1. Auto-immunity cases
Con Feighery

2. Auto-immunity Immune mediated damage
Absence of infection or other cause
Auto-antibodies may be present
Detection of auto-antibodies – help in diagnosis
Auto-antibodies often NOT cause of damage

3. Auto-immunity Characteristic features - Female preponderance
Auto-antibodies – some are pathogenic
Genetic association – often strongly associated with MHC class II genes

4. Case 1 – 35 year old female
Joint pain, swelling for 6 months, intermittent
Hands and wrists most affected
Sharp pain in chest on breathing, intermittent
No energy x 2 years
Otherwise generally well

5. Case 1 – 35 year old female Examination – Generally healthy
Some swelling, tenderness of hand, wrist joints
Pulse rate 90 beats per min
Heart and chest exam normal
Skin rash on face

6. Case 1 – 35 year old female
Photosensitive rash – typical of SLE. Referred to as a “butterfly” rash.

7. Case 3 – 35 year old female Test results Haemoglobin 10g/dl – low
White cell count 3.4 – low
Platelets – 100 – low
Chest x-ray – normal
Rheumatoid factor test (antibody to IgG) - positive

8. Case 3 – 35 year old female Questions
What do you think is ‘going on’ in this patient?
Do you think she might have arthritis?
What is the cause of her chest pain?
What might be the cause of her lack of energy?

9. Case 3 – 35 year old female Questions
Do you have any further ideas about what might be the wrong with this patient?
What additional tests might help decide?

10. Case 1 – 35 year old female Answers
Possible diagnoses include “lupus” aka SLE or rheumatoid arthritis
Autoantibody tests will help
Anti-nuclear antibodies found in SLE
Double stranded DNA antibodies only in SLE
Rheumatoid factor (antibody to IgG) is found in rheumatoid arthritis, other diseases

11. Antinuclear antibody test

12. Antibody to double stranded DNA
Crithidia luciliae – kinetoblast contains dsDNA

13. Case 3 – 35 year old female
Answers – common features in lupus (SLE) include -
Low white cell and platelet counts
Skin rash on face “photosensitive” a classic feature
Chest pain – lung lining inflammation occurs – “pleurisy”
Energy – due to anaemia, other causes?

14. Multiple ‘systems’ affected by lupus

15. SLE Classic example of “multi-system” auto-immune disease
Only 1 or 2 systems involved in many patients
Female:male ratio 9:1
ANA positive – 99%

16. Case 2 - 14 year old male Case history JG, 14 year old male
Intermittent diarrhoea x 3 years
Occasional abdominal pain
Mild abdominal distension
Fatigue, arthralgia

18. Clinical history (continued)
Past history – well until 11 years old
Family history – mother has rheumatoid arthritis; aunt is hypothyroid

19. Physical examination Examination –
Thin; weight – 6 stone (38 kg); height – 4 feet, 10 inches (147 cm)
Pre-pubertal
Pale facies; pulse 90/min, regular; chest clear
Abdomen – mild distension, slight tenderness
Joints – no synovitis; skin – no rashes

20. Early blood test results
Hgb – 9g/dl; MCV – 75fl
WCC – 11 x 109/l; platelets 500 x 109/l
ESR – 45mm/hr; CRP 80 mg/l – both raised
Albumin 28g/l; GGT 93 IU/l; Alk phos. – 140 IU/l
Urea, creatinine, electrolytes normal

21. Further blood test results
Complement levels – C3 – 80 g/l; (normal); C4 – 16 g/l (normal 0.16 – 0.70)
Immunoglobulins – IgG – 18g/l; IgM – 2g/l; IgA < 0.05 g/l
ANA +, titre 320; Smooth muscle antibody +, titre 80
ANCA +, perinuclear pattern, titre 80
Gliadin antibodies +, 30 units (normal range < 5 units)

22. Discussion issues
What additional information would you like to have about the patient’s history?

23. Discussion issues
What further physical findings would you look for?

24. Discussion issues
What further diagnostic tests should be considered?

25. Discussion issues How would you interpret the above findings?
What would you include in the differential diagnosis?
What early investigations are warranted?
What specific tests would you perform?

26. Case 2 – further tests
If this is coeliac disease, test for endomysial antibodies – c. 100% specificity
Or perform biopsy of small intestine

27. Endomysial antibody test
> 99% specific for coeliac disease

28. Coeliac disease
The classic ‘flat’ biopsy of coeliac disease is shown

29. If this is inflammatory bowel disease?
Examine bowel via endoscope
Small bowel biopsy
Image the bowel via X-ray with barium

30. Crohn’s - endoscopy Normal small bowel Crohn’s small bowel
with linear ulcers

31. Crohn’s histology
Classic granulomatous inflammation

32. Small bowel barium studies
Crohn’s disease -
stricture of terminal ileum
Coeliac disease
“coin stacking”

33. Inflammatory bowel disease
The Crohn’s picture is from resected tissue from a patient.
The ulcerative colitis image is the typical picture of widespread colitis as seen endoscopically
Ulcerative colitis
Crohn’s disease

34. Capsule endoscopy – Crohn’s
It is now possible to view the entire intestine by so-called “capsule endoscopy”. The patient swallows the capsule (right image) and it transmits images as it descends through the intestine. A disadvantage is that biopsies cannot be obtained.

35. Outcome in patient JG 1.
This patient was incorrectly diagnosed with coeliac disease, on the basis of raised gliadin antibodies, a non-specific test for coeliac disease
He failed to improve on a gluten free diet

36. Outcome in patient JG 2.
A barium follow through examination showed narrowing of the terminal ileum
This was resected and Crohn’s pathology confirmed
He has had several further resections and now has a short bowel syndrome

37. Crohn’s disease Immune mediated disease No female preponderance
No specific auto-antibodies
12 gene loci – GWAS*
No very strong MHC association
* Genome wide association study
Polymorphisms in gene coding for NOD2 protein shown to be associated with Crohn’s disease. Hypothesis that poor neutrophil response to intestinal bacteria might be intimately involved. (AW Segal).

38. Case 3 – 38 year old female Just delivered baby boy
Little weight gain during pregnancy
Told she had ‘anxiety’
Nervous tremor
Family history – sister with coeliac disease

39. Case 3 – 38 year old female
Baby healthy but very fast heart rate beats per min.
Mum also has fast heart rate – 100 beats per min. and irregular beats
Brisk reflexes
Staring eye appearance

40. Case 3 – 38 year old female

41. Prominent, bulging eyes

42. Case 3 – 38 year old female What diagnosis might you consider?
What tests would you do?

43. Case 3 – 38 year old female Patient has hyper-thyroidism
Caused by antibody vs. TSH receptor
Diagnosis
Measure TSH antibody
Measure thyroid hormone levels

44. Case 3 – 38 year old female Cause of rapid heart rate in baby?
Relevance of sister with coeliac disease?

45. Case 3 – 38 year old female Cause of rapid heart rate in baby? Answer
IgG antibody crosses placenta and reacts with baby’s TSH receptor
Neonatal hyperthyroidism - temporary

46. Case 3 – 38 year old female Relevance of sister with coeliac disease?
Co-association of autoimmune diseases
Note – many Graves’ disease patients develop hypothyroidism over time
Hypothyroid patients – develop antibodies to thyroid peroxidase – marker of thyroid inflam
TPO liberates iodine for binding to tyrosine residue on thyroglobulin and hence synthesis of T4 and T3.

47. Endocrine auto-immunity

48. Case 6 – 80 year old female Known hypothyroidism
Loss of energy, dysponea on exertion
GP – pale, yellowish pigment
Hg 4g/dl; MCV 115fl
B12 level – very reduced

49. Case 6 – 80 year old female Diagnosis – B12 deficiency
Pernicious anaemia
Auto-immune gastritis
Parietal cell auto-antibodies
Intrinsic factor antibodies**

50. Case 4 – 25 year old male Easy bruising on thighs
Bleeding following shaving
Attended GP – Hgb 10g/dl, iron deficient
Coagulation tests performed – normal
What other information would you request?

51. Case 4 – skin rash

52. Case 4 – 25 year old male Auto-antibody tests
Anti-nuclear antibody +, titre 1250
dsDNA antibodies negative
Is this information useful?
Other test results you should seek?

53. Case 4 – 25 year old male Platelet count – 25 x 109/l
Auto-immune thrombocytopaenia aka “ITP”
Auto-antibodies against platelets
Platelets removed from circulation by spleen
“Idiopathic” TP
Also found in CVID, HIGM, SLE

54. Case 4 – 25 year old male No good test for platelet antibodies!
Treatment – high dose steroids
High dose IgG infusions
These treatments “interfere” with platelet antibodies – mechanism uncertain

55. Case 4 – 25 year old male Treatment -
Spleen – antibody coated platelets are phagocytosed by splenic cells
Splenectomy
Risk of bacterial infection

56. Case 5 – 17 year old female Repeated ear, sinus inflammation
ENT operations with drainage “grommets”

57. Case 5 – 17 year old female Hearing loss in right ear
Acutely unwell in Sept 2008

58. Case 5 – 17 year old female Severe abdominal pain, vomiting
Inflamed joints in hands, wrists
Widespread painful skin rash – black, blistering areas

59. Vasculitic skin rash. Inflamed and thrombosed small arterial vessels resulting in inflammatory and infarcted skin lesions

60. Case 5 – 17 year old female Possible diagnosis
SLE – negative anti-nuclear antibodies
Vasculitis “blood vessel inflammation”
Wegener’s granulomatosis ?

61. Case 5 – 17 year old female Diagnosis - Wegener’s granulomatosis
Systemic vasculitis
Typically involves ears, sinuses, skin, joints and other tissues
Highly characteristic auto-antibody
Anti-neutrophil cytoplasmic antibody
Target is enzyme – proteinase 3

62. Case 5 – 17 year old female
Highly characteristic auto-antibody – “diagnostic”
Anti-neutrophil cytoplasmic antibody
Target is enzyme – proteinase 3
Unknown if antibody involved in disease mechanism

63. C-ANCA PR3+

64. Case 5 Treatment – immunosuppression Steroids Cyclophosphamide
Anti-B cell monoclonal antibody – anti-CD20