NEW 2011/2012 CRA Recommendations for the
Pharmacological Management of RA
with Traditional and Biologic DMARDs: Part II Safety
Presenter:
Disclosures
 CRA recommendations were supported by the
Canadian Institutes of Health Research (CIHR) and
matched funds from the CRA.
 No pharmaceutical companies were involved in any
phase of guideline development.
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Commonly Used Abbreviations
ABAT = Abatacept
ADA = Adalimumab
Anti-TNF = Anti-Tumor Necrosis Factor
BCG = Bacille Calmette-Guérin
CXR = Chest x-ray
DMARD = Disease modifying anti-rheumatic drug
ETN = Etanercept
IFX = Infliximab
IGRA = Interferon-gamma release assay
LTBI = Latent tuberculosis infection
MTX = Methotrexate
RCT = Randomized controlled trial
RTX = Rituximab
TBST = Tuberculin skin test
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Learning Objectives
1. Briefly summarize how the NEW 2012 CRA safety
recommendations for RA were developed.
2. Review 2012 CRA safety recommendations for RA.
1. Highlight available guideline resources and
implementation tools.
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Preamble
The CRA developed recommendations for the pharmacological
management of RA with traditional and biologic DMARDs in 2
parts.
- Part I: Detailed methodology + 26 RA treatment strategydriven recommendations with traditional and biologic DMARDs
(reviewed separately).
- Part II: Thirteen recommendations focusing on specific safety
aspects of RA treatment with traditional and biologic DMARDs
(reviewed here).
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Scope
 What is covered?
− Perioperative management (2)
− Screening for latent tuberculosis before starting biologic therapy (4)
− Optimal vaccination practices (3)
− Treatment of RA patients with a history of malignancy (4)
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Methods for Developing Recommendations
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Multidisciplinary Working Group
 Rheumatologist expert
 Patient consumer
 General practitioner
 Coordinator
External Clinical Experts:
Johan Askling (Malignancy)
Michael Gardam (TB, Vaccination)
Anne Dooley, Arthritis Patient Advocate
Sharon LeClercq, MD FRCPC
Dianne Mosher, MD FRCPC
Pooneh Akhavan, MD FRCPC
Claire Bombardier, MD FRCPC
Vivian Bykerk, MD FRCPC
Glen Hazlewood, MD FRCPC
James Pencharz, MD CCFP
Janet Pope, MD FRCPC
John Thomson, MD FRCPC
Carter Thorne, MD FRCPC
Majed Khraishi, MD FRCPC
Boulos Haraoui, MD FRCPC
Jean Légaré, Arthritis Patient Advocate
Orit Schieir, Project Coordinator
Michel Zummer, MD FRCPC
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Modified- ADAPTE Framework
Define Key
Key Questions
1.1.Define
Questions
A priori from results of a national needs assessment survey
Identification of Guidelines
2.2.Identification
Guidelines
Systematic review (2000-2010) + Grey literature
QualityAppraisal
Appraisal of
3. 3.
Quality
of Guidelines
Guidelines
Guideline quality – Validated instrument (AGREE)
Expanded searches:
Public health
guidelines, postmarketing surveillance
+ SLR for malignancy
(2008-10)
Synthesis of
of Guidelines
4.4.Synthesis
Guidelines
Evidence
Evidence tables
tables of
of recommendations
recommendations with
with supporting
supporting evidence
evidence
Adapt/develop recommendations
5. 5.
Adapt/develop
recommendations
Full
Full working
working group
group voting
voting and
and discussion
discussion
6. Extended Review & Endorsement
External clinical experts (infectious disease, malignancy) + CRA executive
Dissemination
7.7.Dissemination
Educational meetings/ local workshops + support tools
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Strength of Evidence
Level of Evidence
I
II
Strength of Recommendation
Meta-analyses/systematic reviews of
RCTs, or individual RCTs
Meta-analyses, systematic reviews of
case control/cohort studies or individual
case control/ cohort studies
A
Strong
Direct level I evidence
B
Moderate
Direct level II evidence or
extrapolated level I evidence
OR
RCT subgroup/post hoc analyses
III
Non-analytic studies, e.g. case reports,
case series
Expert opinion
IV
C
Weak
Direct level III evidence or
extrapolated level II evidence
D
Consensus
Expert opinion based on very
limited evidence
Bykerk et al. The Journal of Rheumatology 2011; 38:11; doi:10.3899/jrheum.110207
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Recommendations
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Disclaimer
Recommendations reviewed here are intended to be
read in conjunction with Part I of CRA Recommendations
for RA.
These recommendations address specific safety
questions that were identified a priori. They are not
intended to cover all safety aspects concerning
treatment with traditional and biologic DMARDs.
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Perioperative Care
Recommendation
Level of
Evidence
Strength
1. Methotrexate can be safely continued in the
perioperative period for RA patients undergoing
elective orthopedic surgery.
I
A
2. Biologics should be held prior to surgical
procedures. The timing for withholding therapy
should be based on the individual patient, the
nature of the surgery, and the pharmacokinetic
properties of the agent. Biologic DMARDs may
be restarted postoperatively if there is no
evidence of infection and wound healing is
satisfactory.
II, IV
C
Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165
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Mean half-lives of biologic agents licensed for use in Canada
Mean half-life
(days)
4.3
2 half-lives
(days)
8.6
5 half-lives
(days)
21.5
14
28
70
8-10
16-20
40-50
Golimumab (GOL)
12
24
60
Certolizumab (CTZ)
14
28
70
Rituximab (RTX)
21
42
105
Abatacept (ABAT)
13
26
65
Tocilizumab (TCZ)
13
26
65
Etanercept (ETN)
Adalimumab (ADA)
Infliximab (IFX)
Health Canada Drug Product Database (accessed 04-2011): http://www.hc-sc.gc.ca/dhp-mps/prodpharma/databasdon/index-eng.php
Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165 14
Latent Tuberculosis Infection (LTBI)
Recommendation
3. Screening for latent tuberculosis infection (LTBI)
is recommended prior to starting Anti-TNF therapy
(II), abatacept (ABAT) and tocilizumab (TCZ) (IV).
Screening should consist of a history including an
assessment of LTBI epidemiologic risk factors,
physical exam, tuberculin skin test (TBST) and a
chest x-ray in high-risk groups (II). Physicians should
exercise clinical judgment as to the need to repeat
screening in patients who tested negative in prior
screening and have new epidemiologic risk factors
(IV).
Level of
Evidence
Strength
II, IV
B
Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165
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Latent Tuberculosis Infection (LTBI)
Risk Factors for Latent Tuberculosis Infection (LTBI)
• Close contact with individuals known or suspected to have TB (e.g.,
family members or people sharing living spaces)
• History of active TB or x-ray suggestive of past TB that was not
adequately treated
• Living in (and/or traveling to) communities with high rates of latent/
active TB
• Low income populations (e.g. urban homeless)
• Residents of long-term care and correctional facilities
• Occupational exposure to high risk groups (e.g. healthcare workers)
Public Health Agency of Canada (PHAC) 2008 Tuberculosis Fact Sheet: http://www.phac-aspc.gc.ca/tbpc-latb/fa-fi/tb_can-eng.php
Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165 16
Latent Tuberculosis Infection (LTBI)
Recommendation
4. Interferon-gamma release assays (IGRAs)
may be an option to identify false positive
tuberculin skin tests (TBSTs) in patients who
have received the Bacille Calmette-Guérin
(BCG) vaccine and have no epidemiologic risk
factors.
Level of
Evidence
Strength
IV
D
Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165
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Latent Tuberculosis Infection (LTBI)
Recommendation
5. Any RA patient with latent tuberculosis
infection (LTBI) should be considered for
prophylactic therapy.
Level of
Evidence
Strength
II
B
Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165
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Latent Tuberculosis Infection (LTBI)
Recommendation
6. Biologic agents may be started 1-2 months
after the initiation of latent tuberculosis
infection (LTBI) prophylaxis.
Level of
Evidence
Strength
II, IV
B
Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165
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Vaccination
Summary of CRA Recommendations for Vaccination in
Patients with RA (Recommendations 7-9)
Inactivated/ Killed Vaccines
Live attenuated vaccines
Hepatitis B
Herpes
Zoster
Other
✓
✓†
✓††
Caution
✓
✓
✓†
✓††
Caution
Sulfasalazine
✓
✓
✓†
✓††
Caution
All biologics
✓
✓
✓†
Avoid
Avoid
Influenza
Pneumococcal
(annual)
(booster after 3-5 years)
Methotrexate*
✓
Leflunomide
✓
Recommended; ideally administer prior to initiating therapy.
Recommended in high-risk groups including residents, travelers or close contact with individuals from hepatitis B endemic areas, illicit
drug users, persons engaging in risky sexual behaviors/history of STI, men who have sex with men, chronic liver disease, occupational
exposures, frequent blood transfusions.
†† Recommended in RA patients > 60 years old.
* Methotrexate ≤ 25 mg per week.
†
Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165 20
Vaccination
Classification of Common Vaccines
Live attenuated vaccines
Inactivated/killed vaccines
Bacillus Calmette Guérin (BCG)
Influenza - nasal
Measles/mumps/rubella (MMR)
Polio - oral
Smallpox
Typhoid (oral)
Varicella/ Herpes Zoster
Yellow fever
Diphtheria
Hemophilus influenza type B (protein conjugate)
Hepatitis A
Hepatitis B
Human Papilloma Virus (HPV)
Inactivated poliomyelitis (IPV)
Influenza - intramuscular
Meningococcal
Pertussis
Pneumococcal (23-valent polysaccharide)
Pneumococcal (seven-valent protein conjugate)
Rabies
Tetanus*
Typhoid - intramuscular
* Tetanus + diphtheria toxoids adsorbed + component pertussis (Tdap); tetanus + diphtheria (Td); component pertussis + diphtheria
+ tetanus toxoids adsorbed (DTaP)
Public Health Agency of Canada (PHAC) Canadian Immunization Guide: http://www.phac-aspc.gc.ca/publicat/cig-gci/ p01-eng.php
Rahier et al. Rheumatology 2010
.
Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165 21
Malignancy
Given the limited research evidence for
malignancy, recommendations are generally
grouped as follows:
Medications that are / should be:
1) An option (either evidence that there is no increased risk
or no theoretical increased risk)
1) Used with caution due to unknown risks
1) Used with caution; at least some evidence of  risks
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Malignancy
Summary of CRA Recommendations for Malignancy in RA
(Recommendations 10-13)
An option
Active Malignancy
(Receiving Chemotherapy/Radiation)
*
Use with caution
Use with caution;
(Risk unknown/ no
evidence)
(Some evidence of
increased risk)
*
*
Abatacept
Tocilizumab
Methotrexate
Anti-TNF
Abatacept
Rituximab
Tocilizumab
Anti- TNF
Abatacept
Rituximab
Tocilizumab
Anti- TNF
(melanoma)
History of Malignancy
Lymphoma
Non-melanoma skin
cancer
Solid tumor
Sulfasalazine
Hydroxychloroquine
Rituximab
Methotrexate
Leflunomide
Sulfasalazine
Hydroxychloroquine
Methotrexate
Leflunomide
Sulfasalazine
Hydroxychloroquine
* Treatment decisions should be made on a case-by-case basis in conjunction with a cancer specialist & the patient.
Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165 23
Accessing CRA Recommendations?
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Other Useful Links
Journal of Rheumatology Publications
•
http://jrheum.org/search?fulltext=schieir&journalcode=jrheum%7Cjrheumsupp&submit=yes&x=0&y=0
Drug monitoring
•
Health Canada Drug Product Database
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/databasdon/index-eng.php

Health Canada MedEffect Homepage
http://www.healthcanada.gc.ca/medeffect

US FDA MedWatch Safety Alerts for Human Medical Products
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/default.htm
TB
•
Public Health Agency of Canada 2007 Canadian Tuberculosis Standards:
http://www.phac-aspc.gc.ca/tbpc-latb/pubs/tbstand07-eng.php

Online TST/ IGRA Interpreter Tool (Version 3.0)
http://www.tstin3d.com/en/calc.html
Vaccination
•
2006 Public Health Agency of Canada Canadian Immunization Guide
http://www.phac-aspc.gc.ca/publicat/cig-gci/p01-eng.php
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Acknowledgements
RA Guidelines Working Group
Dr. Pooneh Akhavan
Dr. Vivian Bykerk
Dr. Claire Bombardier
Mrs. Anne Dooley
Dr. Paul Haraoui
Dr. Glen Hazlewood
Dr. Majed Khraish
Dr. Sharon LeClercq
Mr. Jean Légaré
Dr. Diane Mosher
Dr. James Pencharz
Dr. Janet Pope
Ms. Orit Schieir
Dr. John Thomson
Dr. Carter Thorne
Dr. Michel Zummer
For any queries/ comments about
CRA recommendations for RA,
please contact
raguidelines@rheum.ca
Expert Consultants
Dr. Johan Askling (Malignancy)
Dr. Michael Gardam (TB, Vaccination)
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