Rheumatoid Arthritis and SLE Tutorial Flashcards
Connective Tissue Disorders
What are the key connective tissue disorders?
Systemic Lupus Erythematosus (SLE)
Sjorgen’s syndrome
Autoimmune inflammatory muscle disease
- Polymyositis
- Dermatomyositis
Systemic sclerosis (scleroderma)
- Diffuse cutaneous
- Limited cutaneous
Overlap syndromes
What is RA?
Chronic joint inflammation that can result in joint damage
Primarily = synovitis = inflammation in the synovium
Associated with autoantibodies =
- Rheumatoid factor (RF)
- Anti-cyclic citrullinated peptide (CCP) antibodies
What is the main disease in seronegative inflammatory arthritis? How is it characterised?
Ankylosing spondylitis
Chronic spinal inflammation that can result in spinal fusion and deformity
Site of inflammation includes the enthesis (connective tissue between tendon or ligament and bone) = enthesitis
No autoantibodies (‘seronegative’)
What are some other seronegative spondyloarthropathies?
Ankylosing spondylitis
Reactive Arthritis (Reiters syndrome)
Arthritis associated with psoriasis (psoriatic arthritis)
Arthritis associated with gastrointestinal inflammation (enteropathic synovitis)
What is SLE?
Systemic lupus erythematosus
Autoimmune disease = chronic tissue inflammation in the presence of antibodies directed against self antigens
These form antigen-antibody complexes AKA immune complexes that are responsible for glomerulonephritis, vasculitis, and a variety of other SLE manifestations
Multisystem disorder = can affect everywhere but particularly joints, skin and kidneys
Associated with autoantibodies =
- Antinuclear antibodies (ANA)
- Anti-double stranded DNA antibodies (anti-dsDNA)
- Anti-phospholipid antibodies
What are the broad similarities in connective tissue disorders?
More often arthralgia rather than an arthritis
i.e. pain in joints and tenderness, but no redness, swelling, heat
If there is arthritis, this is typically non-erosive
Serum antibodies are characteristic for different connective tissue disorders
Raynaud’s phenomenon is common in these conditions
What is the purpose of serum autoantibodies?
Aids diagnosis
Correlated with disease activity
May be directly pathogenic
What is Raynaud’s phenomenon?
Ischaemic changes affecting the fingers =
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 an isolated and benign condition (‘Primary Raynaud’s phenomenon’)
What demographic is SLE diagnosed in?
Females aged between 15 – 45 years
What are the 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’)
Cerebral disease – ‘cerebral lupus’ e.g. psychosis
What is the pathogensis of SLE?
Currently incompletely understood
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 key autoantibodies in rheumatology and which rhumatological disease are they most relevant in?
RA = rheumatoid factor (RF) and anti cyclic citrullinated peptide(CCP) antibody
SLE = antinuclear antibodies (ANA), anti-double stranded DNA antibodies (anti-dsDNA), anti-phospholipid antibodies
OA = none
Reactive arthritis = none
Gout = none
Ankylosing Spondylitis = none
Systemic vasculitis = antinuclear cytoplasmic antibodies (ANCA)
What investigations are conducted in SLE?
Screen for organ system involvement by investigating:
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
Why might all the investigation results from SLE not be caused by SLE?
If the patient is currently being / has been treated
Some changes in investigations may reflect adverse reactions to medications e.g. abnormal liver function (‘transaminitis’) or fall in neutrophil count (neutropenia)
Why does C3 and C4 decrease as SLE progresses?
Due to activation of the classical pathway leading to inflammation
Immune complexes found in SLE activate the complement pathway - this is part of our innate immunity and causes inflammation
So the immune complexes activate the complement system via the classical pathway, which includes C4 and C3
So the more immune complexes produced in SLE, the more activation of the classical complement pathway = C3 and C4 are used up
Therefore, C3 and C4 being to fall as SLE progresses
So in an SLE (lupus) patient, what will their levels of immune complexes and C3/C4 be?
High levels of immune complexes
Low levels of C3 and C4
Case 1 - 22F Increasing lethargy Arthralgia Shortness of breath Chest pain on inspiration Skin photosensitivity Ankle swelling
HPC = fingers changing colour over the last 3 years
Examination = dull lung bases, quiet heart sounds, peripheral oedema
Bloods = high ESR, normal / low CRP, low lymphocytes, high albumin
What other questions would you ask?
Any mouth ulcers?
Any hair loss?
Any rashes?
Any fevers?
Does your skin photosensitive rash spare your nasolabial folds?
Have you noticed any muscle weakness?
Any PMH of DVT? / Any PMH of miscarriages?
Any FH of autoimmune disorders?
What clinical signs would you look for on examination?
Signs of mouth ulcers?
Pleural rub - pain on inspiration = pleuritis
Dull lung sounds = fluid, so maybe pleural effusion
Quiet heart sounds = pericardial effusion?
Peripheral oedema = nephrotic syndrome / kidney involvement
What tests would you do?
Urine dipstick test - proteinuria
Look for positive ANA and anti-dsDNA
High ESR and normal / low CRP
Kidney biopsy if there is kidney involvement - as management is dependent on biopsy findings
Increased complement deposition in the nephrons = low C3 and C4
What are the differential diagnoses?
SLE = most likely - photosensitive rash, high ESR low CRP, lymphopenia, involvement of lungs
Scleroderma = possible but less likely due to lung involvement
What is the management plan for the most likely diagnosis?
Hydroxychloroquine
Maintenance steroids should be withdrawn
Immunomodulatory agents: methotrexate, azathioprine, mycophenolate- can speed up tapering of of glucocorticoids
In persistently active or severe disease: cyclophosphamide and B cell depletion (rituximab, belimumab)
Asses for antiphospholipid antibody
Assess for infection and CVD risk
Pregnancy planning- some treatments (e.g. cyclophosphamide) need to be stopped
What are anticardiolipin antibodies associated with?Where else might anticardiolipin antibodies be present?
Associated with risk of venous and arterial thrombosis
May be present without SLE in primary antiphospholipid antibody syndrome
What are types of anti-nuclear antibodies?
If ANA is positive we screen for what type. These include: Anti-Ro Anti-La Anti-centromere Anti-sm Anti dsDNA Anti-SCl 70
Cytoplasmic antibodies:
Anti-tRNA antibodies
Anti-ribosomal P antibodies
What are different patterns of ANAs that we see in SLE?
Homogenous
Speckled
Nucleolar
Fine speckled
What is the significance of the different antibodies we see in SLE?
ANA: seen in all SLE cases, not specific for SLE
Anti- dsDNA: Specific for SLE. Serum conc. correlated with disease activity
Anti-phospholipid antibody: associated with venous and arterial thrombosis
Anti-SM antibody: Specific for SLE. Serum level does NOT correlate with disease activity
Anti-Ro and Anti-La antibody: antigen is ribonucleoprotein. Secondary Sjogren’s syndrome. Neonatal lupus syndrome
Anti-ribosomal P antibody: Cerebral lupus
What would be indicative of active glomerulonephritis in SLE?
Large rise in Protein:creatinine ratio
What is Sjogren’s syndrome?
Autoimmune exocrinopathy: lymphocytic infiltration, esp. of exocrine glands and sometimes other organs
Symptoms:
Dry eyes (xerophthalmia
Dry mouth (xerostomia) - can lead to problems in dental hygiene
Parotid gland enlargement
Extraglandular manifestations:
Non-erosive arthritis, raynaud’s phenomenon
Secondary sjogren’s syndrome: occurs in context if another connective tissue disorder e.g. SLE
What test can we do for Sjogren’s syndrome?
Salivary gland biopsy- will should lymphocytic infiltration, mainy helper T cells and some B cells
Schirmer’s test: asses tear production. Filter paper placed under lower eyelid and wetness measured after 5 mins. Abnormal is <5mm
What is inflammatory muscle disease?
Proximal muscle weakness due to autoimmune-mediated inflammation either with (dermatomyositis) or without (polymyositis) a rash
Associated with malignancy (10-15%) and pulmonary fibrosis
What are symptoms of inflammatory muscle disease?
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)
Elevated CPK, abnormal electromyography, abnormal muscle biopsy (polymyositis = CD8 T cells; dermatomyositis = CD4 T cells in addition to B cells)
What are symptoms of systemic sclerosis?
Thickened skin with Raynaud’s phenomenon
• Dermal fibrosis, cutaneous calcinosis and telangiectasia
Skin changes may be limited or diffuse:
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
Limited systemic sclerosis* • Fibrotic skin hands, forearms, feet, neck and face • Anti-centromere antibodies • Pulmonary hypertension • Long history of Raynaud’s phenomenon
*CREST: Calcinosis, Raynaud’s phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasia (spider veins)
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 are key autoantibodies for different connective tissue disorders?
Diffuse systemic sclerosis
• Anti-Scl-70 antibody
• also termed antibodies to topoisomerase-1
Limited systemic sclerosis
• Anti-centromere antibodies
Dermato-/Polymyositis
• Anti-tRNA transferase antibodies
• E.g. histidyl transferase (also termed anti-Jo-1 antibodies)
Sjögren’s syndrome
No unique antibodies but typically see
• Antinuclear antibodies - Anti-Ro and anti-La antibodies
• Rheumatoid factor
Mixed connective tissue disease
• Anti-U1-RNP antibodies
