CT disorder Flashcards
SLE epidermiology
F>M
SLE pathogenesis
Genetics contributes 30%
- Provides susceptibility
- E.g. C1q deficiency (high penetrance for SLE); MHC class (HLADR2, DR3, DRB1), IFN related pathway genes
Environmental
- UV light, DNA damage, skin damage
- Infection ?EBV via molecular mimicry
- Drugs e.g. TNFi, procainamide, hydralazine
- Heavy metals
- Smoking
B cell activation and autoantibody production + IFN production + effector T cells (TH17 cells) + problems with phagocytosis (increased apoptotic material serves as autoantigen)
ACR/EULAR classification criteria 2019
Does not equal diagnostic criteria. Used in research. But useful to look at it to help reach diagnosis.
Must have positive ANA
Different organs affected
If renal biopsy positive for lupus nephritis, and ANA positive, don’t need other organ manifestations.
Cutaneous manifestations for SLE
Butterfly/malor rash - acute cutaneous lupus Subacute cutaneous lupus Chronic discoid lupus (scarring) Photosensitive Bullous Urticaria Chill blains Panniculitis Alopecia (Rx JAKi) Painless nasal ulcers
Remember cutaneous lupus does not equal systemic lupus!
MSK manifestations for SLE
Arthralgia - symmetrical, migratory, polyarticular
Arthritis (like RA< usually non-erosive but can be deforming = Jaccoud’s arthritis)
Serositis in SLE
Pericarditis (big globular heart shadow on CXR)
Also pleuritis
High CRP
Do you get CRP rise in SLE flare?
Not usually - must exclude infection!
Unless there is serositis
Pulmonary manifestations in SLE
Pleurisy/pleural effusion
Acute pneumonitis
Pulmonary haemorrhage (rare)
ILD: NSIP most common
PE ?APLS
Pulmonary HTN
“Shrinking” lung syndrome
- Progressive SOB
- Raised hemidiaphragm, reduced lung volumes
- RFTs restrictive pattern
- Unsure mechanism but can respond to immunosuppression
Cardiovascular manifestations in SLE
Pericarditis (most common) Premature CAD (most common) Vasculitis Libman-sacks endocarditis (valvular lesions as a result of microthrombi on heart valves) Lupus myocarditis
Haematologic manifestations in SLE
Anaemia
- Multifactorial
- Chronic inflammation (most common), IDA, autoimmune haemolytic anaemia (DAT+), aplastic anaemia, anti-EPO ab
Leucopenia
- Low lymphocyte count is common but not severe
- Due to peripheral destruction but the cells are quite normal
Thrombocytopenia
- Overlap with ITP (10% SLE have ITP; 50% ITP meet SLE criteria)
- Mainly peripheral destruction
- Different ab to pure ITP
- MAHA (mainly TTP)
- Myelofibrosis
Lymphadenopathy
Splenomegaly
How to differentiate TTP vs DIC?
DIC - abnormal coags, abnormal fibrinogen
TTP - normal coags. Platelets and Hb abnormal.
Neurological manifestations in SLE
CNS: headache, mood disorder, seizure, cognitive dysfunction, CVA, myelitis etc
PNS: sensory-motor axonal polyneuropathy
Consider catastrophic APLS (seizure, encephalopathy)
Need urgent ICU and immunotherapy and anticoagulation
Ribosomal P abs =
Neuro lupus
Immunologic manifestations in SLE
Antibody findings
Less specific findings
- ANA positive >99% (homogenous pattern)
- Low C3, C4
- Raised ESR:CRP
- Positive RF 15-35%
More specific
- dsDNA 60% (disease activity, renal disease)
- Anti-smith (most-specific)
- SSA (Anti-Ro), SSB (anti-La)
- U1RNP (also in mixed CT disease)
- Ribosomal P (neuro lupus)
SLE and pregnancy
What are 2 important things to know?
Most have successful pregnancies
1) Anti Ro/La positive associated with
- Congenital heart block 1% (increases with subsequent pregnancies if previous babies with CHB)
- Weekly USS
- Consider fluorinated steroids (crosses placenta e.g. dex) +/- IVIG in 2nd degree HB to prevent progression
2) Antiphospholipid status. If positive:
- Asymptomatic: consider low dose aspirin
- Prior obstetric morbidity: low dose aspirin, prophylactic clexane
- Prior thrombosis: therapeutic clexane; continue 6/12 post partum
SLE treatment
Non-pharmacologic
- UV protection
- Smoking cessation
- Immunisation
- Avoid estrogen therapies, sulfonamides (A/W flares)
- Replete vitamin D
- CV risk management
Hydroxychloroquine
- Everyone should be on it
Others Corticosteroids - useful in controlling disease; some stay on small dose lifelong MTX - useful for polyarthritis, stay away in ILD, renal impairment Azathioprine Leflunomide - stay away in ILD Mycophenolate - esp renal/pulmonary Cyclosporin Cyclophosphamide
Rituximab in refractory disease
Risk of HCQ
Retinal toxicity
Accumulative toxicity, dose and duration related
Detected with retinal exam/OCT - “pre maculopathy” may be reversible. Later macular disease “bull’s eye”, visual field loss, often irreversible.
Baseline eye check before starting HCQ
After 5 years, need annual eye checks
Increased risk after 5 years, in older age, renal impairment
Keep dose <5mg/kg Ideal body weight
Biologics in SLE
1) Rituximab and veltuzumab (CD20 ab)
- Modest evidence in trials but does work well in the right patients
- Off label use
- Refractory disease, lupus nephritis
2) Belimumab
- Targets B cell activating factor (BAFF) - promotes B cell survival and differential
- FDA approved in lupus nephritis. SAS access only.
- Moderate SLE that has not responded to HCQ/MYC. Not in severe disease or lupus nephritis.
3) Tibulizumab
- Targets BAFF and IL17
- Ongoing trials
4) Anifrolumab
- Anti-IFN therapy
- Trials look promising
APLS presentation
Primary or secondary (SLE)
Thrombosis +/- obstetric complications
Also thrombocytopenia, cardiac valve abnormalities livedo reticularis, renal microangiopathy, chorea, myelitis
Associated conditions: HELLP, pre-eclampsia, MAHA
When you see livedo reticularis.. what should you check?
APLS ab
APLS ab
Anti-cardiolipin ab
Anti-Beta2-glycoprotein1
Lupus anticoagulant - highest risk for thrombosis
“Triple positive” at highest risk of thrombosis
Look out for the prolonged APTT!!
APLS treatment
Asymptomatic/primary prevention: no treatment
Secondary prevention:
- Lifelong anticoagulation with warfarin (INR2-3)
- DOACS not recommended
Management in pregnancy
Prior thrombosis: therapeutic clexane (continue at least 6/12 post partum) + aspirin
Prior pregnancy loss (meets criteria): low dose aspirin + prophylactic clexane
Asymptomatic: consider low dose aspirin
Pathophysiology Systemic sclerosis
Initially, have vascular damage
Autoimmunity - innate, cell mediated and humoral
Tissue fibrosis is the characteristic end result (by the time we see this its too late)
Systemic sclerosis specific ab
Anti-centromere = Limited SSc or CREST; PHTN
Anti-topoisomerase I = Anti-Scl-70 = ILD
Anti-RNA polymerase III = severe renal and skin disease
Disease subtypes of Systemic sclerosis
Limited cutaneous Systemic sclerosis (CREST)
- Long history of Raynaud’s
- Distal skin sclerosis, digital ulcers
- Major mortality from pulmonary arterial hypertension
- Anti-centromere ab
Diffuse cutaneous Systemic sclerosis
- Short history of Raynaud’s
- Proximal limb or trunk involvement, with skin sclerosis
- Extensive skin disease (contractures) + distal ulcers + more internal organ involvement (lung and kidney)
- Tendon friction rubs
- Awful morbidity and mortality
- Lack of therapy
- Anti-Scl-70 (ILD) and RNA polymerase III (scleroderma renal crisis)
Pulmonary involvement in Systemic sclerosis
1) Lung fibrosis
- Occurs in the first 5 years in dcSSc
- Most have lung involvement. Clinically significant in 30%.
- Now the major cause of mortality
- If >20% lung involvement, they will likely progress
- Most prevalent pattern is NSIP - subpleural sparing, ground glass. No honeycombing.
- May lead to PAH
2) Pulmonary arterial hypertension
- Mostly group 1
- Can occur anytime
- Need to keep screening - 1-2% develop per year
- Very serious
- Present in limited > diffuse
- TTE alone may miss up to 30%. BNP is useful.
Rx for pulmonary hypertension in systemic sclerosis
Endothelin receptor antagonist
- Bosentan, macicentan, ambrisentan
- AE: LFT abnormality, tetatrogenic, fluid retention, anaemia
NO stimulation
- Sildenafil (PDE5), tadalafil (PDE5), Riociguat (GC stimulator)
- AE: headache, bleeding, visual disturbance
Prostacyclin analogues
- IV Epoprostenol (severe SSc-PAH), iloprost, beraprost, trepostanol, selexipag
- AE: headache, muscle cramps, diarrhoea
Lung transplant
- CCBs monotherapy don’t work!
- Benefits of PAH specific therapies were not as good as for iPAH
Cardiac manifestation Systemic sclerosis
Arrhythmias/conduction defects e.g. VT
Myocarditis (often with skeletal muscle disease)
Cardiac fibrosis (80% in autopsy studies)
Valvular heart disease
MSK/skin involvement Systemic sclerosis
Puffy fingers
Proximal progression of skin thickening
Joint contractures +/- arthritis
Unable to open mouth due to skin tightening
Tendon friction rubs (associated with kidney involvement)
- Especially common in diffuse SSc with RNA polymerase III
Calcinosis
GI involvement Systemic sclerosis
Most frequent internal organ manifestation ~90%
Dental disease
Oesophageal dysmotility, strictures, candidiasis
Reflux
Watermelon stomach (GAVE) - poor motility, telangiectasia that bleed
Small bowel overgrowth (due to gut wall scarring and motility disturbance) - bloating, diarrhoea, weight loss, high folate
Large bowel, diverticular disease
Faecal incontinence due to reduced sensation, altered bowel habits, constipation overflow diarrhoea
What’s an important renal manifestation in Systemic sclerosis?
Scleroderma renal crisis!
- Occurs in the first 5 years in dcSSc
- Accelerated hypertension (retinal changes, hypertensive encephalopathy, PRES). Normally these people have low BP ~90, so when they raise 20mmHg this is significant. OR new onset BP >150/85.
- Renal impairment
- Associated with RNA polymerase III, tendon friction rubs
- Diffuse subtype
- Association with steroids (be careful in using steroids in diffuse subtype)
- 40% will need dialysis but recovery can happen up to 2 years after
Vasculopathy in Systemic sclerosis
Treatment
1) Raynaud’s (universal)
- Primary Raynaud occurs in those without CT disease. Negative ab. No pain. Short lasting ~15 min.
- Secondary (CT disease) - get tissue damage.
Rx: CCB, PDE5 inhibitor, IV prostacyclin (iloprost, epoprostenol) in severe disease after oral therapy
2) >50% have digital ulcers
- IV Prostacyclin (iloprost) or PDE5 inhibitor or endothelin receptor antagonist (Bosentan)
- IV prostacyclin can be protective for a few months after. Very effective
- May need surgical debridement in necrosis
Pregnancy in Systemic sclerosis
Limited: generally do well
Diffuse: high maternal mortality
Increased risk of hypertension, preeclampsia and CS, preterm birth, IUGR, organ complication
Dangerous in pulmonary HTN
Alot of the drugs can’t be used
Screening in systemic sclerosis
Screen for ILD and pulmonary HTN
Annual ECHO, PFTs
Baseline CT. If there are change in PFTs, then repeat CT.
Stem cell transplant in systemic sclerosis
Great treatment if patients survive (5-10% mortality)
Good for skin and lung involvement, if done early.
Therapy for systemic sclerosis-associated ILD?
Nintedanib + mycophenolate (combination therapy)
Less drop in FVC over time
Others O2 to maintain SpO2 88% and above GORD therapy Quit smoking Vaccinations
What is Mixed CT disease?
Clinical features
It is an overlap syndrome (doesn’t mean we don’t know what it is)
Features of SLE, scleroderma, rheumatoid, myositis
Raynaud's very common Hand oedema (puffy hands) Arthralgia/arthritis Myositis, trigeminal neuralgia ILD Pulmonary HTN (commonest cause of death)
Mixed CT disease labs
ANA + speckled
Characteristic ENA: U1RNP (high titre)
Leucopenia, thrombocytopenia
Raised ESR
70% RF (more likely to have arthritis). CCP negative.
Important negatives
- dsDNA, anti-SM
“Puffy hands”, RNP without dsDNA
Dx?
Mixed CT disease
Sjogren’s syndrome presentation
Gland involvement
- inflammation, fibrosis, lymphocyte infiltration
- Dry mouth (dental caries, oral candidiasis), dry eyes
- Glandular enlargement occurs in 30% (high rate of lymphoma)
Extraglandular
- Fatigue, arthralgia/arthritis (universal)
- Palpable purpura often on legs
- Cystic ILD
- Distal renal tubular acidosis/glomerulonephritis
- Cryoglobinaemia (renal involvement, rash, mononeuritis multiplex)
- Dorsal root ganglionopathy
- Peripheral neuropathy
- NHL
Sjogren’s syndrome can be primary or secondary. Which conditions can it be secondary to?
RA >SLE > SSc
HIV
Sjogren’s syndrome management
Symptomatic
Dry mouth Citrus fruit or gum to stimulate saliva Saliva replacement/lubricants Secretagogues (pilocarpine) for both dry mouth and eyes. But side effects. Avoid meds that cause dryness
Dry eyes Lubricating eye drops (preservative free) Topical cyclosporin Punctal plugs Secretagogues
Extraglandular
Exercise
NSAIDs
HCQ for systemic manifestations
Life-threatening: pulsed methylpred +/- plasma X +/- RTX if cryoglobulinaemia
DDx of parotid mass
Infections - viral (mumps, EBV, HCV, HIV); bacterial (acute parotitis, TB), fungal
Autoimmune - Sjogren’s, GPA
Inflammatory - IgG4 disease, allergic parotitis, kilmura disease
Metabolic - diabetes, bulimia, alcholism, hyperlipoproteinaemia
Neoplastic - lymphoma, leukaemia, Warthin tumour
Granulomatous - sarcoidosis
What’s Schirmer’s test?
Leave blotting paper under lower lid
Then measure distance of moisture
Correlate with tear production
Useful in Sjogren’s
Investigations in Sjogren’s
Anti-SSA (Anti-Ro60) and/or Anti-SSB - diagnostic
Positive RF & ANA titre >1:320 - diagnostic
Schirmer’s test (tear production)
Salivary gland biopsy
dsDNA absent Elevated ESR Polyclonal hypergammaglobulinaemia 30% Anaemia, leucopenia (usually neuts) and thromboctopenia Cryoglobulinaemia in 15%
What are the subtypes of idiopathic inflammatory myopathies?
1) Dermatomyositis
2) Anti-synthetase syndrome
3) Immune-mediated necrotising myopathy (IMNM or NAM)
4) Inclusion body myositis
5) Polymyositis ?does this exist as a distinct entity
Presentation idiopathic inflammatory myopathies
3 “Ps”
Progressive, painless, proximal weakness
BUT all will have extra-muscular manifestations - cutaneous, diaphragmatic and intercostal muscle weakness = T2RF, oesophageal muscle weakness = aspiration, dysphagia, ILD, myocarditis, MI
Classic dermatomyositis cutaneous manifestations
Gottren’s sign/papules (over extensors of large joints)
Shawl sign
V sign
Heliotrope rash (peri-orbital)
Holster sign (lateral thigh where your gun holster would be )
Periungual (around finger nail) erythema
Skin findings may precede muscle weakness
Myositis specific ab
Antisynthetase syndrome
Skin disease (dermatomyositis)
INMN
IBM
Antisynthetase syndrome
- 9 ab involved - Jo-1 (most common), PL7, PL12; all 3 are associated with lung disease
Skin disease (dermatomyositis) - SAE, Mi-2, MDA5 (ILD), NXP2, TIF1
INMN
- SRP, Anti-HMGCR (very specific to stain associated IMNM)
IBM
- Anti-CN1A
Anti-synthetase syndrome
Clinical Presentation
Myositis Jo1, PL7, PL12; total 9 ab ( all 3 are associated with lung disease) ILD - most important cause of mortality Mechanic's hands Raynaud phenomenon Inflammatory polyarthritis Oesophageal dysmotility (distal) Fever
Inclusion body myositis
Clinical presentation
Treatment
M>F, older demographic 50-60yo
Muscle pattern is different to the other myositis
***Asymmetric
Distal upper limb (finger flexors, wasting of forearm muscles, watch falling off)
Proximal leg weakness (quadricep weakness, frequent falls going downstairs)
Mildly elevated CK (but not >10x ULN)
Anti-CN1A
Less responsive to IS unlike other inflammatory myopathies. Can have limited trial of glucocorticoids.
Statin-associated IMNM
Clinical Presentation
Treatment
1:100,000 statin users
Associated with HLADRB1*11:01
Usually after months on treatment, persist after cessation (ongoing immune reaction), CK usually >10x normal
Anti-HMGCR ab very specific
Treatment
Statin cessation won’t work
Often will need steroids +/- IVIG
MDA5+ dermatomyositis
Clinical presentation
Treatment
May not have muscle disease, or if they have, its subtle
Associated with rapidly progressive ILD
Very high mortality 50-60% in 6 months
Some distinctive features from other DM - ulcerating lesions, inverse gottren’s or palm papules (instead of MCP, PIP distribution, gottren’s papules are located on the palm), pneumomediastinum
Rx: EARLY AGGRESSIVE IMMUNOSUPPRESSION (may survive 2 years if done early)
Do we need to avoid statins in idiopathic inflammatory myopathy?
NO
Unless they’re anti-HMGCR positive (statin-associated IMNM)
Behcet disease
Clinical features
Cardinal features
- Relapsing oral and genital ulcers with bilateral posterior or panuveitis
Other features
- Recurrent papulopustular lesions, erythema nodosa like lesions, non-erosive mono/oligo arthritis
- Pathergy (exaggerated skin lesion after minimal trauma)
- Vasculitis involving all vessels (thrombotic, pseudoaneurysms)
Which genetic factor is associated with Behcet disease?
HLA-B*151
What is sarcoidosis characterised by?
Systemic inflammatory disorder characterised by non-caseating granulomas
Sarcoidosis presentation
Acute and chronic arthritis (knees and ankles)
Muscle involvement common although often asymptomatic
Bilateral hilar lymphadenopathy
Pulmonary infiltrates
Uveitis
Also cardiac, neurologic, cutaneous
What’s Lofgren syndrome?
Acute sarcoidosis
Erythema nodosa
Acute polyarthritis (typically ankles)
Hilar lymphadenopathy
Fever
What’s CREST syndrome?
Type of limited cutaneous sclerosis
C - calcinosis R - Raymaud's (years) E - esophageal dysmotility S - skin changes limited to UL, face; gradual onset T - telangectasia
Does pulmonary hypertension occur in limited or systemic sclerosis?
Both
~10% in both subtypes (maybe slightly more in limited)
ANA with centromere pattern is associated with which disease?
Limited sclerosis
ANA with homogenous pattern is associated with which disease?
Lupus (dsDNA, histone +)
Main causes of mortality in scleroderma
ILD and pulmonary HTN
Previously was scleroderma renal crisis but ever since the introduction of ACEI, mortality has fallen
Who with systemic sclerosis-ILD is likely to progress in their ILD?
Early dcSSc with anti-Scl70
Early dcSSc with high CRP
= High risk phenotypes = need treatment
ANA with nucleolar pattern is associated with which disease?
Progressive overt systemic sclerosis
How do we monitor patients with systemic sclerosis-ILD?
Rapidly progression is likely to occur in the first 5 years
Monitor with spirometry and DLCO every 3-4 months for 5 years after disease onset then yearly
No advantage in serial HRCTs if PFTs stable
Who with systemic sclerosis-ILD should receive immunosuppressive treatment?
Clinical ILD
- FVC% predicted or DLCO% predicted
What investigations to do in someone with SSc-ILD and worsening respiratory symptoms?
Repeat
- PFTs + DLCO
- HRCT ?progressive ILD
- ECHO
- NT-proBNP
- DETECT algorithm (online calc for pHTN)
Things to suggest pHTN
- FVC/DLCO ratio >0.6
- TR velocity >3.2msec (should = systemic pulmonary pressures)
- NT-proBNP >2 fold ULN
How to screen for pulmonary HTN in systemic sclerosis?
METHOD ONE
Screen every 12 months
PFTs - DLCO ≤50%
ECHO - sPAP ≥40mmHg
= If positive, do RHC
= ECHO uses TR jet which is absent in up to 39% of patients
= $$$, expertise required, poor image quality
= Sensitivity 88%, specificity 83%
METHOD TWO
Screen every 12 months
PFTs - DLCO pred <70% with FVC/DLCO ≥1.8
NT-proBNP ≥210
= If either positive, do RHC
= 98% NPV
= Cheaper than annual ECHOs
*If recent decline in ET, syncope, RHF or ECHO features of Rt heart strain, should do RHC regardless of ECHO/DLCO findings
How is iron related to systemic sclerosis?
Iron deficiency in SSc-PAH is associated with worse survival
Replace iron!
Signs of severe scleroderma renal crisis
Microangiopathic haemolytic anaemia and thrombocytopenia HF and flash APO Blurred vision due to retinopathy Headache, fever, malaise Encephalopathy, generalised seizures Pericardial effusion
Treatment of scleroderma renal crisis
Control BP with ACEI within 72h
- Captopril preferred due to short t1/2
- Avoid beta-blockers
- Aim 10% reduction in SBP/DBP per day
- Can stabilise or improve renal function and survival
If CNS involvement: captopril + IV nitroprusside
MAHA: consider PLEX
When might you consider haematopoietic stem cell transplant in systemic sclerosis?
In those with early progressive SSc at risk of organ failure
Idea is to wipe out the existing immune system and replace with non-autoreactive immune system with stem cells
High early treatment-related mortality!! Also 1/3 get disease relapse
How does drug induced lupus present?
Usually mild
Common to get skin and joint manifestations
ANA +, dsDNA +, histone ab +
Generally resolves with stopping the drug
GI manifestations of SLE
Abnormal LFTs (significant liver disease rare)
Lupus hepatitis (ribosomal P ab)
Ileal/colonic perforation (associated with vasculitis)
Acute pancreatitis
Renal manifestations of SLE
Glomerulonephritis
6 classes (based on histology) Class 3-4 +/- 5 reflect activate inflammation and warrants prompt immunosuppression
When does someone with SLE need a renal biopsy?
1) Increased serum Cr without alternate cause
2) Proteinuria ≥1g/24h
3) Proteinuria ≥0.5g/24h AND haematuria
4) Proteinuria ≥0.5g/24hr AND cellular casts
Treatment of lupus nephritis
Treat class 3, 4, +/- 5
INDUCTION PHASE
IV pulse steroids AND
MMF or CYC
Refractory disease: rituximab or calcineurin inhibitor (cyclosporin)
MAINTENANCE PHASE
MMF or AZA
Should you continue hydroxychloroquine in lupus during pregnancy?
YES
Reduce risk of cardiac neonatal lupus (CHB)
What’s overlap myositis?
Combination of myositis and another CT disorder e.g. SLE, scleroderma, Sjogren
OR
Myositis with overlap features without fulfilling criteria for another CT disorder (clinical feature or antibody)
Which subtypes of idiopathic inflammatory myopathy do you get increased risk of malignancy?
Dermatomyositis (x5-7 times)
- Colon, lung, breast, ovarian
IMNM
Empirical therapy for DM, PM, IMNM (idiopathic inflammatory myopathy)
1) high dose glucocorticoids tapering over 1 year
2) steroid sparing agents - AZA, MTX, IVIG, rituximab, PLEX
3) monitor CK, muscle power, PFTs
