SLE Flashcards

Question

is NETosis the only source of oxidised mitochondrial DNA (ox mtDNA)?

Answer 1

NETs aren’t the only way that ox mtDNA is present in SLE sera - In cells other than neutrophils, oxidised and damaged mito DNA is removed by mitophagy - In neutrophils, ox mtDNA is dephosphorylated and TFAM protein is removed by cAMP-dependent process. This allows ox mtDNA to be degraded in lysosomes

Answer 2

In SLE, due to TLR7 stimulation by autoantibodies or free nucleic acids, ox mtDNA degradation in neutrophils is inhibited - Ox mtDNA isn’t removed via lysosome, and leaks out from neutrophil into serum - Mito DNA can then activate pDCs to produce type 1 IFNs

Answer 3

In clinic, serum levels of complement are measured for SLE - Low C3 and C4 levels (often) associated with active SLE disease - Some patients have genetic deficiency of C1q (rare) and C4 (more common) which predispose to development of SLE C1q: important for clearance of apoptotic blebs on cells containing potential autoantigens – genetic deficiency leads to autoantigen exposure C4 (C4a): reacts with immune complexes → in absence of C4a, there is increased immune complex precipitation In SLE autoantibodies against C1q, C3, C4 (activating) have been identified

Answer 4

Polymorphisms associated with SLE development, classified by cell type or pathway that is affected - Each confers only modest risk of developing lupus - SLE is likely polygenic, where a number of polymorphisms may contribute to disease - Genetic load: no. of polymorphisms within genes are calculated to produce a risk score

Answer 5

aicardi-goutieres syndrome (AGS) - type 1 interferon-opathy - Severe chilblains with swelling of fingers/toes, arthritis, Oral ulcers, Low lymphocytes/platelets, Rashes, CNS inflammation, ANA positive, Occurs in childhood Overlap of clinical features with sporadic SLE

Answer 6

Number of genes implicated in AGS - Trex1 – cytosolic enzyme involved in destruction of damaged DNA in cytoplasm - In children with LOF mutation in Trex1, there is overactivation of DNA sensor cGAS, which with its adaptor STING, leads to signal cascade resulting in increased type 1 IFN levels which drive clinical disease Shows importance of IFN1 in SLE pathogenesis

Answer 7

pDCs are the professional IFN1 producing cells - Responsible for majority of type 1 IFN production

Answer 8

In SLE, reduced no. of pDCs present in circulation, but increased numbers in tissues, particularly skin and kidney - This suggests that pDCs are activated and migrate into tissues and drive inflammation - produce IFN1s - pDCs also have role in T cell proliferation, inducing Th1 proliferation but not Tregs

Answer 9

In SLE population, IFN1 levels has bimodal distritubtion - Some patients have low levels of IFN1, others have high - interferon-stimulated gene score = surrogate measure for IFN - Association between amount of IFN in blood and autoantibodies: as patients have higher levels of autoantibodies, there is strong association with levels of IFN1

Answer 10

Levels of IFN1 production is linked to nucleic acid sensors - no. of sensors in endosomes e.g. TLRs and within cytosol - In SLE, TLR7,8,9 are implicated as they measure ssRNA and short strands of DNA – directly lead to IFN1 production - Within cytoplasm, RIG1 and MDA5 detect RNA. C-gas and STING recognise DNA

Answer 11

In SLE patients, apoptotic debris can be endocytosed into cells via FcRs, along with immune complexes bound to nucleic acid antigens e.g. anti-dsDNA, and can activate both TLRs and CLRs to drive IFN1 synthesis and release This process is active in pDCs and in B cells and neutrophils

Answer 12

Number of pathways by which type 1 interferon is produced, either due to activation of TLRs via immune complexes or free nucleic acids due to netosis or ox mtDNA, or due to T cells, B cells, myeloid cells - End product is production of IFNa

Answer 13

due to a failure of tolerance

Answer 14

B cells in SLE are more active: - Particularly including HLA-DRhigh/CD27++/CD20-/CD19+ plasmablasts - These are associated with active disease and with presence anti-dsDNA - Plasmablasts have clinical correlation – in patients treated with rituximab, no. of plasmablasts 6 months after treatment predicts which patients are likely to relapse - Plasmablasts can lead to autoimmune state

Answer 15

Principle: - In SLE, there are high levels of IFN1 and development of autoantibodies which cause organ damage and loss of tolerance to activate T cells - Early stages in the pathway include exposure of autoantigens due to failure of apoptosis and NET formation, leading to activation of nucleic acid sensors to drive IFN1 production

Answer 16

Heterogenous disease - Affects patients differently - Features can be common to other conditions – hard to distinguish from other diseases and diagnose - Symptom onset to formal diagnosis is around 5 years - SLE mimics many diseases

Answer 17

Fatigue Muscle pains Joint pain mouth ulcers, many at once (normal population has 1 at a time), unusual locations, uncomfortable Lymphadenopathy – swollen lymph nodes Fever These symptoms can be manifestation of other conditions e.g. infection or lymphoma Loss of appetite Weight loss

Answer 18

Butterfly rash is a hallmark of SLE - Photosensitive disease – on face and chest - Some patients have more profound skin involvement e.g. discoid rashes in deeper layers of skin – can resemble other conditions like psoriasis

Answer 19

yes: One of the reasons why SLE is managed by rheumatologists - Some patients have pain in joints (arthralgia) without clear inflammation - Others develop inflammatory arthritis – symmetrical but without erosive synovitis - Destruction in tendons and ligament of hands – leads to abnormal shape - X-ray shows that joints themselves are preserved This is called Jaccoud’s arthropathy – these deformities are reducible, which contrasts with RA where joints are fixed - Deformities can be pushed back into position

Answer 20

- Raynauds – common in young women, so alone doesn’t represent SLE - livedo reticularis – lace-like purple discoloration to skin. This is linked to anti-phospholipid syndrome - Alopecia – hair loss – distressing can be diffuse with widespread hair loss and normal looking scalp or severe inflammation with scarring of hair follicles causing permanent hair loss and pigmental changes - This is a problem for those with discoid lupus in scalp

Answer 21

Serositis = hallmark of SLE - Doesn’t occur commonly in other systemic autoimmune diseases - Inflammation of serosal surfaces – lining of lung, heart and abdominal cavity - Causes pericarditis, pleurisy and abdominal pain - Inflammation can be sufficient to cause accumulation of fluid around lung (pleural effusion), heart (pericardial effusion) - Often associated with changed on ECG and X-ray

Answer 22

Can affect central and peripheral nervous system - Usually related to either inflammation or vascular phenomenon - Inflammation: Epilepsy spinal cord inflammation (transverse myelitis) - Vascular: stroke, aseptic meningitisneuropathy, “Brain fog” = difficulties in memory retention and cognitive function Lupus headache = severe unremitting headache which doesn’t respond to opioid analgesia – this is very rare and often requires immunosuppression to treat May be more common in patients with anti-ribosomal P antibodies which is rare in SLE patients

Answer 23

Can cause permanent kidney damage - Glomerulonephritis due to lupus can occur as part of systemic disease, but lupus nephritis can occur in isolation - Important that urine is examined at every visit to check for both protein and blood - Both protein and blood can be due to other problems e.g. due to infection, frequent use of NSAIDs – important to identify whether changes in urine are due to active lupus, so renal biopsy may be needed

Answer 24

Renal biopsy either at diagnosis or late in disease are helpful - Histological classification of glomerulonephritis (between class 1 and 5) may relate to SLE prognosis - Immunohistologists describe an activity index and chronicity index – Kaplan meier curve: more severe renal histology end up with worse renal function over time - If inadequately treated end-stage renal failure can develop – requires dialysis or renal transplant

Answer 25

Leukopenia: White cell count – more common to cause reduction in lymphocytes than neutrophils Neutropenia causes concern more so than lymphopenia; Low neutrophils = increased risk of bacterial infection This doesn’t occur in every patient - Can also cause low platelets – thrombocytopenia – tends to be modest, but can be severe and requires high dose steroid treatment - Anaemia is common – anaemia of chronic disease due to ongoing inflammation, or due to development of autoimmune haemolytic anaemia

Answer 26

Low platelet count, white cell count, and haemoglobin changes can be due to - Reduced production in bone marrow - Increased destruction by antibodies in periphery White cell counts may not be related specificity to active SLE, but may be due to immunosuppressive drugs to manage condition or infection

Answer 27

APS associated with SLE in 30% cases - Recurrent thrombosis in venous system (presents as DVT or PE) or in arterial system (presents as heart attack, stroke, infarction of limbs) - APS is referred to by patients as having sticky blood - Also associated with natal problems – miscarriages early or late stages of pregnancy - Increased thrombosis is more problematic in SLE patients positive for APS, and in patients who are IgG positive rather than IgM

Answer 28

Anti-cardiolipin antibodies (IgG and IgM), anti-B2GP1 antibodies, lupus anticoagulant - history of recurrent miscarriages, a thrombosis any of these antibodies

Answer 29

In healthy population, over 30% have positive ANA at low titer e.g. 1:40 - Once above 1:160, this is only present in 5% of general population - ANA positivity increases in general population with age - anti-dsDNA is most prevalent in SLE

Answer 30

SLE is a clinical diagnosis: Combination of features and antibodies is used for clinical diagnosis - NO diagnostic test (positive ANA is not a diagnostic test) - Classification criteria for research – can be helpful as an aide memoir, but not used for diagnosis looks at skin involvement, ulcers, arthritis, renal disorder, neurological disorder, haematological disorder and ANA positivity

Answer 31

Many rheumatological and non-rheumatological that mimic lupus - e.g. RA, infection, malignancy, drug-induced conditions - This is important for patients with low ANA levels or atypical autoantibodies – may be due to infection or malignancy This explains the long time to diagnosis

Answer 32

Are symptoms due to active lupus or other problems? - Need to differentiate between active lupus and lupus-related damage e.g. complications with treatment - example: blood and protein in urine could be due to active lupus nephritis or infection or NSAID use

Answer 33

Irreversible changes to organs due to either - Previous active SLE - Complications of treatment e.g. long-term GCCs examples of damage due to lupus activity: - Pulmonary fibrosis - End-stage renal disease Or due to lupus and/or complications due to GCC treatment - Osteoporosis (with vertebral collapse) - Diabetes mellitus For damage to be scored in the ACR damage index (DI), it needs to be present for at least 6 months

Answer 34

- Because accrual of damage is associated with mortality - If patient has symptoms due to damage, then they wont respond to immunosuppression so treatment change wont work

Answer 35

No. factors associated with damage - African/Caribbean background – increased SLE severity - Types of lupus activity e.g. renal and neurological disease can drive damage - High dose steroids - Immunosuppressants – reverse causation – those with more severe disease are more likely to have severe damage and more likely to need immunosuppressants - Anti-ribonucleoproteins, anti-phospholipids, but there are no other serological predictors of damage accrual in lupus

Answer 36

topical steroids for mild rash, use of analgesics for pain - low dose steroids - anti-malarials - mainstay - Immunosuppressants: azathioprine and methotrexate - Even low-dose steroids have complications, so ideally patients are on antimalarials with/without immunosuppressants whilst being steroid-free, but in many cases this isn’t possible

Answer 37

Basic Advice for all: - Sunblock (SPF50) and sun avoidance – vitamin D supplements - Contraception and pregnancy planning - Cardiovascular risk: diet, exercise, smoking – address modifiable factors if have infection, pause immunosuppressants Hydroxychloroquine and high factor SPF and sun avoidance are mainstay treatments for all patients

Answer 38

stronger agents needed: Pulses of IV steroid IV cyclophosphamide Biologics Immunosuppressants from renal transplant field - calcineurin inhibitors, MMF More severe disease – enter clinical trial for new treatments

Answer 39

Look at haemotological abnormalities and renal function to identify active disease - look at leukopenia - autoantibody profile at diagnosis as it can be associated with certain disease features - in long term, only anti-dsDNA are measured to track disease - Measure of C3 and C4 is useful – in active disease, as anti-dsDNA go up, complement consumption increases, so levels of C3 and C4 go down - check secondary APS

Answer 40

Principle of managing severe SLE - start with induction phase to control disease, then move onto maintenance phase For lupus nephritis: - induction IV cyclophosphamide, rituximab, mycophenolate - Maintenance, taper dose of oral steroids and mycophenolate

Answer 41

most patients have hydroxychloroquine and systemic steroids - 70-90% have received these use of immunosuppressant depends on type of disease features e.g. methotrexate is useful for arthritis management biologic use is low

Answer 42

- Increased risk of recurrent miscarriages in those with secondary ASP - Increased risk of fetal growth restriction and preaclampsia - Increased risk of lupus flare in pregnancy and post-partum In those with anti-Ro and anti-La – associated with 5% increased risk of neonatal lupus syndrome due to passage of antibodies across placenta, and risk of heart block in baby (small risk, only 1%, but in mothers who already had a child with heart block the risk is increased to 10-15%) Premature menopause (<40 years) – related to lupus itself but also treatments like IV cyclophosphamide – monitor bone health and osteoporosis

Answer 43

HRT not advised in patients with SLE, especially those with APS - Risk of flare with combined oral contraceptive pill is less clear – contraindicated in SLE patients with APS - Suggest that progesterone-only pills or local contraception like the coil are preferable - Contraception is crucial as many immunosuppressants are incompatible with pregnancy, resulting in birth defects

Answer 44

Identify, treat and prevent active disease - inflammatory and/or thrombotic Prevent organ damage Prevent infection Prevent death Prevent pregnancy loss Maintain function Improve quality of life, reduce fatigue Improve adherence to therapy

Answer 45

Many drugs licensed for RA - Only a few for lupus – absence in new licensing for SLE, only prednisolone, antimalarials and belimumab - May be due to clinical trial design and the outcomes that are assessed in trials

Answer 46

Endpoints are crucial! - Determines success of trial - How do you assess disease activity?: Complex disease – multiple organ systems affected differently in patients; Relapsing-remitting nature – active disease/flare vs remission - Other medications allowed? – SLE patients on antimalarials, corticosteroids, immunosuppressants – can they have these or have changed dose? - Placebo as control? - difficult due to background medication - Most trials compare active drug to standard of care - Leaving patients with no treatment and just placebo would be too challenging

Answer 47

Activity = outcome most commonly used - lupus-specific disease activity indices Damage (ACR) = slow process, occurs within year-long trial Adverse events = infection risk, hospitalisation, death Quality of life = important measure for patients - Tends to be secondary outcome for trials - Generic measure e.g. SF-36 - Lupus-specific measure e.g. LupusQol

Answer 48

In RA, disease activity score (DAS28): tender, swollen joints, global score and inflammatory marker e.g. CRP In RA trials: use composite endpoint ACR50 - 50% improvement in tender and swollen joints Can this approach be used in multi-organ disease? Can we compare skin disease improvement in one patient to kidney disease improvement in another?

Answer 49

SLEDAI - simpler, numerical scale - added to give score - many versions BILAG - DAS measured in terms of 8 or 9 organ systems - captures data to see if one organ is improving whilst another worsens - more detail - 9 domain score can be converted to global BILAG score - This loses ability to compare between different organ systems Both are weighted indices to allow for some organs to be more “important” than others

Answer 50

Brain involvement = 8 points arhritis, kidney disease = 4 points each rash = 2 points (rash is not specific enough as it doesn't specify total body coverage) fever, leukopenia = 1 point each

Answer 51

Physician's intention to treat: Things should only be scored in BILAG if in normal circumstances the physician would change treatment on the basis of these manifestation - Things that are scored also must be due to active lupus – exclude other things like infection or damage classic BILAG = 8 systems BILAG 2004 = 9 systems

Answer 52

Scored on scale from 1-4 - New manifestation = 4, - Improving = 1 - 3 = worse - 2 = same Number of BILAG components score yes/no e.g. Renal biopsy showing lupus nephritis within last 3 months All of these, via a glossaries, are converted into score from A to E A = severe disease, requires major immunosuppression D = organ disease has resolved (similar to E except E suggests there was no disease there ever) E = inactive disease, no evidence of disease in this system

Answer 53

BILAG score is better than SLEDAI and is sensitive to change - BILAG is comprehensive, reliable and sensitive to change, and can study each organ system individually

Answer 54

Severe disease activity - Neurological inflammation - Severe inflammatory arthritis with disability - Haematological abnormalities

Answer 55

10cm visual analogue scale 0-3 - Number 3 refers to the most severe possible disease in all SLE patients - Significant deterioration is >0.3 (>10%) point worsening in PGA vs. baseline - Change in over 10% is clinically significant

Answer 56

SRI-4 for SLEDAI - ≥ 4 point reduction in SLEDAI, No worsening of BILAG score, No worsening in PGA (0.3 points), No treatment failure BICLA for BILAG Improvement in BILAG score (A → B or better) (B → C or better), No new BILAG A scores (1 new B allowed), No worsening in SLEDAI, No worsening in PGA (>10%), No treatment failure

Answer 57

Time-to-flare Serological markers Steroid use

SLE Flashcards

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