Extraintestinal Manifestations

1. Extraintestinal Manifestations Tim Orchard St Mary’s Hospital and Imperial College London

2. 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

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

4. 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

5. IBD - Aetiologic Concepts Susceptibility Genes Environmental Factors IBD UC CD Disease Specificity Genes Genes Determining Phenotype Environmental factors Environmental factors

6. 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

7. 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

8. 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

9. 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

10. 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%)

11. Ankylosing Spondylitis

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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.

18. O/E Pale and thin Abdo - Very tender in R IF Bilateral knee effusions R>>L Bloods Hb 9.0 MCV 72 Plts 485 ESR 48 CRP 93 Working diagnosis: Crohn’s disease

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. Pyoderma Gangrenosum • May be difficult to treat • Options include • Steroids • Ciclosporin/Tacrolimus • Azathioprine • Biologics

34. 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% (p=0.025) • Open label phase 29 patients received infliximab • Response at week 6 in 69% Remission in 21% Brooklyn et al Gut 2006

35. 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

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

37. 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

38. EIM’s: Overlapping clinical syndromes

40. 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

41. Linkage disequilibrium What is it and is it important?

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

43. 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

44. Polymorphism at –1031 in TNFa gene P=NS Pc=0.016

45. Genes of the HLA - Now Nature Oct 1999

46. 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