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Extraintestinal Manifestations. Tim Orchard St Mary’s Hospital and Imperial College London. Extra-intestinal manifestations previously reported in inflammatory bowel disease. Musculoskeletal Peripheral arthritis Granulomatous arthritis and synovitis Rheumatoid arthritis Sacroiliits

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Extraintestinal manifestations l.jpg

Extraintestinal Manifestations

Tim Orchard

St Mary’s 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

Osteoporosis & osteomalacia

Rhabdomyolysis

Relapsing polychondritis

Skin and mucous membranes

Oral ulceration

Cheilitis

Pyostomatitis vegetans

Erythema nodosum

Pyoderma gangrenosum

Sweet’s syndrome

Metastatic Crohn’s 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

Hyposplenism

Anticardiolipin antibody

Takayasu’s arteritis

Wegener’s arteritis

Renal and genitourinary

Nephrolithiasis

Retroperitoneal fibrosis

Fistula formation

Glomerulonephritis

Renal amyloidosis

Drug related nephrotoxicity

Hepato-pancreato-biliary

Primary sclerosing cholangitis (PSC)

Small duct PSC

Cholangiocarcinoma

Cholelithiasis

Autoimmune hepatitis

Primary biliary cirrhosis

Pancreatitis

Ampullary Crohn’s disease

Granulomatous pancreatitis

Ocular

Conjunctivitis

Uveitis, iritis

Episcleritis

Scleritis

Retrobulbar neuritis

Crohn’s 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 Crohn’s disease – No stricturing

  • Settled on Entocort


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DB

  • Back pain at presentation

    • Didn’t 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

  • Crohn’s 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

    • M:F ratio 3:1 in idiopathic, 1:1 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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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

Isolated Sacroiliitis


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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 NSAID’s - Marginal improvement

Due to sit GCSE’s - 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 R>>L

Bloods

Hb 9.0MCV 72Plts 485

ESR 48

CRP 93

Working diagnosis: Crohn’s disease


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Small Bowel Enema

Terminal ileal Crohn’s 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 Crohn’s patients compared with age and sex matched controls

    % arthralgia% arthritis

    Crohn’s patients44 7.4

    Controls46 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)

    • NSAID’s – 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

  • F>M 3:1

  • 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

  • CD>>UC F>>M (5:1)

  • Often occurs with relapse of IBD

  • ? More common in colonic disease

  • Associated with other EIMs

    • Arthritis, uveitis

    • Sweet’s Syndrome


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Pyoderma Gangrenosum

  • Uncommon <1% 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 Behcet’s disease with intestinal involvement

    • 20% of Behcet’s have intestinal involvement

    • Lesions tend to be deep punched out ulcers

    • Round rather than serpiginous

    • Skip lesions similar to Crohn’s

    • Recurs after surgery

    • Associated with HLA-B*51


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LC

  • HLA status sent

    • HLA B*35, B*44 DRB1*0103

  • B35 and 44 associated with arthritis in UC and CD

  • B44 associated with recurrent oral ulceration in IBD

  • DRB1*0103 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 246% vs 6% (p=0.025)

  • 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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EIM’s: Overlapping clinical syndromes


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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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MICA

TAP/

LMP

DP

DQ

DR

C4

C2

HSP

TNF

B

C

A

Genes of the HLA

Kilobases

1000

2000

3000

0

Telomeric

Centromeric

CLASS II

CLASS III

CLASS I


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Polymorphism at –1031 in TNFa gene

P=NS

Pc=0.016


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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


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