Rheumatology Flashcards
Anti DNA Topoisomerase I / Scl-70
Diffuse Cutaneous Systemic Sclerosis dcSSc
Anti-Centromere Ab (ACA)
Limited Cutaneous Systemic Sclerosis (lcSSc)
- only 5% of patients with dcSSc will be positive for ACA
Anti-RNA Polymerase III
If present in patients with dcSSc is associated with rapidly progressive skin involvement and high risk for renal crisis.
Classification of Inflammatory Myopathies
Idiopathic Inflammatory Myopathies:
- Polymyositis, Dermatomyositis with the subsets of Anti-Synthetase syndrome and Amyopathic Dermatomyositis (Anti MDA)
Immune Mediated necrotizing myopathy:
- Anti SRP and anti-HMGcoR
Inclusion Body Myositis
Classification of Inflammatory Myopathies
Idiopathic Inflammatory Myopathies:
- Polymyositis, Dermatomyositis with the subsets of Anti-Synthetase syndrome and Amyopathic Dermatomyositis (Anti MDA)
Immune Mediated necrotizing myopathy:
- Anti SRP and anti-HMGcoR
Inclusion Body Myositis
Polymyositis
By far the rarest form of myositis (5%)
Timeline: Subacute (weeks)
Clinical Features:
- proxima, symmetrical
Extra-Muscular:
- Lung - NSIP
- Heart - pericarditis, conduction block
- Oesophageal dysmotility
10-50 fold CK
No specific serology
Good response to immunosupression
Dermatomyositis
Subacute (weeks)
Similar pattern to PM.
Cutaneous findings:
- Gottron papules
- Heliotrope Rash
- V and Shawl Sign
Extra-muscular:
- ILD more common (20-25%)
- Cardiac - CHB, pericarditis
CK 10-15 fold
Anti-Mi2 Ab (good treatment response)
Anti-MDA5 (Rapidly progressive ILD)
Associated with malignancy (poor prognosis)
Good response to treatment apart from ILD or malignancy associated.
Immune mediated Necrotising Myositis
Rapidly progressive, acute presentation
Symmetrical, proximal
May be seen after statin exposure, but different to common statin induced myopathy.
CK 10-50 fold elevated
Anti-SRP Ab
Anti-HMGCR
Biopsy: Necrosis without inflammation
Immunosuppression, escalation in therapy may be needed.
Inclusion body myositis
Slowly progressive over years
Asymmetrical
Proximal + long finger extensors + knee extensors + dysphagia (cricopharyngeal)
CK only 10-15 fold
Male > Female
>50 years
cN1A Ab
Biopsy: “invasion” of muscle fibres, amyloid deposition
Slowly progressive, wheelchair within 10-15 years
Does not respond to Immunosuppression.
Anticentromere Ab
90% of LcSSc, associated with risk of PAH
Anti-Scl 70 (DNA topoisomerase 1)
dcSSc, risk of ILD
Anti-RNA Pol III
DcSSc, associated with rapidly progressive skin disease and high risk of scleroderma renal crisis
Anti-U3-RNP
dcSSc, associated with poor outcome and skeletal involvement
Pattern of arthritis is SSc
12-60% of patients with SSc will have joint involvement.
- Hand and wrist predominance, often affects DIP
Significance of tendon friction rubs
Can be felt or heard over a tendon, indicator of active disease.
Raynauds Phenomonon
Occurs in 95% of SSc.
Earliest manifestation
If you have Raynauds, an associated SSc Ab and nailfold capillary changes - 80% chance of developing SSc.
Scleroderma Renal Crisis:
5% of patients.
Anti-RNA Pol III gives increased risk
Use of glucocorticoids gives increased risk
Clinical: Hypertensive crisis
Tests: Micro-angiopathic haemolytic anaemia.
Tx: ACE inhibitor to control BP (captopril), continue even in the setting of rising Cr and dialysis as late improvement may occur.
Prophylaxis: Calcium channel blockers
Lung Involvement:
ILD in 50% of patients with dcSSc (85% if anti Scl 70 positive)
Pattern: NSIP > UIP
Tx: Nintedanib now approved for SSc with ILD
PAH in 10% of patients (more likely in anti-centromere +ve lcSSc
- WHO Group 1 with function class II-iV can have treatment with vasodilating therapy.
Anti-HMG Co-R AB
Immune mediated Necrotising myopathy
- Severe myopathy
- no extra-muscular involvement.
Treatment of PAH
Endothelin R antagonists:
- Bosentan, Ambrisentan (selective)
- Macitentan (non-selective)
PDE-5 Inhibitors
- Sildenafil, Tadalafil
Riociguat
Prostatcycline antagnosist
- iloprost, epoprosteonol
Combination therapy with ambrisentan and tadalafil better than mono-therapy.
Anti-Jo 1
Anti-synthetase Syndrome
Anti-Mi2
Classical Dermatomyositis
Anti-MDA5
DM with rapidly progressive ILD
Anti-SRP
Immune mediated Necrotising myopathy
- Severe myopathy
- no extra-muscular involvement.
Mixed Connective Tissue Disease
Features of at least 2 of:
- SLE, Polymyositis, SSc
Positive anti-U1-ribonucleoprotein (anti-U1-RNP)
Spondyloarthpropathies
Axial Spondyloarthropathies:
- Non-Radiographic SpA
- Radiographic SpA = Ankylosing Spondylitis
Peripheral Spondyloarthropathies:
- Reactive Arthritis
- Psoriatic Arthritis
- Enteric or IBD associated arthritis
Pathophysiology of Spondyloarthropathies
T cell Activation with Th17 phenotypes
- TNF-Alpha
- IL1, IL-17, IL23
Enthesitis –> bone erosion –>new bone formation. Causing boney proliferation and destruction.
HLAB27
Found in 6% of northern europeans.
Only 5% of those carrying it will develop at SpA, and not all those with SpA have it.
Sensitivity varies:
- 95% in AnkSpon
- 50-75% on IBD-Arthritis
-
Ankylosing Spondylitis Peripheral
Enthesitis
Asymmetical, Large joint Oligoarthritis (hips, shoulders)
Dactylitis uncommon
Ankylosing Spondylitis Extraarticular manifestations
Opthal: Anterior Uveitis (unilateral, recurrent)
Cardiovascular: Aortic valve disease (regurgitation), conduction disease
Pulmonary: Restrictive lung disease, rarely apical lung fibrosis
Bone: High risk of vertebral fractures
Psoriatic Arthritis
Occurs in 10-40% of patients with psoriasis.
Skin psoriasis occurs first or co-occurs in 90%.
therefore 10% of cases occur before skin (up to 10 years in advance)
No correlation between extent of joint involvement and severity of skin disease.
Nail involvement (pitting and onycholysis) is a risk factor for joint disease.
5 patterns:
- symmetrical polyarthritis
- asymetrical oligoarthritis
- DIP predominant
- spondyloarthritis
- arthritis mutilans
Psoriatic Extra-articular manifestations
Opthal: Conjunctivitis more common than uveitis
Skin and nail changes
IBD Associated Arthritis
4-46% of patients with IBD.
3 patterns:
- Sacroilitis (most common), strongly associated with HLAB27, not related to bowel flare.
- Acute polyarticular peripheral arthritis, knees most commonly involved, may parallel exacerbations of bowel disease.
- Chronic polyarticular peripheral arthritis, less than 5%, not correlated with bowel activity.
Reactive Arthritis
Occurs within 2 weeks following certain GI or GU infections.
Chlamydia trachomatis, Ureaplasma urealyticum in the urethra.
Campylobacter, E Coli, Salmonella, Shigella and Yersinia in the intestine.
Asymmetrical monoarticular or oligoarticular.
- Knee, ankle and wrist most common
Enthesitis very common 90% - achilles tendonitis or plantar fasciitis.
Management of axial spondyloarthritis
Physical Therapy
NSAIDs
Anti-TNF: Infliximab, Adalinumab, Golimumab, Certolizumab, Etenercept
IL-17A inhibitors: Secukinumab, Ixekizumab
JAKi: Upadacitib
DMARDS for peripheral arthritis: Sulfasalazine and Methotrexate.
All have RCT evidence of both radiographic SpA and non-radiographic SpA. No head to head studies, choice depend on patient factors.
Role of non-biological DMARDS like methotrexate in Ank Spon?
These is NO ROLE in axial arthritis, and does have some role in peripheral arthritis.
Diagnostic Criteria for Ank Spon
New York Criteria:
Clinical:
- Restriction in lateral or forward flexion of spine
- reduced chest expansion
- Inflammatory lower back pain > 3 months
Radiological:
- Bilateral grade 4 sacro-ilitis on XR
- Unilater grade 3-4 sacro-illitis on XR
BUT this is now old, terminology is now “axial spondyloarthritis” which is split into radiographic and non-radiographic.
IL-17A Therapy
Secukinumab and Ixekizumab:
Increased risk of UNcomplicated fungal infections (candida)
JAK Inhibitor therapy for SpA
Upadacitinib
- Selective JAK inhibitor (JAK1, JAK3, less JAK2)
Risk of viral infection esp Herpes Zoster
Diagnosis of Psoriatic Arthritis
1 - Presence of MSK inflammtation (either peripheral arthritis, axial arthritis or enthesitis)
2 - Plus:
- Skin psoriasis
- Family history of psoriasis
- Dactylitis
- Nail changes (pitting, onycholysis)
- RF negative
- Evidence of juxta-articular bone formation f XR
Treatment options in psoriatic arthritis
NSAIDs and Physical Therapy - Symptom benefit
Local Corticosteroid injections for peripheral arthritis.
csDMARD: Sulfasalazine, MTX, Leflunamide. Not for axial disease.
Anti- TNF
Anti IL17A: Secukinumab, Ixekizumab
anti- IL12/23: Ustekinumab (p40 subunit)
JAK1/3i: Tofacitinib
anti-IL 23: Guselkumab (p19 subunit)
Comparison of antiTNF Adalinumab with antiIL17A (Secukinumab, Ixekizumab)
Similar results for arthritis.
Anti-IL17A superior for skin.
Is there a role for co-prescription of csDMARD and biologic DMARD?
No.
SEAM Trial.
TNF mono-therapy as effective as TNF + MTX.
Giant Cell arteritis epidemiology
Female>male. Peak age 70-79 (80% of patients are > 70)
Association with HLA DRB1*04
Association with PMR:
- 50% of GCA will have PMR sx
- 10-15% of PMR will get GCA as some point.
How to differentiate between CRAO and NAAION
Both present in older people with vascular risk factors.
Both present with acute monocular vision loss.
On exam : Both will have RAPD.
The differentiation is on fundoscopic examination:
- NAAION will show optic disc swelling
- CRAO will show cherry red spot
Management:
- NAAION, vascular risk factor management and exclude AAION
- CRAO - this is a stroke, work up and manage as per stroke
Imaging in GCA
TA US: Halo sign has 90% specificity, 70% sensitivity.
-Useful for ruling out those with low pre test probability
CTA/MRI/PET may be considered to assess for large vessel involvement.
GCA management
No visual sx –> PO steroids
Visual sx –> IV MP 3 days then PO
GiACTA Study for GCA
Tocilizumab with steroids resulted in
ANCA vasculitis - GPA vs MPA relapse rate?
Regardless of the clinical presentation - PR3 positive disease is more likely to relapse than MPO positive disease.
CYCLOPS TRIAL
For treatment of ANCA Vasculitis:
PO and IV Ciclophosphamide are equivalent
RAVE Study
For treatment of severe GPA/MPA
Rituximab induction vs PO Cyclophosphamide Induction
Rituximab non-inferior to cyclophosphamide - many would choose rituximab due to better side effect protocol.
Role of PLEX in ANCA associated vasculitis?
PEXIVAS Trial showed no benefit of PLEX for treatment of severe GPA/MPA including in the subset of people with pulmonary haemorrhage.
PLEX MAY have a role in:
- Double positive ANCA Anti-GBM disease
- Severe renal impairment (controversial)
- Severe pulmonary haemorrhage (contraversial)
Avacopan
Avacopan is a C5a Receptor inhibitor.
ADVOCATE trial compared Avacopan vs prednisolone taper in ANCA associated vasculitis.
Avacopan was non-inferior to PNL at 26 weeks and superior to PNL at 52 weeks.
Treatment of non-Severe MPA/GPA?
Methotrexate + low dose pred
Remission maintenance for MPA/GPA?
Relapse is common, more common with PR3+ than MPO+
Traditionally Aza, MTX, Cyclophosphamide used.
Rituximab 6 monthly infusions is superior for remission maintenance.
Remission maintenance for MPA/GPA?
Relapse is common, more common with PR3+ than MPO+
Traditionally Aza, MTX, Cyclophosphamide used.
Rituximab 6 monthly infusions is superior for remission maintenance.
Treatment of EGPA?
Can be ANCA negative or ANCA MPO positive (is almost never PR3 positive)
Mepolizumab (Anti-IL5) is superior to placebo but prognosis is still poor.
Rheumatoid Arthritis HLA
Shared epitope = a 5 amino acid sequence commonly encoded by the HLA DR locus, especially HLA-DRB101 and HLA-DRB104
Risk factors for RA
HLA DRB1*01/04
STAT4
PADI
PTPN22
Smoking
Periodontitis
Gut dysbiosis
Anti-CCP
Key Cytokines in RA
IL-1, IL-6, TNF
Key Cell in RA
MAcrophage, T cell, B cell
PMN is the most abundant cell in the synovial fluid
XR features of RA
Joint space narrowing
subchondral osteopenia
DIP sparing
Rheumatoid factor
Ab against Fc portion of IgG
Utility in RA - RF positive disease is associated with more rheumatoid nodules, vasculitis, and worse prognosis.
Highly associated with RA, Sjogren Syndrome, Cryoglobulinaemia.
Also seen in non-rheumatic disease:
- Hepatitis B and C
- Endocarditis
- Viral infection
- Other chronic infections
AntiCCP/ACPA
High specific for RA (90%)
Predictive or developing RA in asymptomatic and early undifferentiated arthritis.
Sensitivity 70%
Marker of severe and erosive disease.
Methotrexate MOA
Inhibits purine (adenine and guanine) nucleotide synthesis by inhibition of enzyme dyhydrofolate reductase (DHF).
Methotrexate adverse effects?
Pancytopenia
Liver Transaminitis
Pneumonitis
Give Folinic Acid rescue if sepsis + leukopenia
Leflunomide MOA
Inhibits pyrimidine (cytosine, thymine, uracil) synthesis.
Leflunomide adverse effects?
Pancytopenia, transaminitis, pneumonitis.
Cholestyramine rescue if sepsis and leucopenia.
Leflunomide adverse effects?
Pancytopenia, transaminitis, pneumonitis, diarrhoea
Cholestyramine rescue if sepsis and leucopenia.
Methotrexate and Leflunomide
Think of the two as brothers:
MTX - purine synthesis
LFN - Pyrimidine synthesis
Same side effect profile, but LFN more likely to cause diarrhoea.
Rescue if sepsis and leukopenia:
- MTX - Folinic Acid
- LFN - Cholestyramine binds LFN
Etanercept
Anti TNF however is a soluble TNF receptor - structurally it is a Fc portion of human Ig fused to a TNF receptor.
Weekly subcut injection, shorter halflife of 4 days.
Infliximab vs Adalinumab
Infliximab is a chimeric (75% humanised, 25% murine) mAb, Adalinumab is 100 humanised mAb.
Infliximab has halflife of 10 days and is given IV 8 weekly
Adalinumab has a halflife of 14 days and is given sub cut fornightly.
Precautions for TNF blockade?
TB
Congestive heart failure
Demyelinating disease
Lymphoma
Lupus like syndrome of ANA/dsDNA positive
Cancer in last 5 years
Adverse effects of TNF blockage?
Infections (normal bacterial)
Herpes Zoster
Chronic HSV (ophthalmic)
Melanoma
Immunosuppression drugs and risk of skin cancer?
TNF blockage - melanoma
Thiopurines - non-melanoma SC
Management of TB if wanting to start anti-TNF?
Latent TB:
- Isoniazid for 4-6 weeks before starting TNF, and continue for 9 months treatment.
- Latent TB is not a contraindication to anti-TNF
- liver enzyme derangement is a common problem with isoniazid
Active TB:
- Treat with standard therapy RIPE
- Should have at least 2 months treatment by a TB speciality prior to anti-TNF therapy
Tocilizumab
iL-6R mAb (Blockage)
A/E:
- LFT derangement, especially in combo with MTX
- Increased total and HDL(but decreased CRP leads to decreased CVS risk)
- Diverticular perforation (rare)
Rituximab
-imab (chimeric Ab)
IV Infusion
90% of B cells depleted in 3 months (measure CD 19+ levels)
Does not deplete early pre-B cells or Plasma cells, therefore no fall in Ig initially.
B cells are restored between 6-18 months later.
Abatacept
CTLA-Ig fusion protein, therefore it acts as CTLA would do. Binds to B7 (CD80/86) on APC and prevents B7 binding to CD28 (co-stimulation).
This is opposite to the effect of Anti-CTLA4 mAb used in cancer immunotherapy.
Tofacitinib
Inhibits Jak 1 and Jak 3
Blocking the JAK-STAT pathway will block signalling of multiple cytokines, therefore these are more immunosuppression than IL inhibitors.
Risk of herpes zoster reactivation. Give shingrix vaccine.
Other JAK inhibitors:
- Bari (JAK 1/2)
- Tofa (JAK1/3)
- Upa (JAK1) more selective
RA in pregnancy:
Methotrexate - cease >6 weeks prior to conception, cannot use if breastfeeding (same for leflunamide - brothers)
Sulfasalazine, low dose pred, and Aza are all safe to continue.
- remember small increase risk of cleft lip with prednisolone.
Certalizumab does not cross placenta and therefore can be used.
- other anti-TNF cannot be used.
Management of RA drugs peri-operatively:
csDMARDs can be continued through the peri-operative period.
bDMARDs should be held. Schedule surgery at the end of the dosing interval for that medication and hold until external wound healing is complete (usually 2 weeks)
JAKi - hold for 3 days pre-operatively .
Perioperative management of patients on glucocorticoids:
HPA suppressed = >20mg prednisolone for 3 weeks, or cushingoid appearance.
Intermediate HPA suppressed = between 5-15mg prednisolone for > 3 weeks. Need to do AM cortisol and then ACTH testing to assess HPA axis.
HPA non-suppressed = Any dose of steroid for <3 weeks, or <5mg day doses for any duration. These patients will not be HPA suppressed.
Perioperative management of patients on glucocorticoids:
HPA suppressed = >20mg prednisolone for 3 weeks, or cushingoid appearance.
Intermediate HPA suppressed = between 5-15mg prednisolone for > 3 weeks. Need to do AM cortisol and then ACTH testing to assess HPA axis.
HPA non-suppressed = Any dose of steroid for <3 weeks, or <5mg day doses for any duration. These patients will not be HPA suppressed.
Urate lowering therapy
Allopurinol
- Competitive inhibitor of XO
- Risk of DRESS with HLAB 5801 (common in Han Chinese)
Febuxostat
- non-competitive inhibitor
- Use in Han Chinese
- Increased risk of cardiovascular events
