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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