Auto-immunity cases Con Feighery. Auto-immunity Immune mediated damage Absence of infection or other...

Auto-immunity cases

Con Feighery

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

Auto-immunity

Characteristic features -• Female preponderance• Auto-antibodies – some are pathogenic• Genetic association – often strongly

associated with MHC class II genes

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

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

Case 1 – 35 year old female

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

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?

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?

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

Antinuclear antibody test

Antibody to double stranded DNA

Crithidia luciliae – kinetoblast contains dsDNA

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?

Multiple ‘systems’ affected by lupus

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%

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

Clinical history (continued)

• Past history – well until 11 years old • Family history – mother has rheumatoid

arthritis; aunt is hypothyroid

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

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

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)

Discussion issues

• What additional information would you like to have about the patient’s history?

Discussion issues

• What further physical findings would you look for?

Discussion issues

• What further diagnostic tests should be considered?

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?

Case 2 – further tests

• If this is coeliac disease, test for endomysial antibodies – c. 100% specificity

• Or perform biopsy of small intestine

Endomysial antibody test

> 99% specific for coeliac disease

Coeliac disease

If this is inflammatory bowel disease?

• Examine bowel via endoscope• Small bowel biopsy• Image the bowel via X-ray with barium

Crohn’s - endoscopy

Normal small bowel Crohn’s small bowel with linear ulcers

Crohn’s histology

Classic granulomatous inflammation

Small bowel barium studies

Crohn’s disease -stricture of terminal ileum

Coeliac disease“coin stacking”

Inflammatory bowel disease

Crohn’s disease Ulcerative colitis

Capsule endoscopy – Crohn’s

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

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

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

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

Case 3 – 38 year old female

• Baby healthy but very fast heart rate - 160 beats per min.

• Mum also has fast heart rate – 100 beats per min. and irregular beats

• Brisk reflexes• Staring eye appearance

Case 3 – 38 year old female

Prominent, bulging eyes

Case 3 – 38 year old female

• What diagnosis might you consider?• What tests would you do?

Case 3 – 38 year old female

• Patient has hyper-thyroidism• Caused by antibody vs. TSH receptorDiagnosis• Measure TSH antibody• Measure thyroid hormone levels

Case 3 – 38 year old female

• Cause of rapid heart rate in baby?• Relevance of sister with coeliac disease?

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

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

Endocrine auto-immunity

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

Case 6 – 80 year old female

• Diagnosis – B12 deficiency• Pernicious anaemia• Auto-immune gastritis• Parietal cell auto-antibodies• Intrinsic factor antibodies**

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?

Case 4 – skin rash

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?

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

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

Case 4 – 25 year old male

• Treatment - • Spleen – antibody coated platelets are

phagocytosed by splenic cells• Splenectomy• Risk of bacterial infection

Case 5 – 17 year old female

• Repeated ear, sinus inflammation• ENT operations with drainage “grommets”

Case 5 – 17 year old female

• Hearing loss in right ear• Acutely unwell in Sept 2008

Case 5 – 17 year old female

• Severe abdominal pain, vomiting• Inflamed joints in hands, wrists• Widespread painful skin rash – black,

blistering areas

Case 5 – 17 year old female

• Possible diagnosis• SLE – negative anti-nuclear antibodies• Vasculitis “blood vessel inflammation”• Wegener’s granulomatosis ?

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

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

C-ANCA PR3+

Case 5

• Treatment – immunosuppression• Steroids• Cyclophosphamide• Anti-B cell monoclonal antibody – anti-CD20