Rheumatology Flashcards
RA autoantibodies
- RF (anti IgG) - high titre has high specificity, low titre is moderate;
also seen in Sjorgen (75-95%), cryoglobulinemia (40-100%), SLE (15-35%), Hep B/C, cancer - Citrullinated peptide (ACPA) - high specificity (95%);
precede onset of disease, associated with more severe disease as well as lung and CVD disease - Peptidyl arginine deaminase 4 (anti-PAD4) - moderate
- Carbamylated proteins (Anti-CarP) - moderate
RA environmental interactions
environmental factors carry 40% attributable risk
Lungs - smoking increases risk (synergistic in the presence of shared epitope alleles), other exposures also carry risk (silica, woodwork etc)
Oral mucosa - periodontal disease by porphyromonas gingivalis»_space; converts arginine to citrulline thus providing antigens
GI - suspected link to microbiome but unproven clinically
Key cytokines (2) and mediators (3) in RA
Cytokines: TNF-a and IL-6
(also involved: IL-1a, 1B, 17A, 17F)
Growth and differentiations factors:
BLyS & APRIL activate B cells leading to ab
GM-CSF & M-CSF enhance granulocyte differentiation in synovium and BM
RANKL matures and activates osteoclasts
Patterns of RA (timing + 2 specific subtypes)
Insidious (55-65%) - can start with systemic or articular with small joints first or morning stiffness
Acute (8-15%), Intermediate (15-20%)
Palindromic
- Pain then swelling and erythema
- Worsen over hours to days then resolve with no residual disease
- 50% go on to develop RA
Remitting, seronegative, symmetric synovitis with pitting oedema (RS3PE) syndrome
- deem of dorm of hand or foot + tenosynovitis
- negative RF and ACPA
- excellent response to steroids
- can be paraneoplastic
Hands and wrists in RA (7)
Wrist synovitis
Radial deviation of wrist
Ulnar deviation of fingers (MCPs)
Rupture of ulnar collateral ligament
Median nerve compression
Swan neck (lateral bands of extensor tendons subluxate)
Boutonniere (rupture of PIP through tendon)
Ankles and feet in RA (6)
36% feet prior to hands
Hindfoot synovitis
Pain with eversion
Lateral subluxation of mid foot
Forefoot synovitis
Subluxation of MT heads (in MTP)
5th MTP - 1st site to develop erosions
Extra-articular manifestations of RA (8)
Dermatologic: rheumatoid nodules, vasculitis, ulcers, treatment related rash
Pulmonary: pleural effusion, nodules, ILD, bronchiectasis, cryptogenic organising pneumonia
Cardiovascular: premature atherosclerosis, pericarditis, arrhythmias, myocarditis, HFpEF
GI: gastritis/PUD from treatment, mucositis from methotrexate
Renal: GN, proteinuria
Hepatic: nodular regenerative hyperplasia, portal fibrosis
Haematologic: 3x risk of lymphoma, Felty syndrome, lymphadenopathy, cryoglobulinemia, amyloidosis
Opthalmologic (<1%): episcleritis, scleritis, sjorgen’s
X-ray findings in RA (5)
- Periarticular soft tissue swelling
- Juxta-articular osteoporosis
- Marginal erosions
- Joint space narrowing
- Symmetric involvement
RA DMARDs (4)
Methotrexate
- 25mg optimal dose, 20-40% response rate (50% in combo with steroid)
- nausea, hair loss, stomatitis, hepatotoxicity, pneumonitis, cytopenias
Sulfasalazine - 8% response rate, cutaneous hypersensitivity, nausea, agranulocytosis
Hydrixychloroquine - use for low disease activity, hyperpigmentation, retinopathy
Leflunomide - 10% response rate, diarrhoea, hypertension, hypersensitivity, hepatitis, pneumonitis, leukcytopenia, teratogenic, peripheral neuropathy
RA biologics and targeted synthetics (5) - how is therapy structured
TNFi
- Infliximab, Etanercept, Adalimumab, Golimumab, Certolizumab
- contraindications: SLE, demylenating disorder, infection (mycobacterial, hep B), CCF, pregnancy
- SE: infections, malignancies, demyelination, autoantibodies, hepatotoxicity, lupus
T-cell costimulation inhibitor (works like CTLA4 on CD80/86): Abatacept
- slightly more effective in seropositive than TNFi
- SE: lower risk of infection, leukcytopenia, injection site
Anti-CD20 (B cells): Rituximab
- long half life with enduring response
- SE: infections, low IgG, infusion reactions (pre treat with hydrocortisone, paracetamol, cetirizine), progressive multifocal leukoencephalopathy, reactivation of hep B, diminished vaccine response
IL-6R inhibitor: Tocilizumab
- comparable as monotherapy
- SE: no CRP response, infections, increased LFTs, hyperlipidemia, thrombocytopenia, neutropenia, GI perforation, hypersensitivity
JAK inhibitors: Tofacitinib Baricitinib Upadacitinib
- SE: cardiac events, cancer, infection (tb, zoster), cytopenia, hyperlipidemia
Monotherapy with Tocilizumab > TNFi
Monotherapy with JAKi > methotrexate
But gold standard is combo with methotrexate, and no specific agent has been shown to be superior over others
Tapering/ceasing therapy in RA
- Maintain therapeutic dose of at least 1 DMARD - - Consider only when LDA/ remission ≥ 6 months: dose reduction > abrupt ceasing
- For those on triple therapy: ceasing SSz > HCQ For those on Mtx + b/ts DMARD: ceasing Mtx > b/ts DMARD
GCA - epi, presentation, and treatment
Female, Scandinavian, >50yo
Systemic inflammation: constitutional symptoms, PMR, arthralgia, myalgia, muscle weakness
Ischaemic complications: headache, abnormal temporal artery on exam, jaw claudication, visual defects
Treatment
- If visual symptoms then IV methyl red 1g daily for 3 days
- 40-60mg daily otherwise
- second line is Tocilizumab (56% vs 18% for placebo; less steroid; risk of relapse)
- (high initial dose leads to less overall steroid)
Cause of vision loss in GCA
anterior ischaemic optic neuropathy due to occlusion of posterior ciliary arteries = 80% of visual impairment in GCA
Others: branch retinal artery occlusion, posterior ischaemic optic neuropathy, central retinal artery occlusion, choroidal ischaemia
1% 5yr risk of vision loss after starting PO steroids (13% if pre-existing visual loss)
4 clinical patterns of GCA
- Isolated cranial GCA (headache, jaw claudication, scalp tenderness) - 80%
- Symptomatic large vessel vasculitis (claudication, pulseless limb) with or without associated cranial signs - 9%
- Isolated fever or inflammatory response - 9%
- Isolated PMR with vasculitis on imaging - 2%
Large vessel GCA (4)
- Younger
- Higher steroids
- Higher risk of relapse
- Less headache, visual loss, positive biopsy
Bloods in GCA (3)
ESR > 50 mm/hour
CRP > 20 mg/L
Plt > 300
specificity 57% for ESR and 68% for CRP
combination of CRP and platelet tests may provide the best diagnostic utility for GCA
Biopsy and imaging in GCA
Cranial GCA - 70-90% sensitive, only 52% in large vessel variant
Causes for negativity
- skip lesions
- specimen <1.5cm
- extra cranial-large vessel GCA
MRI > FDG-PET > US > biopsy in terms of sensitivity
Adjunct treatments in GCA
Methotrexate - reduces risk of first relapse 35% second 51% + reduction of prednisolone dose
small case series for leflunamide
Aspirin reduces risk of stroke in observational studies but not recommended routinely
Complications of GCA + treatment (5)
- Infections (highest in first year)
- Osteoporosis
- Cataracts
- Poor Diabetes control
- 2x Aortic aneurysm
PMR - epi, presentation, bloods, and treatment
> 50yo
2% lifetime risk, women>men
50% of GCA patients (10% of PMR get GCA)
Ache + morning stiffness (>45min) @ neck, shoulders, hips
other systemic: depression, fatigue, weight loss
Elevated ESR or CRP
exclude differentials with RF/CCP, protein electrophoresis, CK
Treatment
- prednisolone 15-25mg/ day (should respond in 48-72hrs) for 4 weeks then taper ~ mean 20 months
- Tocilizumab 63.2 vs 11.8% steroid free remission
- methotrexate
50% relapse
Synovitis is NON erosive
SLE - epidemiology and survival
Female > male (9:1), 16-65yo
22.7% have family history of autoimmune disease
80-90% 10 year survival (early infection, late atherosclerosis)
SLE genetics, environmental, hormonal factors
Risk due to common variations in multiple genes
single gene defects = greatest risk
- Complement deficiencies: C1q, C4A and B, C2
- TREX1 (endonuclease 1)
MHC class - HLA-DR2, DR3, DRB10301/1501
IFN related - IRF5, IRAK1, TLR7, STAT4
T/B cell signalling - PTPN22, OX40L, PD-1, BANK01, LYN, and BLK
Environmental
1. UV
2. Infection
3. Smoking
4. Environmental pollutants
5. Drugs: procainamide, hydralazine, minocycline, diltiazem, penicillamine, isoniazid, IFN-a, methyldopa, chlorpromazine
(TNFi induce auto ab 80% but clinical SLE is rare <1%)
Hormonal
1. Increased oestrogen has inflammatory effect
2. Susceptibility genes on X chromosome
3. Less DHEA and androgen in SLE patients
SLE renal disease classes
Class I Minimal mesangial (IF change only)
Class II Mesangial proliferative
Class III Focal (< 50% of glomeruli)
A: active, A/C: active + chronic, C: chronic lesions
Class IV Diffuse (> 50% of glomeruli) A, A/C, C Class V Membranous
Class VI Advanced sclerosing
SLE diagnosis (8)
Entry criterion = ANA titter of >1:80
Then >10 points from a variety of features
- fever
- Neuropsych: delirium, psychosis, seizure
- Mucocutaneous: alopecia, oral ulcer, discoid lupus, cutaneous lupus
-pleural or pericardial effusion, pericarditis
- joint involvement
- renal: proteinuria, II or V, III or IV
- Hematologic: leukopenia, thrombocytopenia, autoimmune hemolysis
Labs:
- antiphospholipid abs
- low C3 and/ or C4
- anti-dsDNA or anti-smith
SLE disease activity (4)
ESR > CRP (unless concurrent infection/arthritis)
Increased anti-dsDNA
Low C3/C4
Questionares
General measures in SLE (9)
Stress
UV light
Estrogen
Sulfonamides
Vitamin D repletion
Smoking cessation
Diet and exercise
Immunisations
Minimise glucocorticoids and manage side effects
Management in SLE
- Hydroxychloroquine - background therapy for all, remember retinal toxicity
- Steroids - if cannot taper then add in sparing agents: methotrexate, azathioprine belimumab, anifrolumab
Organ or life-threatening - IV cyclophosphamide - if refractory then rituximab
Skin disease - topical first, then as above
Consider antithrombotic
Autoimmune thrombocytopenia - high dose steroids +/- IVIg followed by rituximab
Nephritis
- IV cyclophosphamide or mycophenolate and steroids, consider CNI + belimumab
- continuation for 3 years mycophenolate or CNI + belimumab
A 25yo women with SLE and Class IV nephritis, previously managed with mycophenolate induction and now on maintenance for the past 18 months, presents with new HT and an increase in her urine protein:creatinine. A 24hr urine protein was 970mg/24hr with cellular casts. Which of the following is the most appropriate management:
a. Arrange renal biopsy
b. Commence glucocorticoids and increased/different immunosuppression
c. Consider egg collection or therapy with goserelin
d. All of the above
d. All of the above
First renal biopsy should be considered in all with possible lupus nephritis in order to allow histologic classification
Indications for biopsy in SLE
1. Increased Se Cr without compelling alternate cause
2. Confirmed proteinuria of ≥ 1.0g/24hour
3. Combinations of (confirmed on at least 2 tests)
* Proteinuria ≥ 0.5g/24h and haematuria, defined as ≥ 5 RBC per hpf
* Proteinuria ≥ 0.5g/24h plus cellular casts
Poor prognostic indicators in SLE renal disease
Best single predictor: Improvement in proteinuria to <0.7-0.8g/day at 12 months predicts better long term outcome (aim <0.5-0.7g - complete response)
- Disease severity (Higher Se Cr at presentation, proteinuria)
- Class, Activity and Chronicity Scores
- Presence of interstitial fibrosis and crescents
- Delay in diagnosis/treatment
- Response to treatment
- Hypertension
- Low hematocrit
- Black race
- Socioeconomic class
- Differential gene expression in renal biopsy – BAFF/APRIL, NFKB and IL-6 signalling in responders vs non responders
SLE renal disease treatment
Treatment guided by class of renal disease
Class I, II, VI – no immunosuppression
Class III, IV (+/- V) – immunosuppression
* Induction - IV steroids + MMF or cyclophosphamide, if incomplete response add in CNI or belimumab (BLyS)
* Maintenance - MMF superior to AZA, if not improved give opposite (MMF or CYC), then rituximab (obintuzumab the other cd20 is being investigated)
* Serological monitoring – rising dsDNAcan predict clinical relapse
If class V + class III or IV, treat as for class III/IV
Future therapies in Lupus Nephritis (3)
Belimumamb - IgG 1 A mab for soluble human B lymphocyte stimulator protein (BLyS) improvement in combination with MMF
Voclosporin - novel calcineurin inhibitor - improved complete response
Rituximab - anti-CD20 ab, 2 doses in combination with prednisolone led to 90% response @ 37 weeks, 86% @ 52 weeks
Non-renal SLE target therapies (3)
Rituximab (CD20) - decrease in dsDNA
Belimumab (BAFF/BLyS) - improved response
Anifrolumab (Type I IFN/IFNa) - improved response
Pregnancy in SLE
- Maternal mortality 20x higher
- 2-4 x risk of obstetrical complications: preterm, pre/eclampsia, thrombosis, infection
- Increased risk of fetal complications – fetal growth restriction, low birth weight
*Complete heart block ~2%
*anti Ro and La abs = risk of neonatal lupus
Immune mediated inflammatory myopathies are becoming better categorised, and newly recognised phenotypes are linked to their specific antibodies. Out of the responses below please select the option which correctly identifies the phenotype with its matching antibody.
A. Antisynthetase syndrome - Anti MDA-5
B. Necrotising myopathy - Anti HMG CoA reductase
C. Inclusion body myositis - Anti Mi2
D. Malignancy associated dermatomyositis - Anti-Cytosolic 5’-Nucleotidase 1A
Answer = B
An immune mediated necrotising myopathy - anti-HMGCR and anti-SRP
Inclusion body myositis is associated with anti-Cytosolic 5’-Nucleotidase 1A
malignancy associated dermatomyositis with TIF-1-gamma and antisynthetase syndrome with anti-Jo1anti-PL-7 and Anti-PL-12.
Anti-MDA5 is an antibody associated with a very aggressive syndrome associated with rapidly progressive pulmonary fibrosis and a very poor prognosis.
Familial Mediterranean fever results from the production of which pro-inflammatory cytokine?
A. IL-1
B. IL-2
C. IL-10
D. IL-12
Answer = A
Familial Mediterranean fever (FMF)
- mutation MEFV gene coding for pyrin which is a component of inflammasome and activates IL-1
- attacks of fever and serosal inflammation»_space; abdominal and chest pain
- can be treated with the anti-IL-1A monoclonal antibody- Anakinra