Who gets EIMs? Dr Tim Orchard St Mary s Hospital & Imperial College London

Who gets EIMs? Dr Tim Orchard St Mary s Hospital & Imperial College London

Background Extraintestinal manifestations of IBD are well recognised. They include:- Arthritis - peripheral and axial Eye complications Erythema Nodosum Pyoderma Gangrenosum PSC

Studying predictors of EIMs The clinical phenotype of the EIM has to be well defined The population of patients has to be large enough to allow meaningful comparisons to be made

Problems with EIM studies Small numbers of patients Intermittent symptoms Confounding factors such as control groups So far only single centre small studies in PSC Arthritis, uveitis and Erythema Nodosum

Ways of predicting EIMs Clinical features Serology Genetics

Primary Sclerosing Cholangitis Associated with Males Total Colitis Quiescent disease panca but 70% of UC patients are panca+?hla-dr3 DQ2 but related to extensive UC NO effective predictors of disease

Clinical characteristics UC Crohn s Patients reviewed 976 483 Male : Female ratio 484:492 202:281 Median length of FU 10.7 10.2 (0.03-64.3) (0.03-57.4) Erythema nodosum 9 (0.9%) 27 (5.6%) Eye complications 30 (3.1%) 31 (6.4%) Pyoderma gangrenosum 5 (0.5%) 6 (1.2%)

Joint problems in IBD Back problems Peripheral joint problems Ankylosing Spondylitis (AS) Sacroiliitis Arthritis - Knees / ankles Arthralgia Hands

Ankylosing Spondylitis Well defined clinical condition characterised by Sacroiliitis Inflammatory back pain and immobility Enthesitis Respiratory embarrassment Aortic root problems Peripheral arthritis in 30% Uveitis in 20-40%

Ankylosing Spondylitis

Normal SI joints

Ankylosing Spondylitis in IBD Prevalence 1.5% (1-6%) M:F ratio 1:1 (cf. 3:1 in idiopathic AS) Runs a course independent of the IBD May be diagnosed before or after IBD May be less severe than idiopathic AS

Isolated Sacroiliitis Often asymptomatic Radiology suggests a prevalence of 18% MRI suggests prevalence of 30-40% in UC & 40-50% in CD The rate of progression to AS is unclear The role of HLA-B*27 is not known

Peripheral arthritis Oxford 1964 - Arthritis in 5.6% (Edwards & Truelove) Mainly small joint polyarthritis Leeds 1965 - Colitic arthritis in 11.5% (Wright & Watkinson) Mainly large joint oligoarthritis associated with flares of UC, but could involve small joints rarely USA 1976 - Colitic arthritis in 9% & polyarthritis in 13% (Greenstein et al)

Arthralgia in IBD Stein et al 1993 (Bull Hosp Jt Dis) 54 Crohn s patients compared with age and sex matched controls % arthralgia % arthritis Crohn s patients 44 7.4 Controls 46 0

Enteropathic peripheral arthropathy Type 1 (pauciarticular) Less than 5 joints, always including a large joint Self-limiting episodes often with relapses of IBD Type 2 (polyarticular) More than 5 joints often involving small joints esp. MCP Persistent symptoms running a course independent of the IBD

Erythema nodosum Characteristic skin rash - raised nodules on shins May occur in up to 10% of patients, depending on study population Often occurs with relapse of IBD? More common in colonic disease

Eye complications Acute red eye associated with relapse of IBD Usually iritis or anterior uveitis Rarely posterior uveitis May occur with arthritis Prevalence varies between studies

Can we predict who gets EIMs?

Clinical Predictors

Ovelap between erythema nodosum (EN), uveitis & arthropathy Percentage with complication(%) 30 25 20 15 10 5 0 26.3 24.1 17.1 17.2 16.7 8.6 0.5 1.2 2.1 2.9 4.2 0 No jt probs UC No jt probs CD Type 1 UC Type 1 CD Type 2 UC Type2 CD Type of joint complication EN Uveitis

EIMS and bowel disease phenotype Uncommon in pure small intestinal Crohn s disease More common in females Ileocaecal resection may protect against arthritis

Role of ileocaecal intergrity - Study design n=217 Date of Dx n=192 FU Date of Dx FU ICR 1st clinical relapse FU Length of FU pre & post surgery & date of first onset of arthritis noted

Results Years of FU/joint complication Pre-surgery Post-surgery Surgery pts (Median FU 10.2 yrs) 89 701 Non-surgery pts 83 (Median FU 10.7 yrs)

Kaplan-Meier curves of survival free of joint complications in patients who had never undergone surgery and patients after ileocaecal resection. 1 ICR Cum. Survival.8.6.4 p=0.0001 No ICR.2 0 0 50 100 150 200 250 300 350 400 Time (months)

Genetic Predictors

IBD - Genetic Concepts Susceptibility Genes Environmental Factors IBD UC CD Disease Specificity Genes Genes Determining Phenotype Environmental factors Environmental factors

Phenotype determining genes Do not confer overall disease susceptibility Do affect the clinical phenotype of the disease e.g. extra-intestinal manifestations, disease extent Detection requires precise clinical characterisation of patients

Ankylosing Spondylitis, IBD and genes AS affects 1-3% of patients with IBD 94% of patients with idiopathic AS are HLA-B27+ 50-80% of IBD patients with AS are HLA-B27+ Other spondyloarthropathies are also associated with HLA-B27. e.g. Reactive arthritis (70% B27+)

Genetics & Peripheral arthropathies IBD associated arthropathies are classified with other seronegative spondyloarthropathies No association with HLA-B27 has been shown for peripheral arthropathy in IBD May be due to small studies and lack of clinical characterisation The only positive HLA association was with HLA-DR103 (27% vs 3%) in UC patients undergoing surgery (Roussomoustakaki et al 1997)

HLA associations in IBD arthritis Ankylosing spondylitis Patients Controls (n=16) (n= 603) HLA-B27 56% 7% * HLA-DR1 63% 19% ** *p<0.0001 **p=0.0002

HLA-B27 and Axial Disease in IBD Prospective study of 45 Crohn s patients All had back measurements and MRI scanning 17/45 had sacroiliitis 70% were symptomatic 5 patients in the study were HLA-B27+ ALL had axial abnormalities

HLA Class I in Peripheral arthropathy Type 1 Type 2 Controls (n=57) (n=45) (n=603) HLA-B27 (%) 26 5 7 p=0.0003 HLA-B35 (%) 33 7 15 p=0.015 HLA-B44 (%) 12 62 31 p=0.019

HLA Class II in Peripheral arthropathy Type 1 Type 2 Controls (n=57) (n=45) (n=603) HLA-DR103 35 0 3 p<0.0001 (%) In recurrent arthritis 65% possess HLA-DR103

HLA associations in uveitis Uveitis IBD controls Controls (n=42) (n=124) (n=603) HLA-B27 (%) 40 9 7 * HLA-B58 (%) 12 1 1 ** HLA-DR103 20 8 3 *** (%) *p<0.0001 **p=0.002 ***p=0.001

HLA associations in erythema nodosum EN IBD controls Controls (n=28) (n=124) (n=603) HLA-B62 (%) 25 5 11 * HLA-B14, 45, 21 8 6 ** 47,49 & 53 (%) *p=0.02 **p=0.001

Linkage disequilibrium What is it and is it important?

Linkage disequilibrium Genes far apart - Recombination likely- Genes NOT inherited together Genes close together - Recombination unlikely - Genes ARE inherited together = Linkage disequilibrium

Linkage disequilibrium - its effects Association studies detect associations NOT causal relationships The associations found may be due to another gene located close by (i.e. in linkage disequilibrium) Studies of genes around those where associations are found are often worthwhile

Genes of the HLA 0 Centromeric Kilobases 1000 2000 3000 MICA Telomeric DP TAP / LMP DQ DR C 4 2 C HSP TNF B C A CLASS II CLASS III CLASS I

TNFα Gene Found in the MHC between HLA-B and HLA-DR close to MICA Single nucleotide polymorphisms have been described in the promoter and gene itself Polymorphisms in the promoter are associated with increased production of TNFα in vitro

Polymorphism at 1031 in TNFα gene P=NS P c =0.016 70 Percentage of patients 60 50 40 30 20 10 69 46 36 34 25 EN Type 1 PeA Controls Uveitis Type 2 PeA 0-1031C

EN, Arthritis and Uveitis in IBD These EIM s are all associated with genes in the HLA region The genes that determine the individual EIM s may be in linkage disequilibrium This may account for the overlapping clinical syndromes seen in practice Currently none of the associations is strong enough to be useful in everyday practice

Genes of the HLA (as was) 0 Centromeric Kilobases 1000 2000 3000 Telomeric DP DQ DR TNF B C A CLASS II CLASS III CLASS I

Genes of the HLA - Now Nature Oct 1999