Connective tissue disorders

Question 1

What is the use of serum antibodies?

Answer 1

May aid diagnosis
Correlate with disease activity
May be directly pathogenic

Question 2

What is typical of Arthralgia & arthritis in connective tissue disorders?

Answer 2

non-erosive

Question 3

What is a common sign in Connective tissue disorders?

Answer 3

Intermittent vasospasm of digits on exposure to cold
Typical colour changes – white to blue to red
Vasospasm leads to blanching of digit
Cyanosis as static venous blood deoxygenates
Reactive hyperaemia
Raynaud’s phenomenon is most commonly isolated and benign condition (‘Primary Raynaud’s phenomenon’)

Question 4

What happens in SLE?

Answer 4

Chronic tissue inflammation in the presence of antibodies directed against self antigens
Multi-site inflammation but particularly the joints, skin and kidney

Question 5

Which antibodies are involved in SLE?

Answer 5

Antinuclear antibodies
Anti-double stranded DNA
Anti-phospholipid antibodies

Question 6

What are the clinical manifestations of SLE?

Answer 6

Malar rash – erythema that spares the nasolabial fold
Photosensitive rash
Mouth ulcers
Hair loss
Raynaud’s phenomenon
Arthralgia and sometimes arthritis
Serositis (pericarditis, pleuritis, less commonly peritonitis)
Renal disease – glomerulonephritis (‘lupus nephritis’)
Cerebral disease – ‘cerebral lupus’ e.g. psychosis

Question 7

What is the current pathogenesis of SLE?

Answer 7

Apoptosis leads to translocation of nuclear antigens to membrane surface

Impaired clearance of apoptotic cells results in enhanced presentation of nuclear antigens to immune cells

B cell autoimmunity

Tissue damage by antibody effector mechanisms e.g. complement activation and Fc receptor engagement

Question 8

What antibodies are present in systemic vasculitis?

Answer 8

Antinuclear cytoplasmic antibodies (ANCA)

Question 9

what is the significance of the ant-dsDNA antibody in SLE?

Answer 9

Specific for SLE

Serum level of antibody correlates with disease activity

Question 10

What is the significance of ANA in SLE?

Answer 10

Seen in all SLE cases

Not specific for SLE

Question 11

What is the significance of Anti-phospholipid antibodies in SLE?

Answer 11

associated with risk of arterial and venous thrombosis in SLE

may also occur in absence of SLE in what is termed the ‘primary anti-phospholipid antibody syndrome

Question 12

What is the significance of Anti-Sm antibodies in SLE?

Answer 12

Specific for SLE

Serum level of antibody does NOT correlates with disease activity

Question 13

What is the significance of Anti-Ro and Anti-La antibodies?

Answer 13

Secondary Sjögren’s syndrome

Neonatal lupus syndrome (transient rash in neonate, permanent heart block)

Question 14

Which antibodies signify Cerebral lupus?

Answer 14

Anti-ribosomal Antibodies

Question 15

What are the investigations important in SLE?

Answer 15

Inflammation:
high ESR but C-reactive protein is typically normal unless infection or serositis/arthritis

Haematology:
Haemolytic anaemia, Lymphopenia, Thrombocytopenia

Renal:
very important to measure urine protein (most commonly urine protein:creatinine ratio [uPCR])
look at albumin

Immunological
Antinuclear antibodies
Anti-double-stranded DNA antibodies - highly specific, correlate with disease activity
Complement consumption – e.g. low C4 and C3

Clotting – antiphospholipid antibodies
Lupus anticoagulant and anti-cardiolipin antibodies

In treated patients SOME changes may reflect ADVERSE REACTIONS TO MEDICATION
e.g. abnormal liver function (‘transaminitis’) or fall in neutrophil count (neutropenia)

Question 16

What does an unwell SLE patient have?

Answer 16

Unwell lupus patient has LOW complement C3 and C4 levels and HIGH levels of anti-ds-DNA antibodies

Question 17

What is the management for SLE?

Answer 17

Treatment in SLE aims at remission or low disease activity and prevention of flares
Hydroxychloroquine is recommended in all patients with lupus
Maintenance treatment glucocorticoids should be minimised and, when possible, withdrawn.
Appropriate initiation of immunomodulatory agents (methotrexate, azathioprine, mycophenolate) can expedite the tapering/discontinuation of glucocorticoids
In persistently active or severe disease we use cyclophosphamide and B cell targeted therapies (rituximab and belimumab)

Patients with SLE should be assessed for their antiphospholipid antibody status

Patients with SLE should be assessed for their infectious and cardiovascular diseases risk profile

Pregnancy planning

Question 18

What happens in Sjogrens syndrome?

Answer 18

Autoimmune exocrinopathy
lymphocytic infiltration of especially exocrine glands and sometimes of other organs (extra-glandular involvement)

Exocrine gland pathology results in;
Dry eyes (xerophthalmia)
Dry mouth (xerostomia)
Parotid gland enlargement

Commonest extra-glandular manifestations are non-erosive arthritis and Raynaud’s phenomenon

Termed ‘secondary’ Sjögren’s syndrome if occurs in context of another connective tissue disorder e.g. SLE

Question 19

What will a salivary gland biopsy show in sjogrens syndrome?

Answer 19

Salivary gland biopsy will show lymphocytic infiltration predominantly CD4 helper T cells and to lesser extent B lymphocytes

Question 20

What is Schemer’s test?

Answer 20

Schirmer’s test – a test to assess tear production. Filter paper is placed under lower eyelid and extent of wetness measured after 5 minutes. Abnormal is <5mm after 5 minutes

Question 21

What is inflammatory muscle disease?

Answer 21

Proximal muscle weakness due to autoimmune-mediated inflammation either with (dermatomyositis) or without (polymyositis) a rash

Question 22

What are the skin changes in dermatomyositis?

Answer 22

Lilac-coloured (heliotrope) rash on eyelids, malar region and naso-labial folds
Red or purple flat or raised lesions on knuckles (Gottron’s papules)
Subcutaneous calcinosis
Mechanic’s hands (fissuring and cracking of skin over finger pads)

Question 23

What are the blood tests for inflammatory muscle disease?

Answer 23

Elevated CPK, abnormal electromyography, abnormal muscle biopsy (polymyositis = CD8 T cells; dermatomyositis = CD4 T cells in addition to B cells)
Associated with malignancy (10-15%) and pulmonary fibrosis

Question 24

What happens in Systemic sclerosis?

Answer 24

Thickened skin with Raynaud’s phenomenon
Dermal fibrosis, cutaneous calcinosis and telangiectasia
Skin changes may be limited or diffuse

Question 25

What happens in diffuse systemic sclerosis?

Answer 25

Fibrotic skin proximal to elbows or knees (excluding face and neck)
Anti-topoisomerase-1 (anti-Scl-70) antibodies
Pulmonary fibrosis, renal (thrombotic microangiopathy) involvement
Short history of Raynaud’s phenomenon

Question 26

What happens in limited systemic sclerosis?

Answer 26

Fibrotic skin hands, forearms, feet, neck and face
Anti-centromere antibodies
Pulmonary hypertension
Long history of Raynaud’s phenomenon

Question 27

What is CREST?

Answer 27

CREST describes a sub-type of limited systemic sclerosis.

It stands for Calcinosis, Raynaud’s phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasia

Question 28

What is overlap syndrome?

Answer 28

When features of more than 1 connective tissue disorder are present e.g. SLE and inflammatory muscle disease we can use the term overlap syndrome

Question 29

What is undifferentiated connective tissue disease?

Answer 29

When incomplete features of a connective tissue disease are present we can use the term undifferentiated connective tissue disease

Question 30

What is MCTD?

Answer 30

In one instance a group of patients with features of seen in SLE, scleroderma, rheumatoid arthritis, and polymyositis were identified by the presence of an autoantibody:
Anti-U1-RNP antibody*
….this condition was termed Mixed Connective Tissue Disease (‘MCTD’)

Question 31

What are the antibodies involved in Diffuse systemic sclerosis?

Answer 31

Anti-Scl-70 antibody

also termed antibodies to topoisomerase-1

Question 32

What are the antibodies involved in Limited systemic sclerosis?

Answer 32

Anti-centromere antibodies

Question 33

What are the antibodies involved in Dermatology/Polymyositis?

Answer 33

Anti-tRNA transferase antibodies

E.g. histidyl transferase (also termed anti-Jo-1 antibodies)

Question 34

What are the antibodies involved in Sjogrens syndrome?

Answer 34

No unique antibodies but typically see
Antinuclear antibodies - Anti-Ro and anti-La antibodies
Rheumatoid factor

Question 35

What are the antibodies involved in Mixed connective tissue disease?

Answer 35

Anti-U1-RNP antibodies