Extraintestinal Manifestations

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Extraintestinal Manifestations

• Tim Orchard
• St Marys Hospital and Imperial College
• London

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Extra-intestinal manifestations previously
reportedin inflammatory bowel disease
Musculoskeletal Peripheral arthritis Granulomatous
arthritis and synovitis Rheumatoid arthritis
Sacroiliits Ankylosing spondylitis Clubbing Osteo
porosis osteomalacia Rhabdomyolysis Relapsing
polychondritis Skin and mucous membranes Oral
ulceration Cheilitis Pyostomatitis
vegetans Erythema nodosum Pyoderma
gangrenosum Sweets syndrome Metastatic Crohns
disease Psoriasis Epidermolysis bullosa
acquisita Perianal skin tags Polyarteritis
nodosa Cutaneous vasculitis Neuologic Peripheral
neuropathy Meningitis Vestibular
dysfunction Pseudotumour cerebri
Haematologic Anaemia iron deficiency Vitamin
B12 deficiency Anaemia of chronic
diseases Autoimmune haemolytic anaemia Hyposplenis
m Anticardiolipin antibody Takayasus
arteritis Wegeners arteritis   Renal and
genitourinary Nephrolithiasis Retroperitoneal
fibrosis Fistula formation Glomerulonephritis Rena
l amyloidosis Drug related nephrotoxicity   Hepato
-pancreato-biliary Primary sclerosing cholangitis
(PSC) Small duct PSC Cholangiocarcinoma Cholelithi
asis Autoimmune hepatitis Primary biliary
cirrhosis Pancreatitis Ampullary Crohns
disease Granulomatous pancreatitis
Ocular Conjunctivitis Uveitis, iritis Episcleritis
Scleritis Retrobulbar neuritis Crohns
keratopathy   Bronchopulmonary Chronic bronchitis
with brocnhiectasis Fibrosing alveolitis Pulmonary
vasculitis Interstitial lung disease Sarcoidosis
Tracheal obstruction Cardiac Pleuropericarditis
Cardiomyopathy Endocarditis Myocarditis
Endocrine and metabolic Growth failure
Thyroiditis Osteoporosis, osteomalacia
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Common EIMs

• Arthritis
• Axial Ankylosing Spondylitis
• Peripheral
• Skin
• Erythema nodosum
• Pyoderma gangrenosum
• Eyes
• Anterior uveitis
• Episcleritis/Iritis
• Liver
• PSC
• Autoimmune hepatitis

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EIMs Why do they occur?

• Directly related to gut inflammation
• Large joint arthritis, EN
• Triggered by gut inflammation/abnormalities
• AS, small joint arthritis, ?PG
• Shared genetic predisposition
• ?AS Large joint arthritis
• Related to inflammation in general
• Venous thrombosis
• Dietary insufficiency
• Epidermolysis bullosa

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IBD - Aetiologic Concepts
Susceptibility Genes
Environmental Factors
IBD
UC
CD
Disease Specificity Genes
Genes Determining Phenotype
Environmental factors
Environmental factors
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Treatment considerations

• Is the EIM associated with active bowel disease
• Treatment of the bowel may heal the EIM
• Adaptation of gut therapy may help the EIM
• Does the EIM need specific treatment and does
  that alter the natural history or treat the
  symptoms?
• Topical
• Systemic

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DB 26 y.o. man

• Presented with diarrhoea and abdominal pain
• Weight loss of 5kgs
• Colonoscopy normal
• Small bowel enema terminal ileal Crohns
  disease No stricturing
• Settled on Entocort

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DB

• Back pain at presentation
• Didnt settle with the bowel disease
• Low back
• Worse in the morning
• Improved as the day went on
• Normal SI X-ray and MRI scan

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DB

• Crohns largely quiescent occ diarrhoea
• Persistent back pain exactly the same
• But increasing duration
• OE decreased lumbar flexion
• Repeat MRI scan
• Bilateral sacroiliitis
• HLA-B27
• Diagnosed with Ankylosing spondylitis

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Ankylosing Spondylitis

• Well defined clinical syndrome
• Sacroiliitis
• Progressive ankylosis of the vertebral facet
  joints
• Question mark posture and respiratory
  embarrassment
• 30 have associated peripheral arthritis
• MF ratio 31 in idiopathic, 11 in IBD
• Present in 1-6 of IBD patients
• Strong association with HLA-B27 (although weaker
  than in idiopathic AS (70 vs 94)

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Ankylosing Spondylitis
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Ankylosing spondylitis

• Physical therapies
• Analgesia
• NSAIDs if bowel disease quiescent
• Sulfasalazine
• Injection of SI joints
• Methotrexate
• Biologic therapies
• All treatment in consultation with a
  rheumatologist

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Isolated Sacroiliitis

• May be 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

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Axial Arthritis the role of HLA-B27

• AS is associated with HLA-B27 in IBD
• The association is weaker than idiopathic AS
• Isolated sacroiliitis is not associated with AS
• BUT HLA-B27 IBD patients are at greatly
  increased risk of axial arthritis compared to
  other HLA-B27 subjects
• HLA-B27 and intestinal inflammation may have an
  additive effect

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Low back pain in IBD

• Back pain is common How do AS/SI present?
• Pain and stiffness in the morning
• Improves with exercise
• Radiates into the buttocks
• Impairment of spinal flexion
• In contrast mechanical back pain
• Comes on later in the day
• Is worsened by physical activity

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Miss A.K. 15 y.o. Female

• PC
• Painful swollen knees
• Abdominal pain, and loose motions
• Generally unwell
• HPC
• Knee pain swelling started 18/12 earlier.
  Referred to rheumatologist.
• D Inflammatory arthritis
• RhF - NEGATIVE

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Commenced on NSAIDs - Marginal improvement Due
to sit GCSEs - Started on oral Prednisolone Felt
much better. Steroids reduced after exams - felt
worse generally. Knees swollen and abdo pain Poor
appetite and weight Referred for medical
opinion.
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O/E Pale and thin Abdo - Very tender in R
IF Bilateral knee effusions RgtgtL Bloods Hb
9.0 MCV 72 Plts 485 ESR 48 CRP 93 Working
diagnosis Crohns disease
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Small Bowel Enema Terminal ileal Crohns disease
with multiple fistulae to the colon Rx Steroids
and elemental diet Improved, but relapsed on
reducing steroids and normal diet. Right
hemicolectomy. Good recovery - Well for 18/12 on
oral Mesalazine
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Enteropathic peripheral arthropathy

• Type 1 (pauciarticular)
• Less than 5 joints, always including a large
  joint
• Self-limiting episodes often with relapses of
  IBD
• Associated with HLA-B27 and HLA-DR103
• Type 2 (polyarticular)
• More than 5 joints often involving small joints
  esp. MCP
• Persistent symptoms running a course
  independent of the IBD
• Associated with HLA-B44
• Arthritis is NOT erosive or deforming
• Orchard et al Gut 1998 Gastroenterology 2000

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Arthralgia in IBD

• Stein et al 1993 (Bull Hosp Jt Dis)
• 54 Crohns patients compared with age and sex
  matched controls
• arthralgia arthritis
• Crohns patients 44 7.4
• Controls 46 0

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Treatment strategies for IBD arthritis

• Physical therapies
• May be useful in Large joint arthritis to
  maintain muscle strength
• Assistive devices
• Walking stick for large joint arthritis
• Splints
• Local treatments
• Intra-articular steroid injection

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Treatment strategies (2)

• Analgesia
• Simple analgesia (Paracetamol, Codydramol)
• NSAIDs only if the bowel disease is quiet
• COX 2 specific inhibitors may be better, but
  probably not
• 5-ASA Medication
• An empirical change to Sulfasalazine may help
  some patients
• Recent trial evidence suggests Pentasa may be as
  effective

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Treatment strategies (3)

• Immune suppression
• If already used for the IBD Methotrexate may be
  the best choice
• Occasionally the arthritis alone may require
  immune suppression and low dose MTX is 1st choice
• Low dose oral steroids may be required in some
  patients
• Biological agents
• Infliximab is effective in AS, and has worked in
  small case series of IBD arthritis

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LC 56 y.o. woman

• 1998 Bloody diarrhoea
• 1999 Dx ulcerative colitis
• Rx Prednisolone
• Asacol
• Azathioprine
• 2000 Heavy pr bleeding requiring transfusion
• 2001Colectomy and ileostomy. Rectal stump in situ

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LC

• Subsequently quite well with good ileostomy
  function
• Occasional minor pr discharge
• Jan 2005
• Back ache, joint pains and swelling
• Iritis
• Single lesion on shin 3cm in diameter healed
  with scarring
• Subsequently multiple raised painful lesions on
  shins
• Recurrent oral ulceration
• Labial ulcers

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LC

• OE Multiple raised lesions on shins with
  necrotic ulcerating tops
• Broke down over time
• Labial erythema and ulceration
• Rigid S Mucus and blood. Granular mucosa and
  ulcers
• Bx Mixture of active UC and diversion colitis
• SBFT and ileoscopy - NORMAL

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Eye complications

• Acute red eye associated with relapse of IBD
• Usually iritis or anterior uveitis
• Rarely posterior uveitis
• May occur with arthritis
• Occurs in 3-5 of IBD patients
• FgtM 31
• Needs ophthalomological assessment

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Erythema nodosum

• Characteristic skin rash - raised nodules on
  shins
• Septal panniculitis in subcutis
• May occur in up to 10 of patients, depending on
  study population
• CDgtgtUC FgtgtM (51)
• Often occurs with relapse of IBD
• ? More common in colonic disease
• Associated with other EIMs
• Arthritis, uveitis
• Sweets Syndrome

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Pyoderma Gangrenosum

• Uncommon lt1 of IBD pts
• Sterile ulcerating skin lesions
• Overhung violaceous borders
• Exhibits pathergy
• May be independent of IBD
• May be difficult to treat

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LC

• Possible differential would be Behcets disease
  with intestinal involvement
• 20 of Behcets have intestinal involvement
• Lesions tend to be deep punched out ulcers
• Round rather than serpiginous
• Skip lesions similar to Crohns
• Recurs after surgery
• Associated with HLA-B51

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LC

• HLA status sent
• HLA B35, B44 DRB10103
• B35 and 44 associated with arthritis in UC and CD
• B44 associated with recurrent oral ulceration in
  IBD
• DRB10103 associated with large joint arthritis,
  iritis and extensive colitis

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Pyoderma Gangrenosum

• May be difficult to treat
• Options include
• Steroids
• Ciclosporin/Tacrolimus
• Azathioprine
• Biologics

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Infliximab for Pyoderma Gangrenosum

• 30 patients in randomised placebo controlled
  trial
• 17 placebo 13 Infliximab
• Non-responders were offered open label infliximab
• Response at week 2 46 vs 6 (p0.025)
• Open label phase 29 patients received infliximab
• Response at week 6 in 69 Remission in 21

Brooklyn et al Gut 2006
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PG Unanswered questions

• PG recurs in 35
• No evidence on the efficacy of Azathioprine or
  other immune modulators on the PG
• Empirical treatment algorithm
• Steroids
• Ciclosporin/tacrolimus
• Infliximab /- Azathioprine

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LC

• Discussion with patient about options
• Immediate medical therapies CiA, Aza, Infliximab
• Excision of rectal stump

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LC

• Patient opted for Infliximab
• Dramatic effect improvement within 24 hours
• Underwent 3 dose induction
• Symptoms recurred less severely after 2 months
• Underwent rectal stump excision in May 2006
• Resolution of extraintestinal symptoms

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EIMs Overlapping clinical syndromes
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(No Transcript)
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PG and other EIMs

• Other EIMs are more common in PG pts than in
  IBD pts without EIMs
• PG is also associated with polymorphisms in the
  HLA region
• Type 1 arthritis, uveitis, EN and PG appear to
  be overlapping clinical and immunogenetic
  conditions

Patients ()
Williams HRT et al UEGW 2007
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Linkage disequilibrium

• What is it and is it important?

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Linkage disequilibrium
Genes far apart - Recombination likely- Genes NOT
inherited together
Genes close together - Recombination unlikely -
Genes ARE inherited together Linkage
disequilibrium
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Genes of the HLA
Kilobases
1000
2000
3000
0
Telomeric
Centromeric
CLASS I
CLASS III
CLASS II
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Polymorphism at 1031 in TNFa gene
PNS
Pc0.016
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Genes of the HLA - Now
Nature Oct 1999
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Summary

• EIMs may be determined by genetic predisposition
  and interaction with luminal bacteria
• EIMs associated with active gut disease often
  respond to treatment of the gut
• Specific therapies should be considered if
• They alter the natural history of the EIM
• They are not related to gut activity
• They require specific symptomatic relief
• Simple analgesia may be sufficient for symptom
  control
• Immune modulators may be required to alter the
  natural history