Autoimmune diseases Flashcards
(398 cards)
1
Q
name 2 blistering diseases
A
pemphigus
pemphigoid
2
Q
name 2 CT diseases
A
Sjogrens Syndrome
SLE
3
Q
name 2 vasculitis
A
erythema multiforme
Behcets disease
4
Q
give 4 causes of blistering diseases
A
trauma extreme temp chemical exposure medical conditions -infective -genetic -autoimmune
5
Q
definition of AMBDs
A
Ig-mediated diseases with autoantibodies against desmosomal or basement membrane zone molecules
6
Q
what is the classification of pemphigus based on?
A
different clinical and histopathological features
7
Q
give the 5 broad types of pemphigus
A
pemphigus vulgaris pemphigus foliaceus drug-induced pemphigus paraneoplastic pemphigus IgA pemphigus
8
Q
which is the most common type of pemphigus and the one that gives oral lesions?
A
pemphigus vulgaris
9
Q
give a subtype of pemphigus vulgaris
A
pemphigus vegetans
10
Q
give 2 subtypes of pemphigus foliaceus
A
pemphigus erythematosus - localised
fogo selvagem - endemic
11
Q
pathogenesis of pemphigus
A
autoantibodies against proteins that constitute desmosomes
intraepithelial blister and acantholysis
autoantibodies deposited in epithelium - complement activated and plasmin
12
Q
2 types of intraepithelial blister in pemphigus
A
supra basal (lower) sub corneal (higher)
13
Q
what is acantholysis?
A
when desmosomes separate
14
Q
why are there different types of pemphigus?
A
because desmosomes are complex - attack against a specific desmosome protein gives you a specific type of pemphigus
not just a single attack on a single protein
15
Q
anti-Dsg3 IgG
A
autoantibodies against Dsg3 attack desmosomes
16
Q
how many self-antigens are recognised by IgGs in patients with PV and/or PF?
A
more than 50
17
Q
what does the severity and exact clinical picture of pemphigus depend on?
A
ratio of different kinds of autoantibodies in each particular pt
18
Q
what type of surface does pemphigus affect?
A
any stratified squamous epithelium
19
Q
pemphigus epidemiology
A
uneven geographic and ethnic distribution
high incidence in Ashkenazi jews and those of mediterranean origin
20
Q
what age group does pemphigus usually affect?
A
40-60 years
21
Q
gender distribution of pemphigus
A
M=F
22
Q
where does the mucosal phenotype of pemphigus typically begin and progress to?
A
usually begins oral cavity
can spread to skin - face, back, chest, genitals
23
Q
pemphigus features in the oral cavity
A
desquamative gingivitis
soreness, blistering, erosions
can be covered by yellow fibrinous slough
rare to see intact blisters in oral cavity (trauma) - see erosions
lesions can be painful to brush, but plaque irritates lesions
can easily peel off - leaves haemorrhagic erosion underneath
24
Q
which sites in the oral cavity are most affected by pemphigus?
A
buccal mucosa
tongue
25
pemphigus - what is spongiosis?
blister about to form
| cells in epithelium full of fluid
26
does the mucosal phenotype of pemphigus affect just the skin?
rarely
27
pemphigus prognosis
untreated often fatal due to dehydration/infection
28
pemphigus prognosis mucosal lesions
may persist even though skin lesions are controlled
| topical CS/tacrolimus may then help
29
BM zone
hemidesmosomes
lamina lucida
lamina densa - sub epithelial split
sublamina densa
30
pathogenesis of pemphigoid
autoantibodies against hemidesmosomes deposited in epithelium
complement activated, leukocytes recruited - damage to BM
sub epithelial blister or sub-lamina densa (deeper) split
31
what age group is pemphigoid most common in?
>75s
32
is pemphigoid common?
no
33
gender distribution of pemphigoid
F>M
34
epidemiology of MM pemphigoid
extremely rare
| prevalence 25 per million
35
clinical presentation of MM pemphigoid
mostly affects mucosae - conjunctiva, nasal, oral, genital
| occasionally skin
36
why do blisters in pemphigoid persist longer?
blister has thicker roof and is more attached to the floor of blister
37
which areas of the oral cavity are often affected by MM pemphigoid?
interface of hard and soft palate soft palate
uvula
gingivae
38
pemphigoid prognosis without treatment?
may persist with periods of remission and flare ups for many years
39
pemphigoid prognosis with treatment?
immune response and inflammation can be suppressed
40
is pemphigoid fatal?
no
41
what is Nikolsky's sign?
induce an erosion by rubbing on the skin
42
2 types of Nikolsky sign sites?
marginal - next to blister
| direct - perform on healthy skin
43
Nikolsky's sign in oral cavity
PD probe/spatula under roof - can extend and peel roof off v easily
44
positive Nikolsky sign
indicator you might be dealing with blistering diseases
45
sensitivity and specificity of Nikolsky sign
poor sensitivity - means you miss a lot of cases
| good specificity - pts with no disease test negative
46
aim of biopsy of suspected AMBDs and why is this difficult?
aim for intact blister to send to pathologist so they can determine whether intra or sub epithelial
difficult as tissues fragile
47
biopsy procedure for suspected AMBDs
2 parallel incisions
| hold blister with tweezers and cut underneath
48
why is biopsy of suspected AMBDs easier on attached gingiva?
there is bone underneath
49
what is needed in addition to biopsy/Nikolsky sign to confirm diagnosis of AMBDs?
autoimmmune diagnosis
50
What is direct immunofluorescence done on?
specimen - pts perilesional oral mucosa
- you send some for H and E and some for DIF
added primary antibody labelled with a fluorescent probe - intercellular epithelial staining
51
aim of DIF
to detect tissue bound immunodeposits
- inside epithelium if pemphigus vulgaris
- along BM zone if pemphigoid
52
what is indirect immunofluorescence done on?
pts sera - take blood
53
aim of IIF?
to detect circulating IgG antibodies in bloodstream - identify immunologic signal
54
procedure of IIF
on specific substrate
| added a secondary antibody labelled with fluorochrome to recognise a primary antibody from patients serum
55
substrates used in IIF
monkey oesophagus, normal skin or rat uroepithelium
56
diagnosis of pemphigus - DIF
fishnet like pattern
presence of IgG and/or C3 as well as IgA deposition within the intercellular spaces throughout the epithelium
may also get IgM or IgA (in the IgA variant get this expression)
57
diagnosis of pemphigus - IIF
high % will be positive
| IgG, C3, IgM, IgA
58
histopathology of pemphigus
intraepithelial blisters
59
if DIF in pemphigus shows intercellular epithelial staining and IgA, what is the diagnosis?
IgA pemphigus
60
if DIF in pemphigus shows intercellular epithelial staining and DSG1?
PF
61
if DIF in pemphigus shows intercellular epithelial staining and DSG-3?
OPV
62
if DIF in pemphigus shows intercellular epithelial staining and DSG-1 and 3?
MCPV
63
if DIF in pemphigus shows intercellular epithelial staining and desmocollins 1-3?
PNP/PAMS
64
diagnosis of pemphigoid - DIF
linear pattern at BM zone - u or n serrated
| IgG and/or C3 as well as IgA deposition along the BM zone
65
DIF in pemphigoid - u serrated
EBA
| bullous lupus
66
DIF in pemphigoid - n serrated
bullies pemphigoid
MM pemphigoid
P200 pemphigoid
67
pemphigoid - IIF salt split
mucosal sample incubated at 4 degrees in 5cc NaCl for 24-48hrs
NaCl acts like scissors at lamina lucida - get roof and floor
68
pemphigoid IIF - floor blister (dermal)
bullous lupus
deeper MM pemphigoid
epidermolysis bullosa
69
pemphigoid IIF - mixed floor and roof blister
MM pemphigoid - autoantibody attack between lamina lucida and lamina dura (middle of BP180)
70
pemphigoid IIF - roof blister (epidermal)
bullous pemphigoid
MM pemphigoid
LP pemphigoid
71
pemphigoid histopathology
sub epithelial blister
72
pemphigoid - if DIF shows IgA pattern at BM zone
linear - LAD
| granular - DH
73
what is ELISA?
enzyme-linked immunosorbent assay
| detects anti-Dsg antibodies
74
advantages of ELISA
quantitative method for measuring specific circulating antibody levels
plates read automatically and results do not depend on observer
75
disadvantages of ELISA
may not detect all subtypes of autoantibodies involved in the pathogenesis of AMBDs
e.g. negative result for anti-Dsg1 and 3 does not rule out possibility of other auto antigens in different subtypes of pemphigus
76
how should ELISA be used?
as a complementary test to IIF and not as a substitute
77
ELISA process
plates precoated with recombinant antigen (Dsg1, 3, BP230, BP180)
add pt sera (containing antibodies)
antigen-antibody complex formed
add enzyme (HRPO) conjugated anti-antibody
antigen-antibody-antiantibody complex formed
add substrate (TMB) to enzyme
substrate converted by enzyme to detectable coloured product
78
why is early diagnosis of AMBDs important?
may not be AMBDs
- mucocutaneous side effect of meds e.g. sunitinib for breast cancer
- secondary syphilis
prevent mucosal spread
-nasal, anogenital, ocular, voice box, oesophagus (dysphagia)
prevent mucocutaneous spread
mucosal scarring phenotype of MMP
79
which AMBD can cause scarring and why?
pemphigoid
| subepithelial so BM zone affected - get scar tissue
80
does pemphigus cause scarring?
no as intraepithelial
81
consequences of mucosal scarring phenotype of MMP
oesophageal stricture if scarring
eye scarring - if reaches corneal limbus (contains corneal SCs) pt will develop blindness. opacification of iris and pupil, inflammation of conjunctiva
82
what type of syndrome is Paraneoplastic Autoimmune Multiorgan Syndrome?
mucocutaneous
83
what is PAMS?
```
a distinct clinical entity characterised by heterogeneous group of S+S including
-severe desquamative stomatitis
-a polymorphous cutaneous eruption
-ofren a progressive respiratory failure
develop due to an underlying malignancy
```
84
when may PAMS occur?
well before the discovery of occult malignancy or lymphoproliferative disorder
need extended clinical follow-up
85
haematological malignancies that can cause PAMS
NHL
chronic lymphocytic leukaemia
Castleman disease
86
non-haematological malignancies that can cause PAMS
carcinomas
sarcomas
malignant melanoma
87
pathogenesis of PAMS
cancer cells activate a wide number of immune cells
| activated auto reactive T cells induce both humeral and cell-mediated immunity
88
PAMS - how do humoral and cell-mediated immunity cause its features?
humoral immunity (mostly autoantibodies) - acantholysis (resembles pemphigus)
cell-mediated immunity - lichenoid dermatitis (resembles lichenoid)
both - bronchiolitis obliterates (life-threatening)
get these features based on % of 2 types of immunity
89
what is the major antigenic target in PAMS?
plakins
| - desmoplakin 1 and 2, envoplakin, periplakin, pectin, BP230
90
how many clinical phenotypes of PAMS
may have at least 5 - both humoral and cytotoxic immunities involved in development of PAMS
91
give some clinical phenotypes of PAMS
autoantibody mediated cytotoxicity
```
pemphigus like (aka PNP)
bullous pemphigoid like
EM like
GvHD like
LP like
```
cell-mediated cytotoxicity
92
clinical features of PAMS
ocular - inflammation of conjunctiva, ectropion (eyelid turns outward)
lip lesions
oral lesions
93
is there a diagnostic criteria for PAMS?
no generally accepted diagnostic criteria
94
Components of the suggested diagnostic criteria for PAMS
```
clinical signs
histopathology
DIF
IIF
detection of circulating autoantibodies against
detection of a neoplasm
```
95
suggested diagnostic criteria for PAMS - clinical signs
severe stomatitis - MANDATORY
blisters
LP like plaques
bronchiolitis obliterans
96
suggested diagnostic criteria for PAMS - histopathology
supra basal blistering, acantholysis, lichenoid interface dermatitis with keratinocyte necrosis
97
suggested diagnostic criteria for PAMS - DIF
IgG intercellular in epithelium / and IgG/C3 at BM zone
98
suggested diagnostic criteria for PAMS - IIF
IgG intercellular in epithelium
99
suggested diagnostic criteria for PAMS - detection of circulating autoantibodies against
envoplakin or periplakin - MANDATORY
Dsg 1, 3
desmoplakin 1+2, plectin, BP230, 170-KDa protein
100
suggested diagnostic criteria for PAMS - detection of a neoplasm
MANDATORY
101
mandatory components of suggested diagnostic criteria for PAMS
severe stomatitis
detection of circulating autoantibodies against envoplakin or periplakin
detection of a neoplasm
102
suggested diagnostic criteria for PAMS - if specific detection of antibodies against envoplakin or periplakin is not available what do you use as mandatory criterion?
DIF or IIF - needs to be positive
103
why is PAMS usually non-responsive to immunosuppressive therapies?
related to an underlying neoplasm
104
treatment of PAMS
treat underlying malignancy
| not always sufficient
105
why is early diagnosis of PAMS essential?
early diagnosis and treatment of underlying malignancy - more favourable prognosis
106
coordinated MDT in AMBDs
```
oral med
dermatology
ENT
ophthalmology
gynecology
gastroenterology
infectivology
endocrinology
urology
psychiatry
```
107
what should you do before making a treatment plan for AMBDs?
determine the extent of disease
108
determining the extent of disease in AMBDs
```
routine lab work
screening for infections
tumour markers and instrumental exams - EKG, CT, DEXA
medical consults
additional exams for biologic therapies
```
109
why do you need to screen for infections before treating AMBDs?
don't want to reactivate any silent infections as you will be using immunosuppressive meds
110
why do you need to carry out instrumental exams and tumour markers before treating AMBDs?
ensure no underlying malignancy
111
what do you need to screen for before using biologic therapies to treat AMBDs?
thrombophilia
112
conventional therapy in PV
attack phase - CSs immunosuppressive
+/- adjuvant CS sparing agents
CHX 0.12% alcohol free rinse
topical and/or systemic anti-mycotic agents if you see candidiasis overgrowth
113
PV - first line attack phase of treatment
corticosteroids: prednisolone 1-2.5mg/kg
114
PV - adjuvant corticosteroid sparing agents
```
azathioprine
mycophenolic acid
cyclophosphamide
methotrexate
cyclosporine
dapsone
tetracycline
nicotinamide (vitB3)
```
115
PV - adjuvant corticosteroid sparing agents - dose of azathioprine
1-2.5 mg/kg
116
PV - adjuvant corticosteroid sparing agents - dose of mycophenolic acid
35-40 mg/kg
117
PV - adjuvant corticosteroid sparing agents - dose of cyclophosphamide
2-2.5 mg/kg
118
PV - adjuvant corticosteroid sparing agents - dose of methotrexate
10-20 mg/wk
119
PV - adjuvant corticosteroid sparing agents - dose of cyclosporine
3-5 mg/kg
120
PV - adjuvant corticosteroid sparing agents - dose of dapsone
50-200mg
121
PV - adjuvant corticosteroid sparing agents - dose of tetracycline
2g
122
PV - adjuvant corticosteroid sparing agents - dose of nicotinamide (vit B3)
1.5g
123
intra and perilesional injections of triamcinolone in PV
often used if stubborn remnant lesions and you want to taper the systemic corticosteroids
reduces healing time
124
indications for advanced therapeutic options in AMBDs
1. pts non-responders to at least one standard regimen inc the combination of systemic glucocorticoids (at min dose of 1mg/kg body weight prednisolone equivalent) and other immunosuppressants or immunomodulators
2. pts who developed significant SE from conventional systemic therapies
3. pt unable to achieve a sustained clinical remission on standard regimens
125
types of advanced therapeutic options in AMBDs
```
IV IgG
rituximab
antiTNFa
plasmapheresis
immunoadsorption
```
126
IvIgG in AMBDs
anti-inflammatory properties
increases catabolism of autoantibodies
decreases synthesis of autoantibodies
neutralises pathogenic autoantibodies
127
AMBDs - rituximab contraindications
active severe infections
severely immunocompromised
severe heart failure/uncontrolled cardiac disease
pregnancy
128
AMBDs - rituximab action
anti-CD20 medication - monoclonal antibodies that attack molecule on B cells
129
2 ways in which rituximab works as an anti-CD20 medication
1. directly targets CD20+ autoreactive B cells as progenitors of autoantibody secreting plasma cells
- B cells destroyed so don't get autoantibodies produced - ADCC cytotoxicity, complement-dependent cytotoxicity, apoptosis
2. indirectly decreases the freq of autoreactive T cells, which initiate and perpetuate the autoimmune response in pemphigus
130
effectiveness of rituximab in AMBDs
low rate of relapses and side effects
131
what is the issue with treating MM pemphigoid?
lack of evidence
132
low risk MM pemphigoid
oral mucosa only
oral mucosa and limited skin
no ocular, genital, oesophageal, laryngeal
133
high risk MM pemphigoid
diffuse oral mucosa
progressive oral mucosa
ocular, genital, oesophageal, laryngeal
134
initial treatment of low risk MM pemphigoid
```
topical CS
dapsone
tetracycline and nicotinamide
sulphametoxypyridazine
sulphapyridine
```
can also use high risk txs if needed
135
initial treatment of high risk MM pemphigoid
CS +/- (0.5-1.5mg/kg)
azathioprine\cyclophosphamide
mycophenolic acid
can also use low risk txs
136
tx of MM pemphigoid if partial response or progressive disease
IvIgG
| RTX
137
IvIgG dose in MM pemphigoid
2-3g/kg/day diluted on 3-5 days, monthly
138
RTX dose in MM pemphigoid
375mg/sqm²/day, 4 weekly infusions
or
1g/day, 2 infusions (TO-TIS)
139
MMP treatment - biologics as a first line adjuvant indications
contraindication to systemic CS
paediatric/young pts
rapid progression (ocular, laryngeal, oesophageal)
140
Primary SS triad
exocrinopathy (often results in dryness of mouth and eyes)
fatigue
joint pain
- main features but there are others
141
what does the prevalence of SS vary depending on?
classification criteria used
142
most common age for SS
40-60yrs
143
incidence of SS
4 per 100 000
144
gender distribution of SS
much higher in F
145
proposed immunopathogenic mechanisms of SS
microbial trigger
destroys salivary gland epithelium
produces autoantigens - nucleic acid and T1 interferon
triggers reaction of B cell and CD4 T cell
differentiation of B cells in plasma cells
produce autoantibodies - form immunocomplex with autoantigens
captured by DCs - produces T1 interferon amplifying immune response
activation of cytotoxic CD8 - directly destroys salivary gland epithelium through cytotoxic granules
produces new neoantigens and amplifies immune response
innate and adaptive immunity pathways
146
SS env factors
no single causative env factor identified
data continue to support infections as an important risk factor
biological factors
organic chemical factors
inorganic chemical factors
lots interact in a temporal contribution
147
SS biological factors
```
bacteria
viruses
vaccination
hormones
vit D
stress
```
148
SS organic chemical factors
alcohol
smoking
solvents
149
SS inorganic chemical factors
silicone
| silica
150
SS genetic factors
may both determine the baseline disease susceptibility and disease phenotype as well as interact with the different types of env factors
151
what 2 broad factors may contribute to the development of SS?
env factors
| genetic factors
152
in what % of SS pts do systemic manifestations occur?
about 30-40%
153
systemic manifestations of SS
```
constitutional symptoms
lymph nodes
renal
articular
cutaneous
peripheral neuropathy
muscular
pulmonary
glandular
CNS
```
154
systemic manifestations of SS - constitutional symptoms
fever
weight loss
night sweats
155
systemic manifestations of SS - LNs
benign lymphadenopathy/lymphoma
156
systemic manifestations of SS - renal
interstitial nephritis
157
systemic manifestations of SS - articular
arthralgia with morning stiffness or synovitis
158
systemic manifestations of SS - cutaneous
purpura
vasculitis
subacute cutaneous lupus
159
systemic manifestations of SS - muscular
myositis
| pain/weakness
160
systemic manifestations of SS - pulmonary
chronic bronchitis/bronchiolitis
| interstitial lung disease
161
systemic manifestations of SS - glandular
palpable parotid, submandibular or lacrimal swelling
162
systemic manifestations of SS - CNS
cerebral vasculitis
transverse myeltiis
demyelinating lesions
163
what does ESSDAI stand for?
EULAR Sjogren's Syndrome Disease Activity Index
164
what is ESSDAI?
a clinical index designed to measure disease activity in pts with primary SS
each has a weighting - give score for each depending on severity
165
ESSDAI clinical factors
```
constitutional
lymphadenopathy
glandular
articular
cutaneous
pulmonary
renal
muscular
PNS
CNS
haematological
biological
(Raynaud associated in 15% cases)
```
166
oral S+S in primary SS
```
salivary hypofunction
caries
fungal infections
oral trauma
lip dryness
orofacial pain
dysphagia
dysgeusia
swollen salivary glands
gastroesophageal reflux
oral lesions of autoimmune aetiology
```
167
primary SS - salivary hypofunction/dysfunction
diminished secretions on palpation
thicker, opaque or viscous secretions
recurrent salivary gland infection
168
primary SS - why is there enlarged salivary glands?
initial acute inflammation of glands, then chronic inflammation with fibrosis, decrease in volume of gland due to progressive destruction of the parenchyma - also lacrimal gland
169
primary SS - caries
pts with hyposalivation also have decreased secretion of IgA - antibody responsible for oral mucosal immunity that prevents caries
also saliva in primary SS does not act as an effective buffer therefore increases risk of caries
cervical caries and other atypical sites e.g. lingual surface, incisal edge and cusps
170
primary SS - fungal infection
```
pts with pSS have higher prevalence of oral fungal infections
mainly candidiasis
- erythematous
- angular cheilitis
- atrophic
- pseudomembranous
```
171
primary SS - which is the most common enlarged salivary gland?
parotid
30-40% pts
bilateral swelling can be found in 25-60% pts - acute or chronic
(submandibular can also be affected but less frequently)
172
primary SS - acute salivary gland enlargement
can be unilateral/bilateral
| usually painful
173
primary SS - salivary gland enlargement inflammatory infiltrate
mixed - T,B cells, abundant cytokine secretion that promote local chemotaxis, exacerbating the gland inflammation
174
primary SS - autoimmune/immunomediated lesions
oral lichen planus/lichenoid lesions
RAS
MM pemphigoid
pemphigus vulgaris
175
what is the other major organ affected in primary SS?
eye
176
primary SS - ocular manifestations
```
dry eye
extraglandular ocular complications
- corneal inflammation
- conjunctival inflammation
- uveitis
- scleritis/episcleritis
- optic neuritis
- retinal vasculitis
```
177
secondary SS
when pt already has another autoimmune disease then presents with extreme dryness of eyes and mouth
178
diagnosis of SS - lab testing
anti-SSA antibodies - anti-Ro
anti-SSB antibodies - anti-La
present in 2/3 pts and should be assessed when SS is suspected
other autoantigens
- muscarinic receptors
- vasoactive intestinal peptide receptor
- platelet(p)-selectin
- kallikreins
179
What classification criteria is used for the diagnosis of SS?
American College of Rheumatology European League against Rheumatism
180
SS diagnosis- inclusion criteria
at least one symptom of ocular or oral dryness (answer yes to 1 or more Qs):
have you had daily, persistent, troublesome dry eyes for >3m?
do you have a recurrent sensation of sand/gravel in the eyes?
do you use tear substitutes >3 times a day?
have you had a daily feeling of dry mouth for >3m?
do you freq drink liquids to aid in swallowing dry food?
or when there is suspicion of SS from the European League Against Rheumatism SS Disease Activity index questionnaire (1 or more domain with a + item)
181
SS diagnosis - exclusion criteria
```
history of H+N radiation tx
active hep C infection (confirm by PCR)
AIDS
sarcoidosis
amyloidosis
GvHD
IgG4-related disease
```
182
SS - if the patient meets inclusion criteria, doesn't have. any exclusion criteria, what do they need to score for diagnosis?
4 or more
183
SS diagnosis - what are the aspects of the scoring system?
```
biopsy
anti-SSA/Ro positive
ocular staining score
Schirmer's test
unstimulated whole saliva flow rate
```
184
SS diagnosis - biopsy
labial salivary gland with focal lymphatic sialadenitis and focus score of 1 or more foci/4mm²
- presence of 1 or more dense aggregates of 50 or more lymphocytes usually located in perivascular or periductal locations
score = 3
185
SS diagnosis - biopsy technique
5 or more minor glands
L lip in paramedian region
incision parallel to labial frenum, identify minor gland, lift, remove, suture
186
SS diagnosis - antiSSA/Ro positive
score = 3
187
SS diagnosis - ocular staining score
5 or more
(or Van Bijsterveld score 4 or more in at least 1 eye)
lissamine green or fluorescein
score = 1
188
SS diagnosis - Schirmer's test
5 or less mm/5min in at least one eye
filter paper in lower eyelid - tears
score = 1
189
SS diagnosis - unstimulated whole saliva flow rate
0.1ml/min or less
don't eat or drink 90mins before
score = 1
190
SS diagnosis - scores
```
biopsy - 3
antiSSA/Ro positive - 3
ocular staining score - 1
Schirmer's test - 1
unstimulated whole saliva flow rate - 1
```
191
what could the classification criteria of primary SS be extended to?
could be applicable to secondary SS
192
SS - what do you do before starting therapeutic interventions?
baseline evaluation of salivary gland function by measuring whole salivary flows
always rule out SS-unrelated conditions - candidiasis, burning mouth syndrome
may consider salivary scintigraphy
193
SS - what would you measure if the UWSF is less than 0.1ml/min?
SWSF
194
SWSF SS - normal/mild dysfunction
>0.7ml/min
195
SWSF SS - mod dysfunction
0.1-0.7ml/min
196
SWSF SS - severe dysfunction
<0.1ml/min
197
SS - normal/mild salivary dysfunction treatment
non-pharmacological
if no response/intolerance - pharmacological stimulation
rescue therapies
198
SS - mod salivary dysfunction treatment
non-pharmacological and pharmacological stimulation
if no response/intolerance - saliva substitutes
rescue therapies
199
SS - severe salivary dysfunction treatment
saliva substitutes
rescue therapies
200
SS - salivary dysfunction rescue therapies
mucolytic (NAC)
choleretic
electrostimulation
201
non-pharmacological saliva stimulation
```
gustatory stimulants (sugar-free acidic candies, lozenges)
and/or
mechanical stimulants (sugar-free chewing gum)
```
202
lozenges containing malic acid
increase saliva production and xerostomia relief
203
pharmacological saliva stimulation
pilocarpine
cevimeline
both licensed to treat oral dryness (but only pilocarpine licensed worldwide)
204
cevimeline dose
30mg 1-3x day
205
what not to recommend as pharmacological saliva stimulation
hydroxychloroquine
oral corticosteroid
immunosuppressive agents
rituximab
206
ideal saliva substitute properties
neutral pH
contain F and other electrolytes
-mimics composition of natural saliva
207
give 3 forms of saliva substitute
spray
gel
rinse
208
why is pilocarpine not always useable?
need residual secretory capacity - still need functioning parenchyma
209
disadvantages of pilocarpine
£ (useful galenic preparations)
several 5mg lozenges needed each day (3-6)
several disease interactions
may have no protective effect on caries, periodontitis or candidiasis in pSS patients
210
pilocarpine dose
3-6 5mg lozenges each day
211
contraindications for pilocarpine
```
uncontrolled asthma
uncontrolled COPD
uncontrolled cardiorenal diseases
narrow-angle closure glaucoma
gall bladder stones
acute iritis
```
212
SS - caries prevention
```
frequent recall (4-6m)
meticulous OH
F
non-F remineralising agents
salivary stimulation
antimicrobial agents e.g. CHX
```
213
what malignancy does SS carry a risk of?
haematological - lymphoma
214
what origin are most lymphomas in SS?
B cell origin
215
3 subtypes of lymphoma account for what % of cases in pSS pts?
>90%
216
3 main subtypes of lymphoma in SS?
Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma
Diffuse Large B-Cell Lymphoma (DLBCL)
Marginal Zone Lymphoma (MZL)
217
what % of haematological neoplasias in pSS pts do MALT lymphomas account for?
63%
218
where is the most common localisation of MALT lymphomas in SS?
```
salivary glands (mainly parotids)
but other mucosal sites can also be affected
```
219
what may MALT lymphomas transform into over the course of disease?
DLBCL
220
what other malignancy can a small number of SS pts get?
non-B cell haematological cancers
| myeloid leukaemia, Hodgkin disease or T/NK cell lymphoma
221
main primary sites of lymphoma in pSS
```
SALIVARY GLANDS (parotid)
lungs, gastric, ocular, oral/ENT, spleen
```
222
what risk do SS pts have of developing lymphoma compared to the general population?
22-260x higher risk of parotid gland B cell lymphoma
| 90-1000x higher risk for parotid gland MALT lymphoma
223
risk factors for developing lymphoma in pSS
```
recurrent swelling of parotid glands
splenomegaly, lymphadenopathy or both
purpura
>5 score on ESSDAI
RF
cryoglobulinemia
low C4 level
CD4 T cell lymphocytopenia
presence of ectopic germinal centres
focus score of >3
germinal mutations in TNFAIP3
```
224
what tests can be done to monitor for lymphoma development in SS?
```
lymphocyte count
protein electrophoresis
RF
C3+4 protein
cryoglobulin
```
225
how often should simple monitoring tests for malignancy in SS pts be carried out?
every 1-2yrs
| pts considered higher risk - every 6m
226
if lymphoma is suspected in SS pts, what should be done?
tissue biopsy
| imaging studies such as positron-emission tomography may also be helpful
227
give 2 ways of treating SS by targeting innate immunity pathways
inhibit pro inflammatory cytokines
| interfere with T1 interferon production
228
treating SS by targeting innate immunity pathways - inhibiting proinflammatory cytokines - drugs
tocilizumab
anakiura
infliximab/etanercept
iguratimod
229
treating SS by targeting innate immunity pathways - interfering with T1 interferon production - drugs
hydroxychloroquine
230
SS treatment - adaptive immunity therapeutic targets
```
antigen presentation/costimulation
B-cell activation
germinal centre formation
T cell proliferation
immunobiologics
```
231
SS treatment - adaptive immunity therapeutic targets - immunobiologic targets
anti-B cell
anti-TNFa
costimulatory signal inhibitors
anti-CD40
232
SS treatment - adaptive immunity therapeutic targets - immunobiologic targets - anti B cell
```
rituximab
high evidence level
improve USFR
effect on xerostomia not indicated
significant improvement in glandular parenchyma in 2 studies
```
233
SS treatment - adaptive immunity therapeutic targets - immunobiologic targets - anti-TNFa
infliximab
234
SS treatment - adaptive immunity therapeutic targets - immunobiologic targets - costimulatory signal inhibitors
abatacept
235
SS treatment - adaptive immunity therapeutic targets - immunobiologic targets - anti-CD40
CFZ533
236
definition of SLE
the prototype of an autoimmune multisystem disorder which clinically presents with a broad spectrum of clinical manifestations involving almost all organs and tissues, and serologically the appearance of antinuclear antibodies
237
what 2 processes contribute to the clinical picture of SLE?
systemic inflammation
| tissue damage
238
what are the potential severe outcomes of SLE?
disability or death
239
which continent does SLE tend to be lower in?
europe
240
gender distribution of SLE?
F>M
241
factors contributing to SLE
can act either sequentially or simultaneously on the immune system
1. genetic predisposition
2. env
3. hormonal
4. epigenetic
5. immunoregulatory factors
242
SLE genetic predisposition
have identified genes - cellular functions that have lupus susceptibility genes related to them
- priming/autoantigen presentation
- lymphocyte activation
- cell survival/apoptosis
- innate response/IFN-1
- apoptotic clearance
- immune-complex-dependent response
243
SLE environmental factors
smoking
UV exposure
EBV
exposure to silica dust, petroleum, organic solvents and mineral oils
244
SLE hormonal factors
mainly affects women in their reproductive age, F:M 9:1 - suggests role for female hormones
245
SLE epigenetic factors
DNA methylation
| histone modifications
246
SLE immunoregulatory factors
```
presentation of unknown antigens by MHC molecules leads to priming of CD4+ T cells
these cells activate B cells in auto reactive germinal centres; undergo class switching, affinity maturation and differentiation into plasma cells
PCs secrete high levels of soluble autoantibodies of the IgG isotype. form immune complexes by binding autoantigens
- autoantibodies: anti-nuclear, anti-cardiolipin
this can support inflammation and tissue destruction through the recruitment of inflammatory cells to tissues - complement fixation
apoptotic cells from damaged tissues can be taken up by phagocytes, which present novel autoantigens, supporting further priming and autoreactivity
env triggers e.g. viral infection or DNA damage by UV rays contribute by inducing secretion of IFN-1 and other cytokines, supporting lymphocyte autoreactivity as well as tissue destruction
```
247
SLE-DAS factors
```
arthritis
localised skin rash
generalised skin rash
alopecia
mucosal ulcers
systemic vasculitis
mucocutaneous vasculitis
neuropsychiatric involvement
cardiac/pulmonary involvement
serositis
myositis
proteinuria
hypocomplementaemia
increased anti-dsDNA
thrombocytopenia
leucopenia
haemolytic anaemia
```
- then use formula to work out score
248
Constitutional S and S of SLE - broad factors which contribute to fatigue
disease related factors
psychosocial factors
others
249
Constitutional S and S of SLE - disease related factors which contribute to fatigue
disease activity and inflammation
history of neuropsychiatric lupus
co-morbidities: AI hypothyroidism, anaemia
250
Constitutional S and S of SLE - psychosocial factors which contribute to fatigue
depression
poor sleep pattern
personality traits
low perceived social support
251
Constitutional S and S of SLE - other factors which contribute to fatigue
```
vit D deficiency
obesity
physical inactivity
meds
fibromyalgia
```
252
SLE - investigations if pt presents with fatigue
FBC
serum iron/B12/folic acid (if anaemic)
thyroid fct
serum vit D
253
what are the 2 most common constitutional symptoms of SLE?
fatigue
| fever
254
Overall management of SLE - 5 features
treat active disease - hydroxychloroquine and immunosuppressants
treat anaemia/hypothyroidism
address co-morbid psychosocial factors
exercise
behavioural therapy, psychoeducational intervention
255
SLE - possible aetiology of fever
infection - viral, bacterial, mycobacterial, fungal, protozoal, haematodes
malignancy - lymphoma, primary carcinoma, metastatic carcinoma, myeloma
256
differential diagnosis of splenomegaly in SLE
```
neoplastic and lymphoproliferative disease
hepatic
vascular occlusive
immunological
infection
inherited haemoglobinopathies
```
257
differential diagnosis of weight loss in SLE
```
infection
malignancy
GI
organ damage
meds
```
258
SLE renal manifestations
lupus nephritis
- immune-complex glomerulonephritis, which is defined by a combination of clinical and lab features (proteinuria, high level of creatinine and blood urea nitrogen)
259
SLE classification of LN - categories
```
1
2
3
4
5
6
```
260
SLE classification of LN - 1
minimal mesanginal LN
261
SLE classification of LN - 2
mesanginal proliferative LN
262
SLE classification of LN - 3
focal lupus nephritis (<50% of glomeruli)
| - active/active and chronic/chronic
263
SLE classification of LN - 4
```
diffuse LN (>=50% of glomeruli
- active/active and chronic/chronic
```
264
SLE classification of LN - 5
membranous LN
265
SLE classification of LN - 6
advanced sclerosing LN (>=90% globally sclerosed glomeruli without residual activity)
266
SLE musculoskeletal manifestations
```
arthritis/arthropathy (most common)
tendon rupture (rare)
myalgia/myositis
avascular bone necrosis
osteopenia/osteoporosis
```
267
SLE musculoskeletal manifestations - arthritis/arthropathy
non-erosive non-deforming arthritis primarily affecting small joints of hands, wrists, knees
5-15% progresses to deforming arthropathy, may show as erosive on X-ray, rhupus syndrome, or non-erosive the Jacoud's arthropathy
268
SLE musculoskeletal manifestations - tendon rupture
rare
| patellar and Achilles tendon
269
SLE musculoskeletal manifestations - myalgia/myositis
generalised myalgia and muscle tenderness common
| more rarely, myositis involving proximal muscles +/- elevated muscle enzymes, typically creatinine phosphokinase (CPK)
270
SLE musculoskeletal manifestations - avascular bone necrosis
asymptomatic with abnormal findings on imaging
severe disease with pain and disability from advanced cortical destruction
most common site hip, but most pts will have multisite involvement
271
SLE CV manifestations
```
pericarditis (most common)
myocarditis (rare)
cardiomyopathy
CAD
valvular disease
```
272
SLE CV manifestations - pericarditis
most common
| typically present with tachycardia, substernal or precordial chest discomfort, dyspnea and positional pain
273
SLE CV manifestations - myocarditis
rare
can present with symptoms of HF inc resting tachycardia and dyspnea, also sometimes chest discomfort, fever and/or myopericarditis
274
SLE CV manifestations - cardiomyopathy
can be directly caused by SLE or secondary to CAD
275
SLE CV manifestations - CAD
most common cause of death in pts with late-onset or long-standing SLE
risk of fatal MI increases with time from SLE diagnosis
276
SLE CV manifestations - valvular disease
most common - a sterile endocarditis/Libman-Sacks endocarditis, which usually affects mitral valve (but any can be affected)
clinically significant valvular dysfunction secondary to L-S is rare
277
CV risk factors in SLE
traditional risk factors
inflammatory risk factors
lupus-related risk factors
278
neuropsychiatric manifestations of SLE
wide spectrum - can affect all levels of the NS inc brain and spinal cord, as well as PNS
CNS - myelitis
PNS - myasthenia
279
neuropsychiatric manifestations of SLE - CNS
myelitis
- NV disease
- seizures
- menngitis
- movement disorders
- psychiatric disease
- cognitive dysfunction
280
neuropsychiatric manifestations of SLE - PNS
myasthenia
- cranial neuropathy
- mononeuritis multiplex
- inflammatory demyelinating neuropathy
- axonal polyneuropathy
281
pulmonary manifestations of SLE
lung parenchyma - acute lupus pneumonitis, interstitial lung disease
pleura - lupus pleuritis +/- effusion
airways - laryngeal involvement, bronchiectasis, small airways disease
vessels - alveolar haemorrhage; pulmonary arterial hypertension, anti phospholipid syndrome
muscles - shrinking lung syndrome
infectious pneumonia
lung cancer
282
SLE GI manifestations
```
lupus mesenteric vasculitis
protein losing gastroenteropathy (PLGE)
SLE-related intestinal pseudo-obstruction (IPO)
SLE-related acute pancreatitis
celiac disease
IBD
eosinophilic enteritis
pneumatosis cystoides intestinalis
```
283
SLE GI manifestations - lupus mesenteric vasculitis
acute ischaemic enteritis - mainly SI
chronic multiple ulcers - mainly colon
mild, non-specific abdominal pain, bloating, loose stool - necrosis and intestinal perforation
284
SLE GI manifestations - PLGE
oedema and severe hypoalbuminemia secondary to excessive loss of serum protein from GIT
285
SLE GI manifestations - IPO
ineffective intestinal propulsion with clinical features of intestinal obstruction without an identifiable organic obstructive lesion and an abdominal distension with a very sluggish or absent peristalsis
286
SLE GI manifestations - SLE-related acute pancreatitis
acute inflammation of pancreas presenting in 83% of cases with also pain, in only 23% pain radiates to back
diagnosis based on lab evidence of elevated serum amylase or lipase levels
clinical symptoms and suggestive tomographic findings are helpful
may have nausea and vomiting
287
ocular manifestations of SLE
```
keratoconjunctivitis sicca
mild lupus retinopathy
mild retinal artery and vein occlusion
6th nerve palsy
neovascular glaucoma
uveitis
scleritis
ischaemic optic neuropathy/neuritis
vasculitis
```
288
SLE cutaneous manifestations - specific
derma-epidermal LE - acute, subacute, chronic/discoid
289
SLE cutaneous manifestations - non-specific signs
dermal LE
hypodermal (subcutaneous) LE
signs indicative of a thrombotic vasculopathy
neutrophilic cutaneous LE
other, of yet uncertain pathogenic significance
290
Acute Cutaneous Lupus Erythematosus (ACLE)
can be first sign of SLE, preceding onset of systemic disease by weeks or months
classic malar/butterfly rash
in generalised ACLE, may affect arms, elbows, shoulders, knees and trunk
oral lesions - ulcerations - mainly hard palate, intense erythema +/- petechiae
291
ACLE - classic malar/butterfly rash
discrete erythematous macules, papules and plaques in central areas of face, without typically affecting nasolabial folds and periorbital regions
lesions may become confluent with scaling, erosions and crusting
292
Subacute Cutaneous Lupus Erythematosus (SCLE)
erythematous macules or papules, evolve into either
-scaly papulo-squamous psoriasiform lesions
-annular patches and plaques
in 50% cases
mixed form lesions also found
oral lesions rare and clinically similar to CCLE
293
SCLE healing
post-inflammatory hyper and/or hypo pigmentation, greyish atopic scarring and telangiectasias
294
Discoid or Chronic Cutaneous Lupus Erythematosus (CCLE)
most common clinical manifestation of CLE, usually affects ears, face, scalp and/or neck
annular erythematous and violaceous plaques with follicular hyperkeratosis, can progress to scars and atrophy
if scalp involved, scarring alopecia can develop
oral mucosa can be affected by lichenoid lesions
295
what is the most common clinical manifestation of CLE?
CCLE - Discoid or Chronic Cutaneous Lupus Erythematosus
296
Discoid or Chronic Cutaneous Lupus Erythematosus - oral lesions
lichenoid lesions
-well-demarcated, round or irregular red lesions, atrophic/ulcerated with a white radiating keratitis striae
-can have verrucous aspect or be linear fissured or have ulcerative lesions
-asymmetrically distributed mainly on hard palate, followed by lips
oral DLE (or CLE) is an OPMD, though malignant transformation is extremely rare
297
SLE oral manifestations
```
oral mucosa
-ulcerations
-lichenoid lesions
-erythematous lesions
-leukoplakias
-petechia
-cheilitis with erythema
salivary gland involvement - low flow rate - SLE associated with SS
caries
TMJ involvement - pain, crepitus, difficulty opening
PDDs
```
298
SLE diagnosis - lab testing
positive ANA mandatory entry criterion
99% cases present
anti-Sm and anti-dsDNA
299
SLE diagnosis - ANA specificity and sensitivity
v high sensitivity for SLE but limited specificity - occur in other CT diseases
300
SLE diagnosis - anti-Sm and anti-dsDNA specificity and sensitivity
highly specific but less sensitive
301
is SLE classification criteria diagnostic?
no
302
entry criterion for SLE
ANA titre >=1:80
303
SLE additive criteria
don't count a criterion if there is a more likely explanation than SLE
one occasion sufficient
don't need to occur simultaneously
need at least one clinical criterion and >=10 points
in each domain only count highest criterion
304
SLE classification - clinical domains (each has a different weighting)
constitutional - fever
haematological - leukopenia, thrombocytopenia, AI hemolysis
neuropsychiatric - delirium, psychosis, seizure
mucocutaneous - non-scarring alopecia, oral ulcers, subacute discoid/cutaneous, acute cutaneous
serosal - pleural/pericardial effusion, acute pericarditis
MS - joint involvement
renal
-proteinuria >0.5g/24 hr
-renal biopsy class 2 or 5 LN
-renal biopsy class 3 or 4 LN
305
SLE classification - immunology domains (each has a different weighting)
antiphospholipid antibodies
- anticardiolipin OR
- anti-B2GPI OR
- lupus anticoagulant
complement proteins
- low C3 OR C4
- low C3 AND C4
SLE-specific antibodies
- anti-dsDNA OR
- anti-Sm
306
what is the pharmacological treatment for SLE mainly guided by?
individual patient manifestations
307
SLE pharmacological treatment
```
corticosteroids - prednisolone
antimalarials - hydroxychloroquine
immunosuppressive agents
-azathioprine
-mycophenolic acid
-methotrexate
-cyclophosphamide
-cyclosporine
-tacrolimus
-sirolimus (rapamycin)
```
308
SLE treatment prednisolone dose
1-2mg/kg
309
SLE treatment hydroxychloroquine dose
400-800mg
310
SLE treatment - pharmaceuticals targeting B cells in different developmental stages
if SEs to conventional immunosuppressive therapy/may not respond
monoclonal antibodies against a specific molecule
anti-CD22 - epratuzumab
anti-CD20 - rituximab
target different receptors in mature and memory B cells
311
is there an increased cancer risk with SLE?
overall slightly increased risk
312
SLE - which cancers are patients at an increased risk for?
haematological (lymphoma, leukaemia, multiple myeloma)
NHL
H+N cancer
313
possible factors suggested as mediating cancer risk in SLE
lupus-related meds e.g. cyclophosphamide
inherent immune system abnormalities e.g. high levels of IL6+10 high risk of NHL
overlap with SS
viral infections e.g. HPV and EBV
traditional cancer risk factors e.g. smoking
314
when was Behect disease first described and how?
1937
| triad
315
Behcet disease triad
oral ulcers
genital ulcers
uveitis
316
how is Behcet disease recognised now in contrast to the triad?
involvement of most organ systems recognised
systemic vasculitis which can involve arteries and veins of all sizes
317
why is the diagnosis of Behcet disease often delayed by several years?
because the diagnostic features may present over months/years
318
why is Behcet disease known as the "Silk Road Disease"?
strikes people with this bloodline more frequently
| e.g. high incidence in Turkey
319
pathogenesis of Behcet disease - overall
genetic predisposition
disruption of innate immunity
disruption of adaptive immunity
= tissue damage + vasculitis
320
pathogenesis of Behcet disease - genetic predisposition
HLA B51 association
321
pathogenesis of Behcet disease - disruption of innate immunity
hyperactivation of neutrophils (neutrophilic vasculitis, enhance chemotaxis, secrete cytokines able to induce a Th1-mediated immune response)
alterations in both number and function of peripheral NK cells
enhanced activation of ydT cells
322
pathogenesis of Behcet disease - disruption of adaptive immunity
Treg downregulation = less of IL-10
Th1 upregulation = increased IFNy, IL2, IL12 and IL18
Th17 upregulation = increase in IL17
323
clinical manifestations of Behcet disease
oral ulcers
genital ulcers
eye lesions - uveitis, blindness
skin lesions - palpable purpura, subcutaneous nodules
324
Behcet disease - pathargy test
needle prick
24-48 hours
exaggerated inflammatory reaction
325
Behcet disease differential diagnosis
```
RAS
infections
skin diseases
Crohns
SJS
pemphigoid
pemphigus
SLE
IBD
sarcoidosis
```
326
Behcet disease more extensive clinical manifestations
```
mucocutaneous involvement
ocular involvement
MS involvement
vascular involvement
cardiac involvement
GI involvement (entero-Behcet disease)
neurologic involvement
pulmonary involvement
```
327
Behcet disease diagnosis
difficult
no diagnostic lab test, mostly clinical
history key - RAS plus other characteristic clinical manifestations should raise suspicions for BD
328
Consensus Classification of Paediatric Behcet Disease
recurrent oral aphtosis - >=3 attacks pa
genital ulceration and aphtosis - typically scar
skin involvement - necrotic folliculitis, acneiform lesions, erythema nodosum
ocular involvement - uveitis, retinal vasculitis
neurological signs - with exception of isolated headaches
vascular signs - venous thrombosis, arterial thrombosis, arterial aneurysm
need to score >=3
329
Behcet Disease ISG criteria
```
ROU >=3 in a year
plus 2 of:
-recurrent genital ulceration
-eye lesions
-cutaneous lesions
-+pathergy test
```
findings applicable only in absence of other clinical explanation
330
International Criteria for Behcets disease
score >=4
- if do pathergy test add 1 to score
- ocular lesions 2
- genital aphthosis 2
- oral aphthosis 2
- skin lesions 1
- neurological manifestations 1
- vascular manifestations 1
331
ISG and ICBD criteria limitations
helpful for diagnosis
but the criteria were described to categorise pts for study purposes and were not developed to diagnose disease in individuals
332
conventional immunosuppressive therapies for Behcet disease
corticosteroids
| - topical for mucocutaneous
333
biologic therapies for Behcet disease
```
infliximab, rituximab, tocilizumab
multiple different targets
-TNFa
-interleukins
-CD cells
```
334
EM definition
an acute immune-mediated inflammatory mucocutaneous disease
| clinically polymorphic lesions triggered by hypersensitivity reactions to various antigens with a tendency to recur
335
what surfaces does EM affect?
mucous membranes and skin
336
what age group does EM typically affect?
young adults 20-4yrs
337
EM gender distribution
more common F 1.5:1
338
estimated annual incidence of EM
<1% (but unknown)
339
prevalence of EM
<1%
340
what is the estimated prevalence of oral EM lesions among patients with cutaneous lesions?
35-65%
341
causes of EM
infections and drugs
| other conditions
342
EM mortality rates
not documented
343
infections as a cause of EM
HSV infection most commonly identified cause of EM
| most commonly identified cause in children - mycoplasma pneumoniae infection
344
drugs as a cause of EM
```
antibiotics
sulfonamides
anti epileptics
barbiturates
NSAIDs
```
345
other conditions that can cause EM
IBD
malignancy
menstruation
346
what is the most commonly identified cause of EM?
HSV
347
what is the most commonly identified cause of EM in children?
mycoplasma pneumoniae infection
| in this context, a new entity of EM named MIRM (mycoplasma induced rash and mucositis) was described
348
basic pathogenesis of EM
T3 hypersensitivity reaction
| T4 hypersensitivity reaction
349
T3 hypersensitivity reaction
immune complex reaction of antigen and antibody
1 form antigen-antibody complex in circulation
2 deposit of immune complex in blood vessels
3 appearance of inflammatory reaction with subsequent vasculitis
350
what does a biopsy on the blood vessel wall of EM patients show?
an increasing level of IgM, complement and fibrin deposits
351
T4 hypersensitivity reaction
T cell mediated immune reaction to precipitating agent
352
what does HAEM stand for?
HSV-associated EM
353
when does HAEM occur?
7-21 days after primary or recurrent viral infection
354
pathogenesis of HAEM
circulating PBMCs, macrophages and CD34+ Langerhans cells engulf HSV-DNA
migrate to epidermis to transfer these antigens to keratinocytes
expression of HSV-DNA in keratinocytes leads to activation of HSV-specific CD41 Th1 cells, which produce IFN-y
in turn this will up regulate cytokines and chemokine that autoreactive attack cytotoxic T cells, NK cells, and monocytes, responsible of keratinocytes lysis and subsequent epithelial damage
355
what does DIEM stand for?
Drug-induced EM
356
DIEM
no IFN-y is found but have TNFa, produced by macrophages, which along with perforin and granzyme B, will induce keratinocytes apoptosis with subsequent epithelial destruction
357
differences between HAEM and DIEM - aetiology
HAEM - HSV1/2
| DIEM - drugs
358
differences between HAEM and DIEM - clinical
HAEM - no/mild prodromal S+S, acute, self-limiting, recurrent
DIEM - flu-like prodrome, acute, self-limiting, not recurrent
359
differences between HAEM and DIEM - predilection site
HAEM - skin, mucosal lesions absent/minimal
| DIEM - skin, mucosal lesions prominent
360
differences between HAEM and DIEM - histopathology
HAEM - focal keratinocyte necrosis, edema, predominant mononuclear infiltration CD4+
DIEM - extensive keratinocyte necrosis, less edema, predominant mononuclear infiltration CD4+
361
differences between HAEM and DIEM - immunochemistry
HAEM - +HSV DNA PCR, +IFNy
| DIEM - -HSV DNA PCR, +TNFa
362
differences between HAEM and DIEM - mortality
HAEM - not reported
| DIEM - 5-15%
363
three EM subtypes
isolated
recurrent
persistent
364
isolated EM
occurs just once
| infections, drugs
365
recurrent EM
frequent occurrence of EM over a period of years, usually >6 episodes p.a.
infections, menstruation
366
persistent EM
continuous occurrence of typical and atypical lesions without interruption
infections, IBD, malignancy
367
EM clinical forms
minor
| major
368
EM minor form
skin <10% BSA
| mucosa uncommon, 1 site only, usually oral
369
EM major form
skin <10% BSA
mucosa >=2 different mucosal sites
oral and genital, ocular, laryngeal, oesophageal or a combination
370
EM typical target lesion
centre is dusky or dark red with a blister or crust
next ring is a paler pink and is raised due to oedema
outermost ring bright red
371
EM atypical target lesion
raised, oedematous lesion with two zones of colour change and a poorly defined border
372
EM diagnosis - criteria
no standardised criteria
373
what is EM diagnosis based on - broad categories?
clinical history
clinical exam
biopsy (skin)
lab studies
374
EM diagnosis - clinical history
acute, episodic, self-limiting
symptoms of HSV, mycoplasma pneumoniae and other infections
thorough meds history (often started 2-3 days prior)
375
EM diagnosis - clinical exam
skin lesions: typical, atypical
morphology: pleomorphic appearance of oral lesions
location: U/L lip and anteriorly in mouth - erythematous, erosions, fibrin, haemorrhagic
376
EM diagnosis - biopsy
skin
H+E
DIF
377
EM diagnosis - lab studies
test for ESR, WCC, LFT, electrolytes
| IIF to rule out AI blistering disease
378
basis of EM treatment
treating underlying infection/medication paramount
symptomatic treatment, guided by clinical severity
prevent infections and local symptom control
379
treatment of mild EM
topical antiseptics
oral antihistamines
analgesics
topical CS
380
treatment of EM affecting MM
high potency CS gel, oral anaesthetic solutions, topical ophthalmic preparations
381
treatment of severe mucosal EM
oral prednisolone 40-60mg
| taper 2-4 wks
382
treatment of recurrent EM
6m trial of continuous antiviral therapy
383
are the lesions raised or flat in EM major?
raised
384
distribution of lesions in EM major?
mostly extremities
| in children often affects trunk
385
does EM major progress to TEN?
no
386
features of SJS - skin detachment
<10%
387
features of SJS - target lesions
atypical
388
features of SJS - raised lesions?
no
389
features of SJS - distribution of lesions
mostly trunk
390
features of SJS - progression to TEN?
possible
391
features of TEN with macules - skin detachment
>30%
392
features of TEN with macules - target lesions
atypical
393
features of TEN with macules - raised lesions?
no
394
features of TEN with macules - distribution of lesions?
mostly trunk
395
features of TEN with no macules - skin detachment
>10%
396
features of TEN with no macules - target lesions?
none
397
features of TEN with no macules - raised lesions?
no
398
features of TEN with no macules - distribution
mostly trunk
