Risk of septic arthritis in patients with rheumatoid - The British ...

Risk of septic arthritis in patients with
rheumatoid arthritis treated with anti-
TNF therapy: Results from the BSR
Biologics Register (BSRBR)
James Galloway

BSRBR Disclosure Statement
BSR receives restricted income financial support from Abbott Laboratories,
Amgen, Biovitrum, Schering Plough, Wyeth Pharmaceuticals and Roche.
This income finances a separate contract between the BSR and the
University of Manchester who provide and run the BSRBR.
All decisions concerning analysis, interpretation and publications are made
autonomously of any industrial contribution.
(I have no personal disclosures or conflicts of interest.)

Septic Arthritis
• Septic arthritis (SA) increased in RA
Explanations:
• RA itself a risk for infection
• Damaged joints more susceptible to colonisation
• Presence of joint prostheses
• Immunosuppressive therapy

The role of TNF in host defense
T lymphocyte
Granuloma
Formation
Mycobacteria
Macrophage
TNF
Listeria
PLoS Image

Anti-TNF therapy and infection
5.0
Follow up period of risk estimate
Incident rate ratio (95% CI)
2.0
1.0
1 2 3
0.6
Adapted from Askling & Dixon, Curr Opin Rheumatol, Volume 20(2).March 2008.138–144

Published evidence regarding SA and
anti-TNF therapy
• RCT data
– No signal apparent
• Case reports
– Unusual organisms
• Observational studies

Aims
• To establish the effect of anti-TNF therapy
upon the risk of septic arthritis
• To describe the pattern of organisms seen
• To analyse the temporal relationship
between drug exposure and risk of SA

BSR Biologics Register
• Prospective cohort of
UK patients treated with
anti-TNF therapy for RA
• Commenced 2001
“All clinicians prescribing anti-TNF
therapy for RA should (with the
patient's consent) register the patient
with the BSRBR”

BSR Biologics Register
Control Cohort
• Prospective cohort of
UK patients treated with
• Active RA
anti-TNF therapy for RA
• DMARD use
• Anti-TNF Commenced naïve 2001
• 29 centres
• Identical follow-up

Data collection
6 Monthly Annually
Physician
Questionnaire
Patient
Questionnaire
& Diary
NHS-IC
Flagging
6 Monthly
Lifelong
Year 0 Year 3 2013

Case validation
• Physician confirmed cases only
• NHS-IC reported on death certificate
• Events classified serious
– IV antibiotics
– Hospitalisation
– Death

Statistical methods
• Multivariable Cox proportional hazard estimates were
used to compare rates between cohorts
• All events occurring on anti-TNF or within 90 days
included
• Analyses adjusted for:
– Age
– Gender
– Smoking
– Diabetes
– Year of registration
– Disease duration
– DAS28
– HAQ
– Baseline steroid use
– Prior joint replacement

Baseline characteristics
DMARD Anti-TNF p-value
Number of patients 3598 11798 -
Mean age:
Years (SD)
60 (12) 56 (12)

Baseline characteristics
ETA INF ADA
Number of patients 4219 3467 4202
Mean age:
Years (SD)
56 (12) 56 (12) 57 (12)
Females: % 77 76 76
Median disease duration: Years
(IQR)
12 (6-19) 12 (6-19) 10 (5-18)
Disease activity:
• Mean DAS28 score (SD)
Range 1-9
• Mean HAQ (SD)
Range 0-3
6.6 (1.0)
2.1 (0.6)
6.6 (1.0)
2.1 (0.6)
6.5 (1.0)
2.0 (0.6)
Baseline prior orthopaedic surgery 26 24 21

Results
Septic Arthritis within the BSRBR
Cohort Pyears fup N Incident rate / 1000
pyears follow up
All cases 202
DMARD cohort 9,094 18 1.9
All TNF cohort 36,230 184 5.1
Individual drug rates
Etanercept 15,784 92 5.8
Infliximab 9,622 43 4.5
Adalimumab 10,733 49 4.6

Hazard ratio for septic arthritis in anti-
TNF exposed patients
Hazard estimate (95% CI)
0 1 2 3 4
2.0
2.4
1.9 1.8
DMARD All Anti-TNF Etanercept Infliximab Adalimumab
*Adjusted for age, gender, disease severity, smoking, steroid exposure, prior joint replacement, entry year, diabetes

Pattern of cultured organisms
Anti-TNF Cohort
N=76
DMARD Cohort
N=7
9%
11%
55%
25%
S. aureus
Coag Neg Staph
Streptococci
Other
43% 43% S. aureus
Coag Neg Staph
Other
14%
Analysis limited to laboratory proven cases:
Adjusted Hazard Ratio 3.5 (1.4 – 9.0)

Event rate / 1000 patient years follow up
2 4
0
Risk of septic arthritis in
anti-TNF cohort
0
1 2 3
Years of follow up

Native joint infection
• Approximately 50% of infections occurred within
native joints in both cohorts
DMARD
Anti-TNF
Adjusted HR for SA limited to native
joints only
ref 2.5*
(1.2 – 5.0)
*Adjusted for age, gender, disease severity, smoking, steroid exposure, prior joint replacement, entry year, diabetes

Summary
• Significantly increased rate of septic arthritis in
anti-TNF exposed cohort
• Most infections are due to typical pathogens
found in joints
• TNF inhibition does confer susceptibility to some
atypical species
• The risk appears greatest in the first year of
therapy

Acknowledgements
• UK Consultant Rheumatologists
• UK Rheumatology Specialist Nurses
• BSRBR Control Centre Consortium
• British Society for Rheumatology
• Wyeth, Schering-Plough, Amgen, Biovitrum,
Abbott, Roche
• Alan Silman
Arthritis Research UK
Epidemiology Unit:
• Deborah Symmons
• Kimme Hyrich
• Kath Watson
• Mark Lunt
• Andrew Ustianowski
• Will Dixon
• Louise Mercer
• Yvonne King
• Katie McGrother
• Pat Creighton
• Lesley Albutt
• Katy Evans
• Steph Fanner
• Flo Baluwa
• James Anderson
• Anthony Marshall
• Lisa Liu
• Ursula Pattinson