Rheumatology

Question 1

RA autoantibodies

Answer 1

1. 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
2. Citrullinated peptide (ACPA) - high specificity (95%);
   precede onset of disease, associated with more severe disease as well as lung and CVD disease
3. Peptidyl arginine deaminase 4 (anti-PAD4) - moderate
4. Carbamylated proteins (Anti-CarP) - moderate

Question 2

RA environmental interactions

Answer 2

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&raquo_space; converts arginine to citrulline thus providing antigens

GI - suspected link to microbiome but unproven clinically

Question 3

Key cytokines (2) and mediators (3) in RA

Answer 3

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

Question 4

Patterns of RA (timing + 2 specific subtypes)

Answer 4

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

Question 5

Hands and wrists in RA (7)

Answer 5

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)

Question 6

Ankles and feet in RA (6)

Answer 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

Question 7

Extra-articular manifestations of RA (8)

Answer 7

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

Question 8

X-ray findings in RA (5)

Answer 8

1. Periarticular soft tissue swelling
2. Juxta-articular osteoporosis
3. Marginal erosions
4. Joint space narrowing
5. Symmetric involvement

Question 9

RA DMARDs (4)

Answer 9

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

Question 10

RA biologics and targeted synthetics (5) - how is therapy structured

Answer 10

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

Question 11

Tapering/ceasing therapy in RA

Answer 11

• 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

Question 12

GCA - epi, presentation, and treatment

Answer 12

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)

Question 13

Cause of vision loss in GCA

Answer 13

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)

Question 14

4 clinical patterns of GCA

Answer 14

1. Isolated cranial GCA (headache, jaw claudication, scalp tenderness) - 80%
2. Symptomatic large vessel vasculitis (claudication, pulseless limb) with or without associated cranial signs - 9%
3. Isolated fever or inflammatory response - 9%
4. Isolated PMR with vasculitis on imaging - 2%

Question 15

Large vessel GCA (4)

Answer 15

1. Younger
2. Higher steroids
3. Higher risk of relapse
4. Less headache, visual loss, positive biopsy

Question 16

Bloods in GCA (3)

Answer 16

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

Question 17

Biopsy and imaging in GCA

Answer 17

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

Question 18

Adjunct treatments in GCA

Answer 18

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

Question 19

Complications of GCA + treatment (5)

Answer 19

1. Infections (highest in first year)
2. Osteoporosis
3. Cataracts
4. Poor Diabetes control
5. 2x Aortic aneurysm

Question 20

PMR - epi, presentation, bloods, and treatment

Answer 20

> 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

Question 21

SLE - epidemiology and survival

Answer 21

Female > male (9:1), 16-65yo
22.7% have family history of autoimmune disease
80-90% 10 year survival (early infection, late atherosclerosis)

Question 22

SLE genetics, environmental, hormonal factors

Answer 22

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

Question 23

SLE renal disease classes

Answer 23

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

Question 24

SLE diagnosis (8)

Answer 24

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

Question 25

SLE disease activity (4)

Answer 25

ESR > CRP (unless concurrent infection/arthritis) Increased anti-dsDNA Low C3/C4 Questionares

Question 26

General measures in SLE (9)

Answer 26

Stress UV light Estrogen Sulfonamides Vitamin D repletion Smoking cessation Diet and exercise Immunisations Minimise glucocorticoids and manage side effects

Question 27

Management in SLE

Answer 27

1. Hydroxychloroquine - background therapy for all, remember retinal toxicity 2. 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

Question 28

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

Answer 28

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

Question 29

Poor prognostic indicators in SLE renal disease

Answer 29

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

Question 30

SLE renal disease treatment

Answer 30

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

Question 31

Future therapies in Lupus Nephritis (3)

Answer 31

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

Question 32

Non-renal SLE target therapies (3)

Answer 32

Rituximab (CD20) - decrease in dsDNA Belimumab (BAFF/BLyS) - improved response Anifrolumab (Type I IFN/IFNa) - improved response

Question 33

Pregnancy in SLE

Answer 33

* 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

Question 34

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 34

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.

Question 35

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 35

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 >> abdominal and chest pain - can be treated with the anti-IL-1A monoclonal antibody- Anakinra