti TNF therapy

020406080

1001 3 5 7 9 11 13

patients

ES

R v

alu

e (n

orm

al

<25

mm

/ho

ur)

Series1

Series2

Change in BASDI & BASFI score after 6 months Etanercept therapy in 3 patients with AS

BASDI Score pre etanercept (Blue) and post (Brown)

0

5

10

1 2 3

number of patients

BASD

I Scor

e Series1

Series2

BASFI Score pre (Blue) and post (Brown) 6 months of etanercept therapy

0

5

10

1 2 3

number of patients

BASFI

score Series1

Series2

Pre starting anti TNF visit

1st Anti TNF assessment by rheumatology specialist nurse

DAS28score,HAQ,SF36 Blood: FBC,ESR,LFT,CRP,U&E CXR, Heaf test Anti TNF information given to the patient include

discussion of side effect, consent taken from the patient

2nd Anti TNF assessment by the RSN (after one month)

DAS28score,HAQ,SF36 Blood: FBC,ESR,LFT,CRP,U&E

1st visit post starting anti TNF

Rheumatology specialist nurse review at 6/52 post antiTNF

DAS28score,HAQ,SF36 Blood: FBC,ESR,LFT,CRP,U&E Physician review (for infliximab infusion) History focus on any sign of infection (sore throat, dysurea) Examination also focus on sign of infection (temp, pulse..) Review blood results Patient will be reviewed by rheumatologist in OPD in

3/12 time

Thank you for attending