lupus and related autoimmune connective tissue diseases Flashcards
What are the 3 types of autoimmune arthritis?
- Rheumatoid arthritis
- Seronegative arthritis (psoriatic arthritis, reactive arthritis, ankylosing spondylitis)
- Lupus and related disorders (autoimmune tissue disease)
What is systemic lupus erythematosus? (SLE)
- Chronic tissue inflammation in the presence of antibodies directed against self antigens.
- Multi-site inflammation but particularly the joints, skin and kidney
Associated with autoantibodies: - Antinuclear antibodies
- Anti-double stranded DNA antibodies
- Anti-phospholipid antibodies
- Prototypic autoimmune disease typically diagnosed in female aged between 15 – 45 years
What are the key characteristics of connective tissue disorders?
- Arthralgia (pain in joints but no obvious swelling) and arthritis (pain + swelling) is typically non-erosive
- Serum autoantibodies
- Raynaud’s phenomenon is common in these conditions (vasospasm of digits on exposure to cold, colour changes white to blue to red)
What can the serum auto-antibodies associated with connective tissue disorders tell you?
May aid diagnosis
Correlate with disease activity
May be directly pathogenic
What are the wide-ranging clinical manifestations of SLE?
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’) [immune complexes deposit in glomerulus]
Cerebral disease – ‘cerebral lupus’ e.g. psychosis
Why are there such wide-ranging clinical manifestations of SLE?
Many circulating immune complexes
Describe the pathogenesis behind SLE?
- 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
What are the main autoantibodies of SLE?
Antinuclear antibodies (ANA):
- Seen in all SLE cases
- Not specific for SLE
Anti-double stranded DNA antibodies (anti-dsDNA):
- Specific for SLE
- Serum level of antibody correlates with disease activity
Anti-phospholipid antibodies:
- 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’
What investigations are used to monitor SLE?
- Inflammation:
- high ESR but C-reactive protein is typically normal unless infection or serositis/arthritis - Haematology: low platelet count
- Haemolytic anaemia, Lymphopenia, Thrombocytopenia - Renal:
- very important to measure urine protein (most commonly urine protein:creatinine ratio [uPCR])- urine protein creatinine ratio= v. early sign of glomerulus lupus
- 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)
Describe the disease activity, in terms of the complement pathway, in SLE
Unwell lupus patient has LOW complement C3 and C4 levels and HIGH levels of anti-ds-DNA antibodies
(as the dsDNA increases, complement dips down)
What are the aims of SLE treatment?
Treatment in SLE aims at remission or low disease activity and prevention of flares
What are the management options/ paths for SLE?
- 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
What is SJÖGREN’S syndrome?
- Autoimmune exocrinopathy (tear/ salivary glands)
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) decreased hygiene
- 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
What investigations are used to monitor SJÖGREN’S syndrome?
- Salivary gland biopsy will show lymphocytic infiltration predominantly CD4 helper T cells and to lesser extent B lymphocytes
- 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
What is inflammatory muscle disease?
- Proximal muscle weakness due to autoimmune-mediated inflammation either with (dermatomyositis) or without (polymyositis) a rash
- Skin changes in dermatomyositis:
- 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)
- Associated with malignancy (10-15%) and pulmonary fibrosis
What investigations are used to monitor inflammatory muscle disease?
Elevated CPK, abnormal electromyography, abnormal muscle biopsy (polymyositis = CD8 T cells; dermatomyositis = CD4 T cells in addition to B cells)
What is systemic sclerosis?
- Thickened skin with Raynaud’s phenomenon
- Dermal fibrosis, cutaneous calcinosis and telangiectasia
- Skin changes may be limited or diffuse
- CREST describes a sub-type of limited systemic sclerosis. It stands for Calcinosis, Raynaud’s phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasia
Describe “diffuse” systemic sclerosis
a) Diffuse systemic sclerosis
* 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
Describe “limited” systemic sclerosis
b) Limited systemic sclerosis
* Fibrotic skin hands, forearms, feet, neck and face
* Anti-centromere antibodies
* Pulmonary hypertension
* Long history of Raynaud’s phenomenon
What is overlap syndrome?
- 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
- When incomplete features of a connective tissue disease are present we can use the term undifferentiated connective tissue disease
- 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’)
What auto antibodies are associated with diffuse systemic sclerosis?
Anti-Scl-70 antibody
also termed antibodies to topoisomerase-1
What auto antibodies are associated with limited systemic sclerosis?
Anti-centromere antibodies
What auto antibodies are associated with dermato/ Polymyositis
Anti-tRNA transferase antibodies
E.g. histidyl transferase (also termed anti-Jo-1 antibodies)
What auto antibodies are associated with Sjögren’s syndrome?
No unique antibodies but typically see
- Antinuclear antibodies - Anti-Ro and anti-La antibodies
- Rheumatoid factor
What auto antibodies are associated with mixed connective tissue disease?
Anti-U1-RNP antibodies
