Connective Tissue Disease 1 Flashcards
What is Lupus (SLE)?
The archetypal connective tissue disease but there are others
What are connective tissue diseases?
Largely autoimmune, multi-system diseases that are often assoc. with specific auto-antibodies, which can help define the diagnosis
They are NOT diseases of connective tissue
Occurrence facts about SLE?
- Females affected more than males (9:1)
- Prevalence is lower in Caucasians and higher in those of ethnic minority, e.g: Asians, Afro-Americans, Afro-Caribbeans and Hispanic Americans
- Uncommon in African blacks
Aetiology of SLE?
Combination of factors: • Genetic • Hormonal • Environmental • Immunological
Describe genetic factors in SLE
High concordance in monozygotic twins and increased incidence amongst relatives
Identification of gene abnormalities predisposing to SLE may be useful
Describe hormonal factors in SLE
Increased incidence in those with higher oestrogen exposure, e.g: early menstruation, oestrogen-containing contraceptives and HRT
Describe environmental factors in SLE
- Viruses, e.g: Epstein-Barr
- UV light may stimulate skin cells to secrete cytokines, stimulating B-cells; a manner of presentation is after a holiday, with a persistent rash
- CIGARETTE SMOKE
Pathogenesis of SLE?
An antigen is presented to a CD4+ T cell by an APC gene
CD4+ T cell produces cytokines which:
• Stimulate antibody production by B cells
• Stimulate cytokine release by CD8+ T cells (destroy cells that have these antigens on their surfaces, i.e: loss of self-tolerance)
There is cell death; normally, clearance of cell contents occurs quickly
In SLE, CLEARANCE IS SLOWER and the nuclear and intracellular auto-antigens, which remain for a prolonged period, are attacked by antibodies
What is defective in SLE?
There is INCREASED and DEFECTIVE APOPTOSIS
Pathogenesis of renal disease in SLE?
Due to deposition of immune complexes (nuclear antigens : anti-nuclear antibodies) in the mesangium
These activate complement, which attract WBCs that release cytokines (perpetuate inflammation leading to necrosis and scarring)
Sign of ACTIVE lupus?
Decreased complement
5 factors that drive SLE?
- Immune complex formation DRIVES disease
- Defective apoptosis
- Delayed clearance of cell contents
- B cell function is abnormal (antibodies produced against internal antigens)
Classification criteria for SLE?
PICTURE 6
Patient must have 1 from each list but 4 in total for lupus
Systemic symptoms of SLE?
- Fever
- Malaise
- Fatigue (levels are CONSTANT and do not fluctuate with disease activity)
- Weight loss
- Poor appetite
Mucocutaneous features of lupus?
MALAR RASH that may/may not be assoc. with sun exposure (photosensitivity); it SPARES the NASO-LABIAL FOLDS
Discoid lupus erythematosus is confined to the skin but often SCARS
Subacute cutaneous lupus
Mouth ulcers (painless)
Alopecia (non-scarring); this may simply be thinning of hair or discrete patches
Compare the appearances of SLE and discoid lupus erythematous?
Discoid lupus has better demarcated lesions with a SCALY/crusted surface
MSK features of lupus?
- Non-deforming polyarthritis / polyarthralgia, i.e: may have a similar distribution and appearance as RA but there are no radiological changes (normal X-ray)
- Deforming arthropathy, e.g: Jaccoud’s arthritis has ulnar deviation of finger, at MCPs, but the X-ray is normal and the deformity is reversible (can make fists, etc)
- Erosive arthritis (rare)
- Myopathy causes weakness, myalgia and myositis
Which systems are affected by SLE?
- Mucocutaneous
- Musculoskeletal
- (Serositis) - inflammation of a lining of something
- Renal
- Neurological
- Haematological
Types of serositis in SLE?
Pericarditis and pericardial effusions
Pleurisy and pleural effusions
Testing for renal disease in SLE?
U&Es are not useful as they tend to be normal
The best test for early detection is URINALYSIS (look for protein and blood); suspicious if proteinuria is >500mg in 24 hrs
Then, RENAL BIOPSY
Neurological features of SLE?
- Depression/psychosis (not always related to disease activity)
- Migraines (very common)
- Seizures
- Cranial/peripheral neuropathy
- Mononeuritis complex (damage to 2 or more separate peripheral nerves in disparate areas of the body)
Haematological features of SLE?
Lymphadenopathy
Leucopenia and lymphopenia
Haemolytic anaemia
Thrombocytopenia
What is anti-phospholipid syndrome?
Autoimmune, hypercoagulable state with arterial and venous thrombosis
It can be a stand-alone disease or it may occur in assoc. with other autoimmune conditions, esp. SLE
Signs of anti-phospholipid syndrome?
Recurrent miscarriage
DVT/stroke at a young age
Livedo reticularis, which tends to affect thighs and abdomen; described as a recticular (lace-like) mottled discolouration of the skin; looks like marble
Prolonged APTT (clotting time) and thrombocytopaenia (low platelets)
In SLE, what intrinsic factors increase susceptibility to infection?
- Low complements
- Impaired cell mediated immunity
- Defective phagocytosis
- Poor antibody response to certain antigens
In SLE, what extrinsic factors increase susceptibility to infection?
- Steroids
- Extrinsic factors
- Other immunosuppressive drugs
- Nephrotic syndrome
Describe the spectrum of disease in SLE and the symptoms and signs at different parts
Mild disease may inv. joint pain, mouth ulcers, alopecia, etc
Moderate disease may inv. pericarditis, inflammatory arthritis, recurrent pleural effusions, etc
Severe disease inv. organ-threatening disease, e.g: renal and neurological disease, very low platelets, etc
What are ANA antibodies? Limitation?
Anti-nuclear antibodies; present in a +ve titre in most patients (95%) but can also be present in healthy patients (20%)
Also found in conditions such as RA, other autoimmune conditions, HIV and Hep C
When should a +ve ANA antibody be taken seriously?
If other anti-nuclear antibodies are +ve: • Anti-dsDNA • Anti-Sm • Anti-Ro • Anti-RNP
When the patient presents with CTD features
What are anti-dsDNA antibodies? Advantages?
Anti-double stranded DNA antibodies that occur in only 60% of SLE patients but are HIGHLY SPECIFIC to SLE
The ONLY antibody where the titre correlates overall disease activity
It may also be assoc. with lupus nephritis
What are the anti-ENAs?
Anti-Ro is present in 60% of SLE patients; it is usually assoc. with anti-La and cutaneous manifestations
There may be secondary Sjogren’s features
Importance of anti-ENA antibodies in neonates?
If a mother is anti-Ro +ve, the child has an increased risk of developing neonatal lupus and congenital heart block
What is anti-Sm?
Only present in 10-20% of patients but highly specific and may have an assoc. with neurological inv.
What is anti-RNP?
Present in 30% of patients; assoc. with overlap features, such as sclerodermatous skin lesions, Raynaud’s phenomenon and low grade myositis
Types of anti-phospholipid antibodies?
2 types:
Anti-cardiolipin antibody
Lupus anti-coagulant
Anti-β2 glycoprotein
How to use anti-phospholipid antibodies for diagnosis?
Must be +ve on 2 occasions 12 weeks apart
Ix for organ involvement?
CXR, pulmonary function tests, CT chest
Urine protein quantification, renal biopsy
ECG
Nerve conduction studies and MRI brain
Methods of monitoring SLE?
Clinical assessment, inc. BP
Anti-dsDNA level correlates with lupus activity
C3/C4 levels fall when there is a disease flare
URINALYSIS at every visit
FBC
Blood biochemistry
Relationship of disease activity with:
Symptoms
Anti-dsDNA antibodies
Complement (C3/C4) level
?
Symptoms of facial rash, pericarditis, seizures and nephritis, etc, are preceded by a rise in anti-dsDNA antibody and a fall in complement levels
General management of SLE?
Counselling
Regular monitoring
Avoiding excessive sun-exposure
Pregnancy issues
Drug treatment of SLE?
- NSAIDs and simple analgesia
- Anti-malarials (HYDROXYCHLOROQUINE) are useful for arthritis, cutaneous manifestations and may reduce systemic complications
- Steroids (short courses and infrequently)
- Immunosuppressives
- Biologics
How are steroids used in SLE?
Small doses (prednisolone <15 mg/d) for skin rashes, arthritis and serositis
Moderate doses (0.5 mg/kg/d) for resistant serositis, haematologic abnormalities and class V GN
High doses (1mg/kg/d or IV) for severe/resistant haematologic changes, diffuse GN and major organ inv.
Types of immunosuppressives used in SLE?
Azathioprine
Cyclophosphamide
Methotrexate
Mycophenolate motefil
Side effects of immunosuppressives?
Can cause bone marrow suppression
Can cause increased susceptibility to infection
Potentially teratogenic
Examples of biologics used in SLE?
Rituximab
Belimumab
Treatment of mild disease?
HCQ, topical steroids and NSAIDs
Treatment of moderate disease?
Oral steroids, azathioprine and methotrexate
Treatment of severe disease?
IV steroids, cyclophosphamide, rituximab
