Rheumatology Flashcards
(299 cards)
1
Q
What are the main considerations re treatment of dermatomyositis?
A
acute vs chronic
skin disease vs combined skin and muscle disease
2
Q
What is the ongoing/chronic treatment for dermatomyositis with skin and muscle disease?
A
1) high dose oral steroids eg prednisolone 0.75-1.5mg/kg/d for 2-4 weeks then taper (use lowest possible dose)
- steroids reduce morbidity, improve muscle strength and motor function
2) Photoprotection - high protection sunscreen
3) topical steroids - even if treated with systemic corticosteroids
- often help control erythema and pruritis
- otherwise consider topical antipruritics and oral antihistamines OR topical tacrolimus
4) simple moisturisers and emollients
IF underlying malignancy - treat underlying malignancy - improvement or complete resolution of DM has been reported in some cases after successful treatment of underlying malignancy
Consider
Antimalarials eg hydroxycholoroquine
2nd line =
Methotrexate (both muscle and skin)
- steroid-sparing
- more rapid onset of effect than azathioprine
Azathioprine (more muscle disease than skin)
- takes longer than MTX to have effect eg >6mths
3rd line =
Mycophenolate
Ciclosporin - skin and early ILD
4th line =
IVIG
3
Q
How do you treat patients with dermatomyositis with skin manifestations unresponsive to topical treatments?
A
Add Hydroxychloroquine
2nd
Methotrexate
Azathioprine
3rd
Mycophenolate
Ciclosporine
recalcitrant disease
IVIG, dapsone, thalidomide
4
Q
How do you treat acute dermatomyositis?
A
If severe muscle weakness (e.g., quadriplegia), interstitial lung disease, myocarditis, respiratory failure, severe dysphagia, or other life-threatening complications.
- IV methylpred1g daily for 3-5 days then PO steroids
+
IVIG
5
Q
What features may predict treatment-resistance to steroid therapy for dermatomyositis and necessitate early adjunctive treatment?
A
Anti-signal recognition particle (SRP) antibodies in patients with DM are associated with acute severe, treatment-resistant necrotising myositis - IVIG is often required at an early disease stage in these patients; alternative = Rituximab
Patients diagnosed with anti-synthetase syndrome may be corticosteroid-resistant and concomitant use of immunosuppressive drugs (e.g. methotrexate, azathioprine) is required
Presence of anti-melanoma differentiation-associated gene 5 (MDA5) is specific to clinically amyopathic DM, and is strongly associated with rapidly progressive interstitial lung disease. Patients often require treatment with immunosuppressive drugs as well as high-dose systemic corticosteroids from an early disease stage
6
Q
What are the specific risks of IVIG in dermatomyositis treatment?
A
acute renal failure
skin rashes
aseptic meningitis
stroke
7
Q
What is the most sensitive muscle enzyme test for the diagnosis of dermatomyositis?
A
CK
8
Q
Other than CK, what other serum markers can elevated in dermatomyositis (incl if CK is normal)?
A
Serum aldolase
ANA - not specific
Myositis specific antibodies (MSAs) and myositis associated antibodies (MAAs)
- Anti-Mi-2 antibodies
- Anti‐U1 ribonucleoprotein (RNP)
- anti‐Ku
- Anti-Jo-1 and other anti-aminoacyl-tRNA synthetase antibodies (anti-ARS antibodies; including anti‐PL‐7, anti‐PL‐12, anti‐EJ, anti‐OJ, and anti‐KS
9
Q
What is the significance of finding Anti-transcription intermediary factor 1 gamma in a patient with dermatomyositis?
A
Strongly assoc with malignancy therefore need extensive search for underlying malignancy
10
Q
What is the significance and association of Anti-signal recognition particle (SRP) antibodies in dermatomyositis?
A
Found almost exclusively in polymyositis and assoc with acute severe, treatment-resistant necrotising myositis - need early IVIG +/- Rituximab
11
Q
What are the key clinical features and antibodies assoc with anti-synthetase syndrome?
A
ILD, fever, myostitis, polyarthritis, mechanic’s hands, raynaud’s phenomenon
Anti-Jo-1 and other anti-aminoacyl-tRNA synthetase antibodies (anti-ARS antibodies; including anti‐PL‐7, anti‐PL‐12, anti‐EJ, anti‐OJ, and anti‐KS
12
Q
What is Anti-melanoma differentiation-associated gene 5 (MDA5; also known as CADM‐140) specific for in dermatomyositis?
A
Clinically amyopathic dermatomyositis (CADM)
It is strongly associated with a rapidly progressive ILD with poor prognosis (need early immunosuppressive tx)
Tender palm papules and diffuse alopecia may be present
13
Q
Anti-NXP2 is strongly associated with what form of dermatomyositis?
A
Juvenile DM with a high proportion suffering from cutaneous calcinosis due to dystrophic calcification
14
Q
Anti-PM-Scl antibodies are often found in patients with?
A
Overlapping myositis and scleroderma
15
Q
Describe the ideal muscle biopsy in patients with suspected dermatomyositis?
A
In symptomatic patients the biopsy should be taken from a weak but not severely atrophied muscle. Quadriceps and deltoid are common sites
Greater yield with open surgical biopsy cf needle biopsy
Greater yield if pre-biopsy EMG or MRI to target biopsy (given possible patchy muscle involvement)
16
Q
What pattern of atrophy on muscle biopsy is diagnostic of dermatomyositis?
A
Perifascicular atrophy is seen due to phagocytosis and necrosis of muscle fibres
17
Q
How are patients with dermatomyositis commonly classified according to severity?
A
Severe disease - those with severe muscle weakness (e.g., quadriplegia), interstitial lung disease, myocarditis, respiratory failure, severe dysphagia, or other life-threatening complications
Non-severe disease - 4/5 muscle power + none of life threatening complications
18
Q
How do you diagnose dermatomyositis?
A
By using the European League Against Rheumatism and American College of Rheumatology (EULAR/ACR) classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIMs)
- based on scoring system results in definite’, ‘probable’, and ‘possible’ IIM
- patients can be further subclassified based on classification tree
19
Q
What is the mode of inheritance of Marfan syndrome?
A
Autosomal dominant
20
Q
What is the most typical genetic abnormality in Marfan Syndrome?
A
FBN1 - encodes the connective tissue protein fibrillin-1
21
Q
What is the most typical genetic abnormality in Marfan Syndrome?
A
FBN1 - encodes the connective tissue protein fibrillin-1
22
Q
What is the clinical hallmark of ankylosing spondylitis?
A
Inflammatory back pain
23
Q
What is the clinical hallmark of ankylosing spondylitis?
A
Inflammatory back pain
24
Q
90% of patients with ankylosing spondylitis have what gene?
A
HLA-B27
25
90% of patients with ankylosing spondylitis have what gene?
HLA-B27
26
Ankylosing spondylitis is more common in which gender?
Males
27
There is a strong genetic risk to developing Ankylosing spondylitis and the disease severity - what genes are implicated?
HLA B27 (but unclear role)
ERAP1
ARTS1
28
What is HLA-B27?
A heterotrimeric complex with beta-2-microglobulin that presents intracellular pathogens for recognition by the T-cell receptor of CD8 T cells. HLA-B27 can also be expressed as cell surface beta2-microglobulin (beta2m)-free homodimers (B27[2])
29
What is the role of antibodies to Klebsiella pneumoniae in Ankylosing spondylitis?
Unclear - Antibodies directed against an epitope of a Klebsiella pneumoniae-derived protein are present in the majority of patients with AS but studies have yet to elucidate role in pathogenesis of AS
30
How does the pathophysiology of ank spond differ from RA?
Both involve inflammation and cartilage erosion but ankylosing spondylitis involves an additional process - repair or ossification
31
What is the Calin criteria for Inflammatory Back pain?
Age <40
Back pain > 3 months
Insidious onset
Improves with exercise
Early morning stiffness
32
In addition to inflammatory back pain, what other disease associations/manifestations may be present in patients with Ank Spond?
Uveitis
Iritis
Enthesitis
Psoriasis
Inflammatory bowel disease
Dyspnoea
Fatigue
Family history of spondyloarthropathy
Sleep disturbance
33
What are some of the key physical examination findings in patients with ankylosing spondylitis?
Loss of lumbar lordosis and flexion
Tenderness at sacroiliac joints
Kyphosis
Peripheral joint involvement
Tragus-to-wall distance
Lumbar flexion
Cervical rotation
Lumbar side flexion
Intermalleolar distance
- these measurements taken together to form Bath Ankylosing Spondylitis Metrology Index
34
What test is diagnostic of Ankylosing spondylitis?
None
35
What is the first test you should order in a patient suspected of having ankylosing spondylitis?
Pelvic XRAY
36
Does a negative pelvic X-RAY exclude Ankylosing spondylitis?
No!
If suspicious need to obtain MRI + often helpful to check if HLA-B27 positive
37
What is the risk of developing AS among HLA-B27-positive first-degree relatives of HLA-B27-positive probands with AS, compared with HLA-B27-positive individuals in the population
16-fold increased risk
38
What is the risk of developing AS among HLA-B27-positive first-degree relatives of HLA-B27-positive probands with AS, compared with HLA-B27-positive individuals in the population
16-fold increased risk
39
What is the classic MRI pelvis finding in a patient with ankylosing spondylitis?
Bone marrow oedema on a T2-weighted sagittal short-tau inversion recovery (STIR) image
40
What are some distinguishing features between Ankylosing spondylitis and Inflammatory-bowel related arthritis?
IBD-related arthritis tend to:
Have a hx of UC or Crohns
Have no sex bias (males and females equally affected)
Less likely to be HLA-B27 positive (only 30%)
More likely to have peripheral joint involvement
May have asymmetric sacroillitis
May have pyoderma gangrenosum or erythema nodosum
41
What are some distinguishing features between Ankylosing spondylitis and psoriatic arthritis?
Patients with psoriatic arthritis tend to:
Develop disease at slightly older age (30-40s as opposed to 20s)
Have asymmetric/unilateral sacroillitis
Have a history of psoriasis
Have dactylitis
Have erosive disease on X-ray
42
What are some distinguishing features between Ankylosing spondylitis and psoriatic arthritis?
Patients with psoriatic arthritis tend to:
Develop disease at slightly older age (30-40s as opposed to 20s)
Have asymmetric/unilateral sacroillitis
Have a history of psoriasis
Have dactylitis
Have erosive disease on X-ray
43
What are some distinguishing features between Ankylosing spondylitis and psoriatic arthritis?
Patients with psoriatic arthritis tend to:
Develop disease at slightly older age (30-40s as opposed to 20s)
Have asymmetric/unilateral sacroillitis
Have a history of psoriasis
Have dactylitis
Have erosive disease on X-ray
44
What are the known
45
What are the known
46
What are the known predictors of radiographic progression of Ankylosing spondylitis?
Syndesmophytes on initial X-RAY
Elevated CRP/ESR
Smoking
47
What are the known predictors of radiographic progression of Ankylosing spondylitis?
Syndesmophytes on initial X-RAY
Elevated CRP/ESR
Smoking
48
What non-pharmacological measures are appropriate for Ankylosing spondylitis?
1) Smoking cessation
2) active physio therapy
3) patient education
4) cardiovascular disease risk calculation and modification
- as px with AS have increased CVD related mortality
49
What is the first line therapy for pain and stiffness in Ankylosing spondylitis?
NSAIDs
- conflicting evidence whether reduced disease progression but helpful for symptoms
- should trial at least 2 at highest tolerated dose before moving on to other treatments
50
What is the role of steroids in Ankylosing spondylitis?
No role for systemic steroids
Can consider intra-articulate or local-site specific steroid injections as required
51
What therapies are indicated for peripheral joint involvement in Ankylosing spondylitis?
Sulfasalazine or methotrexate
- note these do not treat axial disease and evidence is weak
52
For Ankylosing spondylitis patients with axial disease refractory to NSAIDs and physiotherapy +/- steroid injections and sulfasalazine what treatment is indicated?
TNF-alpha inhibitors
Eg Adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab
53
Should you continue NSAIDs in patients with ankylosing spondylitis commenced on TNF-alpha inhibitors?
Yes - recommended to continue continuous NSAIDs whilst active disease / established on TNF-alpha inhibitor then can reduce to PRN use
54
Should you attempt to wean TNF-alpha inhibitor therapy for Ankylosing spondylitis once patients achieve remission/disease control?
You can but high risk of disease flare - individual decision
55
What do you give a patient with ankylosing spondylitis who relapses after initial remission on TNF-alpha inhibitor therapy?
Try another TNF-alpha inhibitor before trying an alternative bDMARD therapy
56
What do you give a patient with ankylosing spondylitis who relapses after initial remission on TNF-alpha inhibitor therapy?
Try another TNF-alpha inhibitor before trying an alternative bDMARD therapy
57
If TNF-alpha inhibitor fails in Ankylosing spondylitis, what should you give?
1) can try another TNF-alpha inhibitor
OR
2) IL-17 inhibitor (eg Secukinumab, Ixekizumab)
- these are more effective in TNF-alpha naive patients and in patients with psoriasis
58
After TNF-alpha inhibitors and IL-17 inhibitors, what is the third line bDMARD therapy for refractory Ankylosing spondylitis?
JAK inhibitors eg tofacitinib, upadacitinib)
59
After TNF-alpha inhibitors and IL-17 inhibitors, what is the third line bDMARD therapy for refractory Ankylosing spondylitis?
JAK inhibitors eg tofacitinib, upadacitinib)
60
What is the mechanism of action of Hydroxychloroquine?
It is an antimalarial drug with anti-inflammatory (and possibly immunosuppressive effects)
Also appears to:
- have lipid lowering properties
- improves glycaemic control
- have antithrombotic/anticoagulant affects by inhibiting platelet aggregation and adhesion (but not increasing bleeding time/risk)
Anti-inflammatory effect:
- blocks constimulation of B cell antigen receptor and Toll-like receptor (TLR)-9 pathways + inhibits TLR signalling
- interferes with normal function of subcellular compartments that depend on an acidic milieu as it is a weak base - so called "lysosomotrophic action" - this may interfere with various processes incl secretion of cytokines/inflammatory mediators
61
Which patients with SLE should receive hydroxychloroquine?
ALL patients unless contraindicated
62
What is the typical/initial dose of hydroxychloroquine in SLE?
5mg/kg up to max 400mg daily
63
What are the 2 most significant side effects of hydroxycholoroquine therapy?
Vision-threatening toxic retinopathy
QTc prolongation
64
What monitoring is required when on hydroxychloroquine therapy?
Baseline ocular assessment/opthal review then annual opthalmology review starting after 5 years of therapy
65
What are the risk factors for vision threatening toxic retinopathy secondary to hydroxychloroquine (HCQ)?
Daily HCQ dose >5mg/kg
Long duration HCQ therapy > 5 years
CKD3+
Tamoxifen use
Female gender
Macular disease
66
What are the benefits of hydroxychloroquine therapy in SLE?
Reduces mortality
Reduces risk of disease flare
Reduces fatigue
Reduces skin and musculoskeletal symptoms
Reduces thrombotic events
Reduces end-organ damage accrual
Reduces cancer
67
What must you do if a patient on HCQ therapy for SLE presents with vision impairment?
Stop HCQ and obtain opthal review
68
What are the symptoms/signs of retinopathy secondary to HCQ therapy?
Early - asymptomatic; only detected by spectral domain optical coherence tomography
Later - symptoms incl dropout of letters when reading, photophobia, blurred distance vision, reduced night vision, visual field defects, flashing lights; o/e - central patchy area of depigmentation of macula surrounded by concentric ring of pigmentation ("bull's eye")
69
Do you need to adjust HCQ dosing in renal impairment?
Renally cleared and tend to reduce dose to 200mg (ie half dose) in ESKD
Note HCQ decreases creatinine clearance by ~10% by competitively inhibiting creatinine secretion (not a true change in kidney function)
70
Is it safe to take hydroxychloroquine in pregnancy?
Yes
71
What are some less significant side effects of HCQ therapy?
Nausea and vomiting
Pruritic maculopapular rash/skin reaction
Headaches
Myopathy
72
What rheumatological drugs are considered relatively safe to take in pregnancy?
Hydroxychloroquine
Sulfasalazine
Low dose aspirin
Azathiopurine
6-mercaptopurine
Colchicine
73
What is the main risk factor for progression from non radiographic axial spondyloarthropathy to ankylosing spondylitis ?
Raised CRP
74
What are the predictors of good response to biological therapy in axial SpA?
Younger age
Shorter disease duration
Limited functional impairment
Increased inflammatory markers
Increased inflammation on MRI
HLA B27 positive
75
Which medications are ineffective for axial SpA?
Methotrexate
Sulfasalazine
IL-12/23 blockers
IL-23 blockers
76
When do you consider biologic therapy in axial SpA?
Confirmed diagnosis of axial SpA
Elevated inflammatory markers and/or positive MRI or radiographic ankylosis
Failure of standard therapies (eg NSAIDs)
High disease activity (ASDAS >2.1)
77
What are the first line biologics for treatment of axial SpA?
TNFi - effective across all domains and preferred if IBD or uveitis (note except for eterancept)
IL-17 blocker - preferred if psoriasis, avoid in IBD
JAKi - reserved for failure of above given safety concerns
78
Have biologics been demonstrated to reduce radiographic disease progression in axial SpA within the first two years of therapy?
No - neither TNFi or IL-17i have
However beyond 2 years some evidence they can
79
What two subtypes of systemic sclerosis are there?
Limited cutaneous and diffuse cutaneous
80
Systemic sclerosis tends to affect which patient demographic?
Middle aged females
81
What is the cause of systemic sclerosis?
Unknown - genetic + environmental
82
What genes are associated with systemic sclerosis?
HLA-DRB1
STAT4
Inteferon
83
What environmental exposures are associated with systemic sclerosis?
Silica/stone bench tops
Organic solvents
Vinyl chloride
84
What is systemic sclerosis?
A heterogeneous, multi-organ disease due to auto-immunity (incl autoantibodies) characterised by:
1) inflammation affecting the skin, synovium and muscles
2) vasculopathy (eg Raynaud's, GAVE, telangiectasis, digital ulcers)
3) Interstitial fibrosis (leading to pulmonary arterial hypertension, renal, cardiac, skin manifestations)
85
How are the two subtypes of systemic sclerosis defined?
By extent of skin involvement
86
What are the key features/differences of diffuse cutaneous systemic sclerosis (dSSc) vs limited cutaneous systemic sclerosis (lSSc)?
dSSc =
early onset of internal oran involvement incl ILD or renal crisis
Short hx of raynaud's with rapid onset of skin changes/contractures
Tendon friction rubs
constitutional symptoms
antibodies to Scl-70 (anti-topoisomerase 1) - assoc with ILD
Anti-RNA polymerase I and II antibodies - assoc with renal crisis
ANA with nucleolar pattern
lSSc =
CREST syndrome (Calcinosis, Raynaud's, Esophageal dysmotility, Skin chanes, Telangiectasis)
Raynaud's long hx
Skin changes are gradual
ILD and renal disease far less frequent
Anti-centromere antibodies
Lower incidence of Scl-70 antibodies
87
Does the incidence of pulmonary arterial hypertension differ between dSSc and lSSc?
No - occurs in about 10% of both subtypes
88
Which subtype of systemic sclerosis has a higher incidence of ILD and renal crisis?
Diffuse systemic sclerosis
89
Which autoantibody in SSc is assoc with overlap connective tissue disorder?
U1-RNP
90
Which autoantibody in SSc is assoc with PAH and portends a worse prognosis?
Th/T0
91
Which autoantibody in SSc is associated with myositis overlap syndrome?
PM-Scl
92
How is SSc diagnosed?
Raynaud's, abnormal nail capillaries + autoantibodies
Score of >9 on 2013 ACR/EULAR classification criteria
93
Which rheumatic disease has the highest mortality?
Systemic sclerosis
Cardiopulmonary causes are the leading cause of death
94
How is disease onset defined in SSc?
Onset of 1st non-Raynaud's feature
95
What is now the most important cause of mortality in SSc?
Pulmonary fibrosis
Prev renal disease but ACEi have substantially improved renal prognosis
96
What are some of the priorities of managing SSc?
Assess for organ involvement
Early treatment of organ involvement (although often symptomatic only)
Close monitoring for new organ involvement esp ILD and renal crisis in 1st five years in dSSc and PAH in both subtypes at any stage
97
Are there any disease modifying therapy in SSc?
No - however there are immunosuppressive agents, vasodilators and anti-fibrotics available
98
How does scleroderma (skin thickening) present?
Often starts as puffy fingers followed by proximal progression of skin thickening, irreversible joint contractures (+/- arthritis) leading to reduced hand function, change in appearance and consequent decreased body image/mood disturbance/social isolation/occupational impairment
99
What is first line treatment of skin involvement in SSc?
1st line = Methotrexate
Physio / OT / splinting / hand exercises
2nd line = mycophenolate, cyclophosphamide
100
How is ILD diagnosed in SSc?
Symptoms
Crackles on exam
Restrictive lung defect on spirometry
Characteristic changes on HRCT
101
What is the most common subtype of ILD in SSc?
Non-specific Interstitial Pneumonitis (NSIP) - accounts for 80%, characterised by GG changes and fine fibrosis
102
Is lung biopsy necessary in SSc-ILD?
No - rarely required to make diagnosis and has no bearing on treatment
103
What are the most characteristic findings on lung biopsy in SSc-ILD?
NSIP = homogenous diffuse involvement
UIP = patchy pattern of heterogenous involvement
104
How is SSc-ILD staged?
Based on HRCT appearance (limited, extensive, indeterminate)
If indeterminate, then based on FVC value - >70% = limited, <70% = extensive
105
What is the high-risk phenotype in terms of SSc-ILD?
Early dSSc AND anti-Scl70 OR elevated CRP
106
Who and when do you treat SSc-ILD?
If you have Progressive Pulmonary Fibrosis (PPF) which is at least 2 of:
- worsening respiratory symptoms
- physiological evidence of disease progression within 1 yr of follow up (eg decline in FVC >5% pred, decline in DLCO >10% pred)
- radiological evidence of disease progression
If nil alternative explanation for decline
107
How do you screen for SSc-ILD and how often?
All px at diagnosis should get RFTs + HRCT
Then if multiple risk factors for ILD eg dSSc - screen with RFTs every 3-4 mths for first 3-5 years
No advantage in serial HRCT scans if RFTs stable
If no decline in RFTs over first few years = better prognosis
If extensive disease on HRCT or decline in RFTs - worse prognosis
108
How do you treat SSc-ILD?
General measures eg smoking cessation, mx of GORD, vaccinations, oxygen supplementation
1st line = mycophenolate
2nd line = cyclophosphamide followed by mycophenolate or azathioprine if severe/progressive disease unresponsive to MMF
Consider anti-fibrotics e.g. Nintedanib
Other treatments:
Rituximab
Tocilizumab (may be considered in raised inflammatory markers)
Lung transplant (end-stage disease)
Autologous stem cell transplant (early disease)
109
What is Nintedanib?
A multi-tyrosine kinase inhibitor that blocks: FGF-receptor 1, VEGF receptor 2, PDGF-receptor alpha and beta52
Has antifibrotic and anti-inflammatory properties
110
What was the benefit of Nintedanib in SSc-ILD?
Reduced progression of ILD specifically decline in FVC by 44% (~41ml/year)
111
What are the PBS criteria to access Nintedanib for SSc-ILD?
Based on IN-BUILD trial incl:
PF-ILD through MDT discussion, ILD not due to IPF
HRCT >10% involvement
FVC >45%
FEV1/FVC >0.7
DLCO 30-80%
Progressive disease in last 2 years incl FVC >5% with worsening symptoms or worsening HRCT or >10% (regardless of symptoms or HRTC changes)
112
What type of pulmonary hypertension occurs in SSc?
WHO Group 1
(pre-capillary - an angioproliferative vasculopathy affecting small pulmonary arteries leading to progressive pulmonary vascular remodelling, increased pulmonary vascular resistance and right heart failure)
113
What are the 5 groups of pul,onary hypertension?
Pre-capillary:
Group 1 = PAH (arteriole level) + Pulmonary veno-occlusive disease - at venule level
Group 3 = Hypoxaemic lung disease
Group 4 = Thromboembolic disease/pulmonary artery obstruction - pulmonary artery
Post-capillary or combined pre- and post-capillary:
Group 2 = Pulmonary venous hypertension due to left HF - post-capillary
Group 5 = unclear or multifactorial mechanisms
114
What are the right heart cath characteristics of pre-capillary vs post capillary/combined pre-and post-cap PH?
All PH require mPAP >20mmHg (mean pulmonary arterial pressure)
Pre-capillary diagnosed if:
PVR >3 WU with pulmonary artery wedge pressure (PAWP) <15mmHg
whereas post-capillary/combined have raised PAWP >15mmHg
if PVR >3 = combined pre- and post
if PVR <3 = isolated post-capillary
115
Is all pulmonary hypertension in SSc due to Group 1 PAH?
No - can have group 1-4 PAH/multifactorial disease
116
How do you practically make a diagnosis of pulmonary veno-occlusive disease (other than lung transplant/autopsy)?
If mPAP high and PCWP low (suggesting isolated pre-cap PAH) AND dramatic worsening in symptoms following initiation of pulmonary vasodilator therapy
117
What is the current recommendation regarding screening for pulmonary hypertension in px with SSc?
All px should undergo annual screening
Good evidence this reduces mortality
118
How do you screen patients with SSc for PAH?
Either:
1. Transthoracic echo (based on peak TR velocity)
2. ASIG algorithm (DLCO <70% +
FVC/DLCO ratio >1.6 +and/or elevated NT-proBNP)
3. Detect algorithm (online calculator which uses multiple RFT components + clinical + serum biomarkers)
119
What is the dominant determinant (RFT component) of survival in SSc-lung disease?
A disproportionate and/or isolated reduction in gas exchange / DLCO
120
How do you treat SSc-PAH?
If isolated SSc-PAH = targeted therapy based on low/intermediate/high risk category
If combined SSc-PAH + ILD or left heart disease - consider combination therapy/clinical trials
121
What are the differences in treatment of PAH between SSc-PAH and idiopathic PAH?
Calcium channel blocker monotherapy not effective for SSc-PAH
Vasodilator challenge not performed at RHC
RCTs did include px with CTD/SSc but the effects of PAH specific tx were not as significant in these px cf iPAH
122
What are the three vasodilating pathways targeted in the PAH?
Endothelin pathway
Nitric oxide
Prostacyclin
Endothelin pathway
- increased endothelin-1 levels lead to vasoconstriction and proliferation
- can be targeted with Endothelin-1 receptor antagonists eg bosentan, ambrisentan, macitentan)
Nitric oxide pathway
- decreased nitric oxide (which normally vasodilates and has anti-proliferative properties)
- can be targeted with PDE-5i eg sildenafil OR soluble guanylate cyclase (sGC) stimulators eg riociguat)
Prostacyclin pathway
- reduced prostacyclin (which normally vasodilates and has anti-proliferative properties)
- can be targeted with prostacyclin agonists/analogues eg iloprost, epoprostenol, selexipag
123
What is a scleroderma renal crisis?
A life-threatening, hyper-reninemic, rapidly progressive renal impairment that usually occurs within 5 years of disease onset
It is characterised by:
- abrupt onset of mod-severe HTN
- normal urine sediment/mild proteinuria or casts only
- progressive renal failure
Occurs in 10-20% of px with diffuse SSc
124
What are the risk factors for Scleroderma renal crisis?
dSSc
RNA polymerase III antibodies
tendon friction rubs
125
What are some triggers for scleroderma renal crisis?
Corticosteroids
126
What are some signs of more severe scleroderma renal crisis?
MAHA
Thrombocytopenia
HF and flash APO
Blurred vision
Headache
Fever
Malaise
Encephalopathy incl seizures
Pericardial effusion
127
How do you treat scleroderma renal crisis?
Mainstay = prompt blood pressure control which improves/stabilises renal function in up to 70% and improves 1yr survival up to 80% cf progression to ESRD over 1-2 mths if not treated
1st line = ACEI eg captopril
Other antihypertensives not proven, avoid beta-blockers
Consider addition of plasma exchange (improved survival) or bosentan (improved BP and renal function) or IV nitroprusside (if CNS involvement)
128
Can blood pressure be normal in scleroderma renal crisis?
Yes - normotensive form - should treat the same with ACEi
129
What is the prognosis of scleroderma renal crisis?
Despite ACEi treatment 20-50% will progress to ESRD
Dialysis tends to be more difficult than for other forms of ESRD
Mortality still high ~35% at 12 months
Whilst renal function may improve ~25% may be dialysis dependent
Limited experience with renal transplantation in SSc - scleroderma renal crisis may recur in 5% of renal transplant px
130
What factors predict better outcome/survival in scleroderma renal crisis (SRC)?
Female gender
Higher BP at presentation (counter intuitively ?easier to diagnose)
ACEi-naive (ie nil ACEi tx prior to SRC)
No or temporary dialysis requirement (cf permanent dialysis)
131
How do you treat Raynaud's phenomenon?
Non-pharm measures:
Treat underlying cause eg cryoglobulinaemia
Cold avoidance + wear gloves/scarves/thermals etc
Stop smoking/caffeine
Moisturise hands/cuticle care
NB: need to ensure remains warm during procedures eg use bair huggers
Pharmacological tx:
1. Dihydropyriodine calcium channel blockers eg Nifedipine/amlodipine
2. ARBs, PDE5i eg sildenafil, topical or systemic nitrates, alpha blockers, SSRI, antiplatelet, statin therapy
If severe esp if critical limb ischaemia -> IV prostacyclin
132
How do you manage calcinosis (soft tissue calcium)?
If not causing problems - leave them alone
May spontaneously discharge and lead to digital ulceration - will need debridement to aid healing + dressings to soften overlying skin + aggressive and prolonged antibiotics (as secondary infection common)
May need to consider surgical debridement if above measures inadequate
133
How do you treat critical digital ischaemia?
Establish diagnosis and treat contributory cause (e.g. vasculitis, large proximal vessel disease, coagulopathy, thromboembolism, smoking)
IV prostaglandin/prostacyclin
Analgesia
Antiplatelet OR short-term anticoagulation
Consider statin + antibiotics + botox around the digital vessel/digital sympathectomy
Surgical debridement if significant necrotic tissue
134
What is the most common organ involvement after Raynaud's in SSc?
GIT
- swallowing/saliva difficulties
- GORD (90%)
- small intestine often functional/SIBO, intussception/ pneumotosis intestinalis
- faecal incontinence
135
What is the role of Autologous haemopoietic stem cell therapy (HSCT) in px with SSc?
It is an option for px with early progressive SSc at risk of organ failure specifically:
Non-smokers non-responsive to standard tx with dcSSc within first 5 yrs and mild-mod organ involvement OR lcSSc with progressive visceral organ involvement
Rationale = eradicate immune response and to create a new and non-auto reactive immune system with CD34+ stem cells
Requires extensive work-up
136
What are Idiopathic Inflammatory Myopathies?
Systemic conditions with predominant manifestations in skeletal muscle but also joints, lungs, GIT and cardiac muscle
They are characterised by proximal skeletal muscle weakness AND evidence of immune-mediated muscle inflammation or necrosis and distinct clinical, serological and histopathological features
137
What are the 4 types of idiopathic inflammatory myopathies?
1. Polymyositis incl anti-synthetase syndrome
2. Dermatomyositis incl amyopathic Dermatomyositis
3. Inclusion body myositis
4. Immune-mediated necrotising myopathy
There is also overlap myositis with SSc
138
Which subtype of Idiopathic Inflammatory Myopathy (IIM) is more common in males?
Inclusion body myositis
139
What is the most common acquired IIM in individuals over the age of 50?
Inclusion body myositis
140
How do dermatomyositis and polymyositis present?
Symmetrical proximal muscle weakness +/- myalgia/muscle tenderness
- typically deltoids, hip flexors, neck flexors
- can involve diaphragm/resp muscles leading to hypoventilation/hypercapnic resp failure
- can involve striated muscle of upper third of oesophagus/oropharynx leading to dysphagia/aspiration
In dermatomyositis - rash precedes muscle weakness in 50%
Other manifestations:
- myocarditis
- increased risk of MI
- ILD 10% of both conditions
- amyopathic DM form (no weakness)
141
What are some of the characteristic skin signs/rashes in dermatomyositis?
Heliotrope rash
Photodistributed poikiloderma - Shawl sign, V sign
Gottron's papules & Gottron's sign
Periungal erythema, ragged cuticles, nailfold capillary abnormalities
Holster sign
Photosensitivity
Facial erythema esp nasolabial fold
Panniculitis
Psorasisform changes in scalp
Calcinosis cutis (juvenile DM)
142
What are the key features of anti-synthetase syndrome?
Mechanic's hands
Constitutional symptoms
Myositis
Raynaud's
Non-erosive arthritis
ILD
Antibodies to aminoacyl-transfer ribonucleic acid (tRNA) synthetase enzymes
143
What is clinically amyotrophic dermatomyositis?
Represents 10-30% of DM
Features - classic cutaneous features of DM without muscle involvement
Increased risk of malignancy
More likely to be MDA5+ve
144
What are the features seen in px with melanoma differentiation-associated gene 5 (MDA-5) antibodies?
Can be amyopathic
Cutaneous ulcers of Gottron's papules, elbows, digital pulp, nailfolds
red painful palmar macules and papules
Alopecia
oral ulcers
arthritis
145
What is the significance of melanoma differentiation-associated gene 5 (MDA-5) antibodies?
Portends higher risk of ILD (incl rapidly progressive presentation with high mortality)
146
Which IIM is assoc with greatest malignancy risk - DM or PM?
DM - dermatomyositis
147
What are the key features of Inclusion body myositis?
Insidious onset of asymmetric, selective muscle weakness
Slower rate of progression than DM/PM however more muscle atrophy
Dysphagia
Elevated CK (,10x ULN)
Inflammatory markers are usually normal
15% have autoimmune disease
Less responsive to immunosuppressive therapy
Weakness tenders to involve quadriceps (leading to inability to lock knees/falls) + distal UL muscles (eg long finger flexor muscles)
Paraspinal muscles
148
What are the various muscle pathologies/spectrum of disease caused by statins?
1. Myalgia
2. Self-limited statin-myopathy (responds to statin withdrawal)
3. Myopathy (persists/progresses despite statin withdrawal)
4. Acute muscle rhabdomyolysis (rapid onset)
5. Trigger for Immune-mediated necrotising myopathy (linked with anti-HMGCR-antibodies)
149
Is all necrotising myopathy immune mediated?
No
Can be assoc with malignancy, active viral infection, drugs (statins), genetic myopathies (eg muscular dystrophy)
150
What are the 3 subtypes of immune-mediated necrotising myopathy?
1. Anti-signal recognition particle(anti-SRP) autoantibodies
2. Anti-HMGCR autoantibodies
3. Seronegative
151
What features may distinguish immune-mediated necrotising myopathy from other IIMs?
More rapid onset
More severe muscle involvement
Much higher CK levels
152
What are some of the key differences between the 3 subtypes of immune-mediated necrotising myopathy?
CK level and semimembranosus muscle involvement highest with HMGCR
Truncal weakness, myocarditis, ILD and extra-articular features highest with SRP
Malignancy highest with seronegative, not present in SRP
ILD + extra-articular features only present with SRP, not present with HMGCR or seronegative
153
How do you diagnose immune-mediated necrotising myopathy?
Clinical course + autoantibodies
Use online IMMM calculator - provides score which if >75 indicates high likelihood of IMMM
154
What is the pathogenesis of IIM?
Unknown
Dermatomyositis - seems to be strong involvement from B cells with antibodies targeting endothelial cells of endomysial capillaries leading to complement (MAC) activation -> results in decrease in number of capillaries/muscle fibres
Polymyositis - seems to involve CD8+ve T cells that invade MHC1-expressing myocytes; perforin pathway is major cytotoxic effector mechanism
IBM - T cell activation incl highly differentiated T cells (KLRG1 specific marker in IBM - crucial role in pathogenesis) + plasma/B cell activation + endoplasmic reticulum overload/degeneration and mitochondrial abnormalities
Immune-mediated necrotising myopathy - genetic predisposed individuals with trigger (eg statin exposure) leads to targeting of specific antigens -> muscle damage
155
What autoantibodies may be present in Inclusion body myositis?
cN1A
(Anti-cytosolic 5'-nucleotidase 1A)
156
Which subtypes of IIM are assoc with malignancy?
Dermatomyositis
Immune-mediated necrotising myopathy
157
What is the gold standard skeletal muscle pathological finding in Dermatomyositis?
Presence of myxovirus resistance protein A (MxA)
158
Elevated CK is a key finding of IIM, how can you identify if it is muscular in origin?
If troponin is negative/nil signs of myocarditis = suggests muscle origin
159
What are some of the caveats when it comes to CK testing in IIM?
Useful to monitor disease activity except in IBM
May not correlate with muscle weakness or function
Occ can be normal in active disease
CK levels can fluctuate daily + with muscle mass, gender, race, age, differences in sarcolemmal permeability to CK
160
What are some other markers of muscle damage (other than CK)?
LDH
ALT
AST
Aldolase
Myoglobin
161
What are some causes of raised CK (other than IIM)?
Endocrine - thyroid, hyperparathyroidism, acromegaly, cushing
Metabolic - hyponatraemia, hypokalaemia, hypophosphataemia
Muscle trauma - seizures, exercise,
Drugs - statins, fibrates, clozapine, ARB, colchicine, hydroxychloroquine, beta-blockers, anti-retrovirals
Pregnancy
Cardiac disease
Coeliac
MacroCK syndromes
Viral infections
Malignancy
Predisposition to malignant hyperthermia
162
What genes are associated with IIM?
HLA-DRB1*03 - IIM in caucasians
A1-B8-DR3 - linked to IBM, PM, DM
HLA-DRB1+11:01 - linked to HMGCR+ve IMNM
DRB1*08:03 + DRB1*14:03 - anti-SRP +ve IMNM in Asian populations
163
What does the presence of myositis-associated antibodies eg Ro52, PM-ScL, U1RNP, Ku often signify?
Overlap syndrome with other autoimmune connective tissue disease
164
What autoantibodies are associated with dermatomyositis?
Anti-Mi2
Anti-TIF1y
Anti-NXP2
Anti-MDA5
Anti-SAE
165
What antibodies are assoc with antisynthetase syndrome?
Jo-1
PL-7
Pl-12
RJ
OJ
KS
Hx
Zo
Collectively referred to as anti-tRNS synthetases
166
Which autoantibodies in dermatomyositis are associated with malignancy?
Anti-TIFy
Anti-NXP2
167
What other investigations are appropriate in the evaluation of patients with suspected IIM?
EMG - to distinguish myopathic weakness from neuropathic disorder
MRI lower limbs - may demonstrate areas of muscle inflammation, oedema, active myositis, fibrosis, calcification; + can be used to target muscle biopsy
Muscle biopsy - can distinguish subtype of IIM but can be normal in 12.5%
Consider organ specific evaluation
168
Which malignancies are more common in dermatomyositis?
Cervical ca
Lung ca
Ovarian ca
Pancreatic ca
Bladder ca
CRC
Stomach ca
NHL
These usually occur in the first 12mths after diagnosis of myositis
169
What are the risk factors for malignancy in patients with patients with dermatomyositis?
Older age
Dysphagia
Cutaneous necrosis on muscle damage
capillary damage or leukocytoclastic vasculitis
Anti-TIF1y
Anti-NXP2
Anti-HMGCR (in statin-naive px)
170
What autoantibodies appear protective against malignancy in IIM?
Anti-synthetase antibodies
Anti-Mi2
Anti-SRP
Anti-RNP
Anti-PM-Scl
Anti-Ku
171
What malignancies may occur in polymyositis?
Lung ca
Bladder ca
NHL
172
How do you treat IIM?
Other than inclusion body myositis, ie DM, PM, IMNM:
High dose steroids (for 1 mth/until CK normal) then taper over 1 year - most respond
Trend to using steroid-sparing agents earlier and in combination incl:
AZA, MTX, Ritux, IVIG, PLEX
Monitor CK, muscle power, resp function
173
How do you treat Inclusion Body Myositis?
Largely avoid immunosuppressive therapy as tend to be refractory
Therefore mainstay is non-pharm mx
Can trial steroids (small chance of benefit) but normally not/not hsown efficacy in most px
MTX and AZA - weak benefit
IVIG may have role in dysphagia tx
174
What treatments may be indicated in px with relapsed/refractory IMNM?
IVIG
PLEX
Rituximab
175
What are some important predictors of outcome in IIM?
Type of IIM - DM/overlap syndromes respond better to steroids than others eg IBM
Jo-1 and SRP antibodies = worse prognosis
Mi-2, overlap abs (RNP, PM-Scl, Ku) = better
More severe manifestations at diagnosis incl greater weakness
Organ involvement eg ILD, resp muscle, dysphagia, cardiac involvement, ca
176
What is Fibromyalgia characterised by?
Widespread somatic pain and tenderness + fatigue + sleep disturbance + cognitive dysfunction + mood disturbance
Often co-aggregates with IBS + chronic fatigue syndrome
177
What does SPACE + GSS stand for in the diagnosis of fibromyalgia?
Sleep disturbance
Pain + widespread muscle tenderness - mixed mechanical and inflammatory features
Anxiety/affect disturbance
Cognitive dysfunction
Energy deficiency
+
GSS - generalised sensory sensitivity
178
How do you treat fibromyalgia?
Multimodal management
- Stress management
- CBT/psychoeducation
- tailored exercise
- mind-body therapies eg tai-chi, yoga
- ?diet
- pain modulatory medication eg TCAs, SNRIs, gabapentin
(rarely - memantine, low dose naltrexone, atypical opioids)
179
What are the predictors of RA severity?
High RF titres.
Presence of anti-CCP antibody.
Erosions
ESR and CRP at presentation
Swollen joint count
High disability HAQ score
Rheumatoid nodules
HLA DR4A
180
What is IgG4-related disease (IgG4-RD)?
An immune-mediated condition assoc with fibroinflammatory lesions that can occur at nearly any anatomic site leading to organ dysfunction/failure and death
181
Which organs are most commonly involved in IgG4-RD?
Salivary glands
Pancreas
Biliary tree (eg sclerosing cholangitis)
Lungs
Kidneys
Aorta
Retroperitoneum
Meninges
Thyroid gland (Riedel's thyroiditis)
182
Do serum IgG4 levels have to be elevated in IgG4-RD?
No - substantial % are normal and it is no longer considered essential to the diagnosis of IgG4-RD
183
What are some radiographic features strongly suggestive of IgG4-RD?
Sausage shaped pancreas
Periaortitis affecting the infrarenal aorta
184
What are some of the exclusion criteria for IgG4-RD/should make you consider alternative diagnosis (eg infection, malignancy, autoimmune disease)?
Persistent fever in the absence of infection
No objective response to steroids
Specific blood abnormalities eg Leukopenia and thrombocytopenia without explanation, Peripheral eosinophilia
Autoantibodies suggestive of other autoimmune diagnoses incl
Positive ANCA
Positive SSA/Ro and La Abs
Positive dsDNA, RNP or Sm antibody
Cryoglobulinaemia
Radiologic findings suspicious for malignancy or infection
Rapid radiologic progression
Long bone abnormalities consistent with Erdheim-Chester disease
Splenomegaly
Cellular infiltrates suggestive of malignancy incl:
Prominent neutrophilic inflammation
Prominent necrosis or necrotising vasculitis
Primarily granulomatous inflammation
Pathologic features of macrophage/histiocytic disorder
Known diagnosis of:
Multicentric Castleman's disease
IBD
Hashimoto thyroiditis
185
What is the highest rated histopathology inclusion criteria for IgG4-RD?
IgG4+ to IgG ratio >71% with IgG4 cells/hpf >51 on immunostaining
Also often see dense lymphocytic infiltrate and storiform fibrosis with or without obliterative phlebitis
186
What are some other key inclusion criteria for IgG4-RD?
Elevated serum IgG4 concentration
Bilateral lacrimal, parotid, sublingual, submandibular gland involvement
Paraveretebral band-like soft tissue in the thorax
Diffuse pancreatic enlargement
Bilateral renal pelvis thickening
Circumferential thickening of abdominal aortic wall
187
How do patients with IgG4-RD often present?
With subacute development of a mass or diffuse enlargement of an affected organ
They are often well at time of diagnosis and afebrile
Lymphadenopathy is common
Weight loss may occur
Alternatively may be diagnosed incidentally based on radiological or histopathological finding
188
What conditions can IgG4-RD mimic?
Sjogren's disease
SLE
GPA
189
What type of autoimmune pancreatitis is IgG4-RD associated with?
Type 1
Accounts for ~2% of chronic pancreatitis
May present as pancreatic mass OR painless obstructive jaundice (& therefore be mistaken for pancreatic ca)
Often assoc with glucose intolerance, T2DM or exocrine pancreatic insufficiency
Most px with type 1 AIP have other IgG4-related conditions eg sclerosing cholangitis, lymphadenopathy, IgG4-related tubulointerstitial nephritis, IgG4-related salivary gland involvement
Classical radiologic appearance is diffuse enlargement of the pancreas with halo oedema, "sausage shaped" pancreas
190
How might you differentiate a patient with primary sclerosing cholangitis and IgG4-related sclerosing cholangitis?
Similar presentations
IgG4-RD may be asymptomatic at diagnosis
Presence of extrabiliary manifestations eg pancreatic disease nearly diagnostic of IgG4-RD
191
How might salivary glands appear differently on imaging in IgG4-RD cf Sjogren's disease?
Enlarged in IgG4-RD
Diffuse inhomogeneity with anechoic/hypoechoic areas in Sjogren's
192
What percentage of cases of retroperitoneal fibrosis are due to IgG4-RD?
30-60%
193
What is Riedel's thyroiditis?
IgG4-RD of the thyroid gland
Rare form of thyroiditis that presents as hard goitre
Can have symptoms of pressure eg dyspnoea, dysphagia, hoarseness
Cytology not always diagnostic so usually diagnosis made after thyroid resection
194
What is the most common renal manifestation of IgG4-RD/
Tubulointerstitial nephritis
Presents with AKI/chronic kidney injury +/- mass lesions (potentially mimicking RCC)
195
When should you suspect IgG4-RD?
In patients with:
- pancreatitis of unknown origin
- sclerosing cholangitis
- bilateral salivary and/or lacrimal gland enlargement
- retroperitoneal fibrosis
- orbital pseudtumour or proptosis
- unexplained mass lesion in organs
- IgG4 serum concentration >5x ULN
Combination of biliary tract and pancreatic disease or bilateral submandibular gland disease nearly diagnostic
196
Is a high serum IgG4 level diagnostic of IgG4-RD?
No - can be seen in other conditions
Also normal IgG4 levels do not exclude diagnosis (normal in 30%)
197
What blood tests should you order in patient with suspected IgG4-RD?
Total IgG
IgG subclasses
IgE
C3/C4
SPEP
- often patients with IgG4-RD have elevated IgG4, IgG1, IgE, polyclonal hypergammaglobulinaemia with beta-gamma bridging, hypocomplementemia
198
Which of the following biopsies sites are most sensitive and specific for a diagnosis of IgG4-RD:
A) Lip
B) Submandibular gland
C) Lymph node
D) GIT
B - others all non-specific or insensitive
199
How do you diagnose IgG4-RD?
Clinical or radiologic evidence of tumour like swelling in involved organ
AND
Biopsy of involved organ demonstrating lymphoplasmacytic infiltrate enriched in IgG4+ cells, storiform fibrosis or obilterative phlebitis
Note ACR/EULAR classification has above + absence of exclusion criteria + score >20
200
What is the gold standard for distinguishing autoimmune pancreatitis from pancreatic cancer?
Biopsy
201
What 3 ways may you differentiate primary sclerosing cholangitis from IgG4-related sclerosing cholangitis?
IgG4-related sclerosing cholangitis more likely if:
- Simultaneous biliary and pancreatic disease
- elevated serum IgG4 >5x ULN
- improvement with glucocorticoid trial
202
What features may suggest cholangiocarcinoma rather than IgG4-related sclerosing cholangitis?
Obstructive jaundice
Enlarged pancreas
Lymphadenopathy
High serum bilirubin
High serum Ca 19-9
Complete obstruction of the hilar bile ducts on ERCP
203
Why is early recognition and treatment of IgG4-RD important?
Because of the risk of progression from a typically treatment-responsive proliferative and inflammatory stage to a poorly responsive fibrotic disease and serious organ damage stage
204
How do you typically treat IgG4-RD?
Induction therapy with glucocorticoids +/- Rituximab (consider combo therapy if multiorgan involvement)
Maintenance therapy - unclear, certain patients may benefit - often use Rituximab or glucocorticoid sparing regime eg MMF, leflunomide
Consider stenting or surgical procedures to relieve mechanical obstruction
205
What is the indication for treatment in IgG4-RD?
Symptomatic, active IgG4-RD
Subset of asymptomatic px should be treated ie those with radiologic or laboratory findings of disease progression in vital organs eg aortitis/retroperitoneal fibrosis
206
What are the risk factors for relapse in IgG4-RD?
Elevated levels of serum IgG4, IgE and eosinophils at baseline
207
Is IgG4-RD associated with an increased risk of malignancy?
Controversial
208
What is Behcet's syndrome?
A chronic, multisystem, inflammatory condition with a relapsing and remitting course - currently classified as a primary systemic vasculitis affecting veins and arteries of any size
209
What patient population doe Behcet's syndrome most commonly affect?
Young people between 15-45 yrs
Equal males:females (although males often have more severe disease)
Geographic variation - highest in Turkey / old silk road
210
What is the pathogenesis of Behcet's syndrome?
Poorly understood
Thought to develop in genetically predisposed hosts after exposure to a wide range of environmental triggers (eg infection, histamine releasing foods, poor oral hygiene, stress)
211
Are there any recognised genetic associations with Behcet syndrome?
HLA-B*51:01 - 6x more likely
212
What is the main infiltrating cell type in Behcet's syndrome lesions?
Neutrophils
213
What is the hallmark/most common clinical manifestation of Behcet syndrome?
Recurrent oral ulceration
Followed by (scarring) genital ulcers, papulopustular lesions and nodular skin lesions
These can be difficult to distinguish from recurrent apthous ulcers or acne
214
What are the typical joint manifestations in Behcet syndrome?
Non-deforming, self-limited monoarthralgia or oligoarthralgia/arthritis affecting the knees, ankles, wrists and elbows
215
What is the most frequently affected major organ in Behcet syndrome and what is the most common manifestation?
Eye - 50%
Panuveitis
216
What factors are associated with a poor visual outcome in Behcet syndrome?
Male sex
Posterior eye chamber involvement
Hx of 3+ attacks per year
Presence of vitreous opacity with macular oedema
217
What is the 5 year cumulative risk of recurrent vascular events in Behcet syndrome and what are the most common manifestations?
40%
Supericial and deep vein thrombosis incl lower limbs, portal/suprahepaptic veins, cerebral sinus venous thrombosis
Arterial aneurysms and thrombotic occlusion of aorta or peripheral arteries may occur
218
What is the most common non-parenchymal neurological manifestation of Behcet syndrome?
Cerebral vein thrombosis
219
What characterises parenchymal neurologic Bechet syndrome?
Involvement of the brain stem (scattered inflammatory lesions with oedema) causing headaches, hemiparesis, seizures and occasional myelitis or pseudotumour cerebri
220
How do you diagnose Behcet syndrome?
Largely clinical presentation and imaging findings - no pathognomonic biologic or histologic diagnostic features and HLA-B51 carriage not helpful (variable in behcet and occurs commonly in gen pop)
221
What prognostic factors are assoc with increased risk of death in Behcet syndrome?
Male sex
Arterial involvement
High frequency of flares
222
What is the risk of visual loss in Behcet syndrome with contemporary therapy?
13%
223
How do you treat Behcet syndrome?
Individualised multidisciplinary treatment given heterogenous clinical manifestations
Main goals are to:
- reduce number/duration/freq of mucocutaneous lesions
- reduce joint pain/swelling
- control ocular inflammation and retain vision
- control vascular inflammation and prevent new vascular lesions
- control neurologic inflammation and prevent new CNS lesions
224
What is the first line systemic therapy for cutaneous, mucosal and articular manifestations of Behcet syndrome?
Colchicine
225
What treatments may be useful for refractory oral ulcers in patients with Behcet syndrome?
Apremilast - PDE4i
Ustekinumab - IL12/23i
- AZA
- IFN-alpha
- thalidomide
- etanercept
226
What is the mainstay of treatment for ocular Behcet syndrome?
Glucocorticoids and systemic immunosuppressants incl consideration of infliximab or IFN-alpha
TNFi reshaping approach to tx by reducing risk of blindness
227
How do you treat DVT in Behcet syndrome?
Immunosuppressants - steroids +/- cyclophosphamide, AZA, TNFi
Anticoagulant controversial
228
How do you treat neurological manifestations of Behcet syndrome?
High dose steroids + cyclophosphamide (or AZA)
229
What is the most prominent behavioural risk factor for the development of RA?
Smoking
230
What are other less important risk factors for the development of RA (besides smoking)?
Obesity
Low vit D levels
Use of OCPs
231
Which factors decrease the risk of RA development?
Mediterranean diet
n-3 fatty acid intake
Fish oil supplementation
Alcohol consumption
232
Which HLA gene is the most established genetic susceptibility/risk factor for RA development?
HLA-DRB1 (*04:01 and *04:04 in particular)
233
Outside of the HLA-DR haplotype, which other genes are implicated in the development of RA?
PTPN22 (*R620W)
PADI-4
CTLA-4
STAT4
TRAF1-C5
OLIG3
Chromosome 6q23
234
Which HLA allele may be protective against RA?
HLA-DRB1*13:01
235
What is the strongest known predictor of later radiographic damage in patients with RA?
Presence of ACPA at disease onset
236
What percentage of overall genetic risk to the development of RA is attributable to HLA genes?
Less than 50%
237
When do you start treatment with DMARDs in a patient with RA?
As soon as they are diagnosed
Rationale - much of the joint damage that results in disability begins early in the course of the disease
Data supports early rather than delayed intervention
238
What is the general goal of RA therapy?
Achieve remission or minimal disease activity without compromising safety
Treat-to-target strategy
239
What additional assessment is required in patients commenced on hydroxychloroquine therapy?
Opthalmoologic examination
Why? Risk of toxic retinopathy causing permanent visual loss
240
What are the risk factors for toxic retinopathy due to hydroxychloroquine?
Daily HCQ use >5mg/kg
Use >5 years
Kidney disease
Concomitant tamoxifen use
Presence of macular disease
241
What should you do if a patient on long-term antimalarials reports visual loss?
Discontinue immediately and obtain opthal review
242
What is the general approach to pharmacological therapy in RA?
Generally start with anti-inflammatory therapy with either NSAID or glucocorticoid (depending on disease activity) + anchor DMARD drug = methotrexate (which will take a few weeks to months to achieve optimal effects)
If unable to take MTx - consider HCQ, SSZ, leflunomide
If resistant to initial MTx therapy - trial combo DMARD therapy eg MTx + SSZ and HCQ OR MTX + TNFi
If resistant to combination therapy - switch therapy to alternative biologic or targeted synthetic DMARD eg
- TNFi - infliximab, certolizumab, adalimumab, golimumab, etanercept
- IL-6 - tocilizumab, sarilumab
- CTLA4-Ig - abatacept
- JAKi - tofacitinib, baricitinib, upadacitinib
- anti-CD20 B cell depleting tx - Rituximab
Use NSAIDs/steroids as adjuncts for temporary control of disease activity eg when starting or switching DMARDs or in px experiencing disease flares
243
What are the key side effects/monitoring required for NSAIDs?
Check GI symptoms eg dyspepsia, N&V, abdo pain
Check renal function
Check blood pressure + peripheral oedema
Check Hb/bleeding
244
What are the key side effects/monitoring required on glucocorticoid therapy?
Mood
Weight gain
Visual changes/cataracts
Insulin resistance/polyuria/polydipsia
Infection
Hypertension
Dyslipidaemia
Osteoporosis
245
What are the key side effects/monitoring required for hydroxycholorquine therapy?
Assess for visual change/opthal review for retinal toxicity
Assess for skin colour change
Assess for neurological changes eg paraesthesiaes
246
What are the key side effects/monitoring required for Sulfasalazine therapy?
Headache
N&V
Photosensitivity/rash
Myleosuppression/infection
247
What are the key side effects/monitoring required for MTx therapy?
Stomatitis
Alopecia
GI intolerance eg N&V, diarrhoea
Flu-like symptoms
ILD eg dyspnoea
Hepatotoxicity
Infection
Lymphadenopathy
Contraindicated in pregnancy
248
What are the key side effects/monitoring required for leflunomide therapy?
GI intolerance eg N&V
Dyspnoea
Paraesthesiaes
Hepatotoxicity
Weight loss
Hypertension
Contraindicated in pregnancy
249
What are the key side effects/monitoring required for AZA therapy?
GI intolerance eg N&V, diarrhoea
Myelosuppression
Infection
250
What are the key side effects/monitoring required for TNFi therapy?
Infection
Malignancy
heart failure
Autoimmune disease
Demyelination
251
What are the key side effects/monitoring required for IL-6i therapy?
Infection
Myelosuppression
Demyelination
Hepatotoxicity
GI perforations
252
What are the key side effects/monitoring required for Rituximab therapy?
Infection
Neutropenia - prolonged
Progressive Multifocal Leukoencephalopathy (due to JCV reactivation)
253
What are the key side effects/monitoring required for Abatacept therapy?
Infection
COPD exac
Malignancy
254
What are the key side effects/monitoring required for JAKi therapy?
Infection
Herpes zoster
Myelosuppression
Hepatotoxicity
Malignancy
GI perforation
255
How might you treat a disease flare in RA?
If only a single or few joints involved - consider intra-articular steroid injection
If widespread joint involvement - consider short-term systemic glucocorticoids
Consider escalating dose or switching therapy if frequently or severely flaring
256
Which dose escalations of bDMARD therapy have not been shown to be effective?
Increasing dose of etanercept (>50mg/wk)
Increasing frequency of adalimumab (ie weekly rather than 2 weekly)
Increasing dose of Infliximab from 3 to 5mg/kg (however decreasing interval between doses may be effective)
257
How do you approach a patient with natural immunity to HBV (ie HBc+, HBs+, HBsAg-, normal LFTs) given DMARD therapy for RA (excluding Rituximab) -
same as HBV-unexposed individuals - check viral loads every 6-12 mths to ensure no reactivation
If above + given Rituximab - give antiviral therapy for at least 12 months after Rituximab therapy
If active HBV - refer for tx before commencing immunosuppressive therapy
258
What do you do with a patient with RA diagnosed with latent TB whom you wish to prescribe bDMARD or tsDMARD therapy to?
Need at least one month of TB therapy before starting immunosuppressive therapy OR if unable to complete anti-TB therapy, use conventional synthetic DMARDs only
If persistent disease activity despite this, consider TNFi (above other bDMARDs)
259
If an RA patient has hx of NMSC (eg BCC, SCC), which DMARDs are preferred?
Conventional DMARDs over bDMARDs/tsDMARDs
No contraindication tho but monitor closely if escalate therapy
260
If a RA patient has hx of melanoma, which DMARDs should be preferred or avoided?
Prefer conventional DMARDs over bDMARDs/tsDMARDs
Avoid abatacept
261
If RA patient has a hx of lymphoproliferative disorder, what DMARDs are preferred?
Conventional DMARDs
If bDMARDs required, prefer Rituximab
262
If RA px has treated solid organ malignancy within the last 5years what DMARD therapy is preferred?
Conventional DMARDs
If biologic required, Rituximab would be first preference
263
If RA px has treated solid organ malignancy beyond 5years what DMARD therapy is preferred?
None - RA tx no different than in those without hx of malignancy
264
In a RA patient with comorbid interstitial lung disease OR COPD, which drugs would you avoid?
Methotrexate (if clinically significant or progressive RA-ILD)
Consider avoiding abatacept in COPD due to risk of COPDx
265
Which of the DMARDs have potential for causing adverse pulmonary effects?
MTx
SSZ
Leflunomide
TNFi
Abatacept
Rituximab
266
Which DMARDs should be avoided in px with moderate to severe HF?
TNFi
Also try to limit:
NSAIDs
Glucocorticoids
267
Which DMARDs should be avoided in a patient with hx of demyelinating disorder (eg MS) or even fhx of MS?
TNFi
268
Which DMARDs may actually lower risk of diabetes in RA or have glucose-lowering effects?
HCQ
SSZ
TNFi
269
Which RA therapies should be avoided in px with renal disease?
NSAIDs
MTx
Cyclosporine
270
Which RA therapies should be avoided or used with caution in px with a hx of diverticulitis or GI perforation?
IL-6i
271
Which DMARDs are viewed as relatively safe to use in pregnancy?
Hydroxychloroquine
Sulfasalazine
Low dose aspirin
Azathioprine and 6-mercaptopurine
Colchicine
272
Which DMARDs may be used selectively during pregnancy (based on individual risk:benefit calculation)?
NSAIDs - up to 20weeks - premature closure of ductus arteriosus, oligohydramnios
Glucocorticoids - shortest course possible - risk of cleft palate, PROM< IUGR + pregnancy HTN/GDM
TNFi - Certolizumab preferred (as may not cross placenta); some suggest stopping before 3rd tri
273
Which biologics / DMARDs are assoc with moderate-to-high risk of foetal harm if used in pregnancy?
Cyclophosphamide - esp T1 - exopthalmos, cleft palate, skeletal abnormalities, growth retardation
Methotrexate - teratogenic (cleft palate, hydrocephalus, anencephaly, meningoencephalocele, abnormal facial features, skeletal abnormalities) and abortifacient
Mycophenolate - pregnancy loss, congenital malformations (cleft lip/palate, limb deformity, heart, oesophagus and kidney deformity)
Leflunomide - teratogenic, no particular pattern
Other bDMARDs and tsDMARDs - limited data/unknown risk
274
What is the treatment approach in a patient with Psoriatic arthritis with predominantly axial disease?
Mild symptoms - NSAIDs
Mod-severe - TNFi (mainstay) or IL17i or JAKi
(note conventional DMARDS not been shown to be effective for axial spondyloarthropathies)
275
How might you choose between TNFi, IL-17o and JAKi for axial disease in psoriatic arthritis?
Depends on associated conditions
TNFi tends to be used first line
Then if disease resistant to TNFi consider:
Alternative TNFi
OR
If psoriasis severe - IL-17 more effective
OR
If IBD or iritis present - JAKi
276
What are some examples of IL-17 inhibitors
Secuinumab
Ixekizumab
Bimekizumab
277
How do you treat enthesitis in psoriatic arthritis?
Physio
Local steroid injections (except achilles tendon due to assoc achilles rupture)
NSAIDs
If above ineffective:
TNFi, IL-17 or JAKi, can consider MTx
278
How do you treat dactylitis in PsA?
Usually parallels disease activity in other domains hence tx of other domains should work
If isolated dactylitis
- mild - NSAIDs or MTx
- mod/severe - TNFi, IL-17i, JAKi, steroid inj
279
Why do you generally avoid oral steroids in psoriatic arthritis?
Risk of psoriatic flare
280
How do you define mod-severe peripheral PsA?
Px with highly active disease (eg multiple joints involved, erosive disease at presentation, functional limitation) OR those with mild disease who fail to improve after 3mths of appropriate tx
281
What is the preferred treatment approach for peripheral PsA?
Minimal disease - NSAIDs
Mild disease - apremilast OR MTx
Mod-severe disease - TNFi
282
Which domains of PsA does TNFi improve?
Peripheral arthritis
Axial arthritis
Enthesitis
Dacytlitis
Skin disease
Also reduce radiographic progression
283
Is MTx effective for peripheral PsA?
It is recommended as first line therapy in mild disease and is effective for skin disease but most studies have not shown significant benefit and its benefit in inhibiting radiographic progression is debateable alongside its known risks (incl risk of hepatic fibrosis in px with obesity/DM)
284
What is different about commencing TNFi in PsA cf RA?
In RA, add TNFi and continue MTx
In PsA, add TNFi and then can generally discontinue MTx in px who respond to TNFi therapy
EXCEPT for infliximab and adalimumab due to risk of forming antidrug antibodies (may continue Mtx to try to reduce this risk)
285
What do you do if a patient with PsA who fail TNFi therapy?
Primary non-response OR experience adverse effect - switch to IL-17i
Secondary non-response (i.e initially responded then lost efficacy) - trial alternative TNFi (usually etanercept if used one of the others and vice versa)
286
Why might a patient fail TNFi and IL-17i therapy for PsA?
Incorrect diagnosis
Non-adherence to treatment
Concomitant fibromyalgia or central sensitisation
287
What is the preferred agent for patients with concomitant peripheral and axial PsA who have failed TNFi therapy?
JAK/STATi eg Tofacitinib or upadacitinib
288
What is the preferred agent for patients with peripheral without axial PsA who have failed TNFi therapy?
IL-23i OR abatacept (CTLA4-Ig)
- IL-23i = guselkumab, risankizumab
289
What is Abatacept?
A selective T-cell costimulation modulator
290
How do you treat Axial spondyloarthritis (eg ank spond and non-radiographic axial spondyloarthritis)?
Non-pharm measures
Mild - NSAIDs
Inadequate response to NSAIDs/Mod-severe - TNFI or IL-17
3rd line = JAKi
291
When would you use a conventional DMARD in axial spondyloarthritis?
If predominantly peripheral arthritis, would trial sulfasalazine prior to TNFi
However, unlike in RA, no benefit to using conventional DMARDs with TNFi etc
292
What are the contraindications to TNFi therapy?
Active infection
Latent (untreated) TB
Demyelinating disease (eg MS, optic neuritis)
Mod-severe HF
293
TNFi induce a rapid and durable clinical response in the majority of px with axial spondyloarthritis; which factors are assoc with highest chance of good response?
Shorter duration of disease
Elevated CRP
Younger age
294
What are the main differences in efficacy (in terms of disease domains) between TNFi and IL-17i?
IL-17i (cf TNFi)
- more effective in controlling psoriasis
- as effective in controlling arthritis
- not effective for anterior uveitis
- ineffective/harmful in IBD
295
What are the key contraindications to JAKi therapy?
Active infection
Age >50
Increased CVD risk
Increased thrombotic risk
Increased malignancy risk
Pregnancy
296
297
Which two signalling pathways do JAK inhibitors not affect?
IL-1
TNF
298
What are JAK inhibitors and how do they work?
Small, orally active drugs categorised as targeted synthetic DMARDs (tsDMARDs) that bind to JAK proteins INSIDE cells preventing the JAKs from transphosphorylating the associated cytokine and growth factor receptor. This means the cytokine or growth factor receptor fails to activate the dedicated pair of signal transducer and activators of transcription (STATs) family members (hence why sometimes known as JAK/STAT inhibitors which suppresses various cytokines or growth factors
299
What do the 4 main JAKi isoforms do?
JAK1 - important for signalling of interleukin (IL) 6, IL-10, IL-11, IL-19, IL-20, IL-22, and interferon (IFN) alpha, IFN-beta, and IFN-gamma
JAK2 - important for signalling of EPO, TPO, GM-CSF, IL-3 and IL-5
JAK3 - expressed on haematopoietic cells and is important for signalling IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 thus regulating lymphocyte activation, function, and proliferation.
TYK2 - IL-12, IL-23, and type 1 IFNs.
