key points AI diseases Flashcards
SS primary
no CT disease
SS triad
exocrinopathy - dryness mouth and eyes
fatigue
joint pain
SS epidemiology
usually 40-60yrs
F
SS aetiology
infections
biological factors
chemical
genetic - HLA association
SS proposed immunopathogenic mechanisms
microbial trigger destroys SG epithelium autoantigens differentiation of B cells into plasma cells auto-ABs form complex with auto Ags captured by DCs - T1 interferon activation of cytotoxic CD8
innate and adaptive
oral S+S SS
salivary hypofct caries fungal infections oral trauma lip dryness orofacial pain dysphagia dysgeusia swollen SGs GORD oral lesions of AI aetiology
SS systemic manifestations
30-40% constitutional LNs renal - interstitial nephritis articular - arthralgias cutaneous peripheral neuropathy muscular - myositis pulmonary glandular CNS
SS ESSDAI
clinical index to measure disease activity in pts w primary SS
each has a weighting - give score depending on severity
SS salivary hypofct/dysfct
diminished secretions on palpation
thicker/opaque/viscous secretions
recurrent SG infection
enlarged SGs in 30% (parotid)
SS caries
hyposalivation - reduced IgA secretion
- AB responsible for oral mucosal immunity that prevents caries
saliva in pSS not effective buffer
cervical and other atypical sites e.g. lingual surface, incisal edge and cusps
what fungal infection is prevalent in SS?
candidiasis
SS AI/immunomediated lesions
oral LP/lichenoid lesions
RAS
MMP
PV
secondary SS
when pt already has another AI disease then presents with extreme dryness of the eyes and mouth CT disease (SLE, RA, systemic sclerosis)
SS eye
dry eye extraglandular ocular complications - corneal inflammation - conjunctival inflammation - uveitis - scleritis/episcleritis - optic neuritis - retinal vasculitis
SS autoABs
anti-SSA ABs - antiRo
anti-SSB ABs - antiLa
present in 2/3 pts
SWSF >0.7ml/min
normal/mild dysfct
non-pharmacological stimulation
(saliva subs/pharmacological stimulation)
SWSF 0.1-0.7ml/min
mod dysfct
non-pharmacological/pharmacological stimulation
(saliva substitutes)
SWSF <0.1ml/min
severe dysfct
saliva substitutes
SS classification criteria - American College of Rheumatology/European League against Rheumatism
inclusion criteria
≥1
daily, persistent, troublesome dry eyes >3m?
recurrent sensation sand/gravel in eyes?
use tear substitutes ≥3 times daily?
daily feeling of dry mouth for >3m?
freq drink liquids to aid swallowing dry food?
or when suspicion of SS from EULAR SS DAI (≥1 positive)
SS classification criteria - American College of Rheumatology/European League against Rheumatism exclusion criteria
history of H+N radio active Hep C AIDS sarcoidosis amyloidosis GvHD IgG4-related disease
SS classification criteria - American College of Rheumatology/European League against Rheumatism - what do you need to score?
meet inclusion criteria
no exclusion criteria
score ≥4
SS classification criteria - American College of Rheumatology/European League against Rheumatism - scoring
biopsy - 3 antiSSA/Ro + - 3 ocular staining score ≥5 - 1 schirmer's test ≤5mm/min - 1 UWSF ≤0.1ml/min - 1
biopsy requirements SS
labial SG with focal lymphatic sialadenitis and focus score of ≥1 foci/4mm2
- ≥1 dense aggregates of ≥50 lymphocytes usually located in perivascular or periductal locations
biopsy technique SS
≥5 minor glands, L lip in paramedian region, incision parallel to labial frenum, identify minor gland, lift, remove, suture
SS non-pharmacological stimulation
gustatory stimulants: SF acidic candies, lozenges
mechanical stimulants: SF chewing gum
SS caries prevention
freq recall 4-6m OH F non-F remineralising agents salivary stimulation AM agents e.g. CHX
why is pilocarpine not always possible?
salivary residual secretory capacity needed - still need fct parenchyma
pilocarpine dose
5mg lozenges
3-6 daily
pilocarpine contraindications
uncontrolled asthma/COPD uncontrolled cardiorenal disease narrow-angle closure glaucoma gall bladder stones acute iritis
main primary sites of lymphoma in primary SS
SALIVARY GLANDS (parotid) lungs, gastric, ocular, oral/ENT, spleen
lymphoma risk in SS
risk of haematological malignancy most B-cell origin 3 subtypes - MALT lymphoma - DLBCL - MZL small number get non-B-cell haematological cancers - myeloid leukaemia, Hodgkin disease or T/NK cell lymphoma
test regularly (1-2yrs, high risk 6m)
SS risk factors for lymphoma
recurrent swelling of parotid glands splenomegaly/lymphadenopathy purpura > on ESSDAI RF cryoglobulinaemia low C4 level CD4 T-cell lymphocytopenia presence of ectopic germinal centres focus score of >3 germinal mutations in TNF AIP3
SS tx
inhibit proinflammatory cytokines - infliximab
interfere w T1 interferon production - hydroxychloroquine
immunobiologics - rituximab, infliximab
sicca syndrome
partial SS findings
American European Consensus Group Revised International Criteria SS
1 - dry eyes subjective 2 - dry eyes objective 3 - dry mouth subjective 4 - dry mouth objective 5 - autoAB findings 6 - histopathology
≥4 positive criteria (must inc 5 and/or 6)
T1 hypersensitivity
IgE - anaphylaxis
T2 hypersensitivity
IgG/M - cytotoxic - AgAB
T3 hypersensitivity
IgG/M - immune complex deposition (Ag-Ab)
T4 hypersensitivity
T cell mediated (delayed type)
what type of blister is pemphigus?
intraepithelial
what hypersensitivity reaction is pemphigus?
T2 - cytotoxic
Ag-Ab reaction - destruction of desmoglein
damage to LP
IgG Abs form
pemphigus HP
take perilesional biopsy of area not ulcerated/blistered - as won’t have epithelium in ulcer
acantholysis
suprabasal split
tzank cells
basal cells still fully attached by hemidesmosomes
acantholysis
spaces between spinous cells
tzank cells
in pemphigus
epithelial cells fall off into blister/bullae
DIF
tissue biopsy
usually for diagnosis
AB and fluorophore
IIF
serum
usually to measure ABs but can be used for diagnosis
can monitor progress and response to therapies
unlabelled Ab (primary) and supporting Ab with fluorophore (secondary)
positive DIF pemphigus
basket weave pattern
reflect where you get Ag-Ab reaction
grey areas - intraepithelial split/cleft
desmosomes
positive DIF pemphigoid
linear pattern
in hemidesmosomes - basal cell layer
what type of blister is pemphigoid?
subepithelial
what type of hypersensitivity reaction is pemphigoid?
T2
pemphigoid HP
sub basal split
no acantholysis or tzank cells
LP shows inflammation - inflammatory cells
eosinophils characteristic of bullous pemphigoid not so obvious in MMP
why do many diseases affect both skin and oral/genital mucosa?
they share many common antigens and epitopes
antigens - provoke immune response but epitope binds
epitopes - part of Ag that binds to Ab
general pathogenesis of AMBDs
auto-AB attack on skin components causing loss of cell-cell adhesion - desmosomes - hemidesmosomes (basal cell layer) split/cleft forms in skin - fills with inflammatory exudate - vesicle (<5mm)/bulla (>5mm)
SS histology minor gland
focal lymphocytic sialadenitis acinar loss fibrosis focal collections of lymphocytes (50+) - ≥1 collection per 4mm2
SS histology major gland
lymphocytic infiltrate, extends to whole lobules
epithelial hyperplasia of duct (myoepithelial islands) eventually occludes
atrophy of acini
pemphigus pathogenesis
autoABs against desmoglein intraepithelial blister acantholysis autoABs deposited in epithelium anti-Dsg3 IgF complement activated and plasmin
pemphigus classification
vulgaris foliaceous drug-induced paraneoplastic IgA
age pemphigus
40-60s
pemphigus foliaceous
superficial form - skin
lacks mucosal involvement
anti-Dsg1
oral lesions rare
pemphigus prognosis
untxed often fatal - metabolic consequences, dehydration/infection
mucosal lesions may persist after skin controlled
- topical CS/tacrolimus
now often complications of tx major cause of death - CS, MAbs
pemphigus mucosal features
progressive - typically begins oral cavity, can spread to skin
oral cavity
- anywhere
- non-healing erosions/ulcers, rarely see intact blisters
- desquamative gingivitis
- yellow fibrinous slough
- painful, plaque irritates lesions
- easily peel off - haemorrhagic erosion
- spongiosis
- no scarring
pemphigus diagnosis
DIF - basket weave/fishnet like pattern in epithelium
- IgG, C3, IgM, IgA (variant)
IIF - high % positive
- IgG, C3, IgM, IgA
histopathology - intraepithelial blisters
pemphigus tx
CS
adjuvant CS sparing agents
CHX 0.12% alcohol free rinse
anti-mycotic agents
triamcinolone injections
advanced therapeutic options
- IVIgG
- rituximab (anti-CD20)
- anti-TNFa
- plasmapheresis
- immunoadsorption
pemphigoid epidemiology
> 75s
rare
pemphigoid pathogenesis
autoABs against hemidesmosomes
complement, leukocytes, BM damage
subepithelial blister
pemphigoid clinical
bullae/vesicles - often blood filled erosions/ulcers - yellow fibrinous slough desquamative gingivitis
MM pemphigoid
mostly mucosae
20% skin
HP/SP, uvula, gingivae
bullous pemphigoid
skin (flexor)
oral 20%
cicatritial pemphigoid
scarring
pemphigoid diagnosis
DIF - linear pattern - u or n serrated - deposition along BMZ - IgG, C3, IgA IIF salt split (NaCl scissors at lamina lucida) - IgG HP - subepithelial blister
pemphigoid tx
low risk - oral +/- limited skin - topical CS
high risk - diffuse and progressive oral mucosa, ocular, genital, oesophageal, laryngeal
CS +/- azathioprine etc
IVIgG/rituximab (partial response/progressive)
diagnosis of AMBDs
Nikolsky sign biopsy need immunologic signal to confirm DIF IIF ELISA
Nikolsky sign
marginal - next to blister
direct - healthy skin
induce erosion by rubbing on skin
DIF
oral mucosa, detect tissue bound immunodeposits
IIF
pts sera
detect circulating IgG autoABs
ELISA
detect anti-Dsg ABs
why is early diagnosis of AMBDs essential?
may not be AMBDs prevent mucosal spread prevent MC spread mucosal scarring phenotype of MMP - oesophageal stricture - eye scarring - blindness
PAMS
MC syndrome heterogeneous S+S - desquamative stomatitis - polymorphous cutaneous eruption - progressive resp failure underlying malignancy
pathogenesis of PAMS
cancer cells activate wide number of immune cells - activated autoreactive T cells induce both humoral and cell mediated immunity
PAMS spectrum
humoral immunity —– cell mediated immunity
acantholysis, bronchiolitis obliterans, lichenoid dermatitis
PAMS spectrum similar to oral diseases
humoral immunity —- cell mediated immunity
pemphigus, bullous pemphigoid, EM like, GvHD like, lichenoid/LP like
what is the major antigenic target in PAMS?
plakins
- desmoplakin 1 and 2, envoplakin, periplakin, plectin, BP230
lesions in PAMS?
ocular
lip
oral
what is the key thing to do in PAMS?
detect a neoplasm
tx of malignancy essential but not always sufficient to tx PAMS
AMBDs
Ig-mediated diseases with autoantibodies against desmosomal or BM zone molecules
PAMS suggested criteria
clinical signs
- severe stomatitis, blisters, LP like plaques, bronchiolitis obliterans
HP
DIF
IIF
detection of circulating auto-ABs - envoplakin/periplakin
detection of a neoplasm
what BPs are the target in pemphigoid?
BP180
BP230
Behcet disease triad
oral ulcers
genital ulcers
uveitis
Behcet disease - what is now recognised along with the triad?
involvement of most organ systems recognised
systemic vasculitis
often delayed diagnosis
what is Behcet disease known as and why?
silk road disease
more common in people of this bloodline
Behcet disease pathogenesis
disruption of innate immunity
disruption of adaptive immunity
AB dependent cellular cytotoxicity to oral epithelium
hypercoagulability
autoABs deposited around blood vessel walls
Behcet disease aetiology
genetic predisposition - HLA B51 association env factors - HSV - s sanguis - pollutants
Behcet disease clinical manifestations
oral aphthous ulcers genital lesions ocular lesions skin lesions - palpable purpura, SC nodules vasculitis
can be more extensive
Behcet disease pathargy test
needle prick (SC puncture)
24-48hrs
exaggerated inflammatory reaction
- pustule/nodule forms
Behcet disease diagnosis
difficult
no lab test
mostly clinical
history key
Behcet disease - consensus classification of paediatric Behcet disease
recurrent oral aphthosis ≥3 a
genital ulceration and aphthosis
skin - necrotic folliculitis, acneform lesions, erythema nodosum
ocular - uveitis, retinal vasculitis
neurological signs (not isolated headaches)
vascular signs - venous thrombosis, arterial thrombosis/aneurysm
score ≥3
Behect disease tx
CS topical colchicine azathioprine biologic therapies
what is the most common manifestation of Behcets?
oral aphthous ulcers 90-100%
Behcet disease differential diagnoses
RAS infections skin diseases Crohns SJS pemphigoid pemphigus SLE IBD sarcoidosis
SLE what is it?
AI multisystem disorder
CT disease
almost all tissues and organs
systemic inflammation and tissue damage
SLE antibody
ANA+
SLE epidemiology
more F
SLE contributing factors
genetic predisposition env - smoking, UV, EBV, exposure to silica dust, petroleum, organic solvents and mineral oils hormonal epigenetic immunoregulatory factors
SLE manifestations
constitutional - fatigue and fever renal - lupus nephritis CV - pericarditis MS - arthritis/arthropathy neuropsychiatric pulmonary GI ocular cutaneous
types of cutaneous lupus
chronic/discoid cutaneous
subacute cutaneous
acute cutaneous
discoid/chronic cutaneous lupus
most common clinical manifestation of cutaneous lupus
disk lesions - plaques, scar
scarring alopecia
dsDNA+
oral mucosa - OLLs 25% (mainly HP)
oral DLE is an OPMD but malignant transformation is extremely rare
subacute cutaneous lupus
erythematous macules/papules, evolve into either
- scaly papulosquamous psoriasiform lesions
- annular patches and plaque
oral lesions rare, similar to discoid
healing - post-inflammatory hyper and/or hypopigmentation, greyish atrophic scarring and telangiectasias
acute cutaneous lupus
can be 1st sign of SLE - preceding onset of systemic disease by weeks/months malar/butterfly rash - erythematous oral lesions - ulcerations - mainly HP - intense erythema +/- petechiae also when your systemic lupus is active
SLE lab testing
+ANA
mandatory entry criterion - 99% cases present
v high sensitivity but limited specificity (occur in other CT diseases)
anti-SM and anti-dsDNA highly specific, less sensitive
SLE oral manifestations
oral mucosa - ulcerations - LLs - erythematous lesions - leukoplakias - petechiae - cheilitis with erythema salivary gland - low flow rate (associated with SS) caries TMJ involvement PDDs
SLE classification criteria (not diagnostic)
entry criterion ANA titre ≥1:80
additive criteria
- don’t count if more likely explanation than SLE
- one occasion sufficient
- don’t need to occur simultaneously
- need ≥1 clinical criterion and ≥10 points
- in each domain count only highest criterion
SLE pharmacological tx
based on pt manifestations CS - prednisolone hydroxychloroquine immunosuppressive e.g. azathioprine NSAIDs for MS pain drugs targeting B cells: rituximab
SLE and cancer
slight increase in cancer risk overall haematologic (lymphoma, leukaemia, MM), NHL, H+N cancer possible factors mediating risk - lupus-related meds e.g. cyclophosphamide - inherent immune system abnormalities - overlap with SS - viral infections e.g. HPV/EBV - traditional cancer RFs e.g. smoking
what oral effect can hydroxychloroquine cause?
oral pigmentation
SLE and lichenoid oral reactions
central atrophic/shallow erosions with white striae at margins
often patchy and unilateral
may be on HP (usually spared by OLP)
EM - what is it?
vasculitic AI disease
acute immune-mediated inflammatory MC disease
triggered by hypersensitivity reactions to various antigens with a tendency to recur
can affect MM and skin
EM epidemiology
usually young adults
EM pathogenesis
T3 hypersensitivity reaction
- form Ag-Ab complex in circulation
- deposit of immune complex in bv’s
- appearance of inflammatory reaction with subsequent vasculitis
EM causes
INFECTIONS and DRUGS
EM - what is the most commonly identified cause?
HSV infection
what is the most common cause of EM in kids?
mycoplasma pneumoniae infection
EM - drugs that can cause it
ABs sulfonamides antiepileptics barbituates NSAIDs
other conditions that can cause EM
IBD
malignancy
menstruation
DIEM immunology
no IFNy but have TNFa
produced by macrophages, which along with perforin and granzyme B, will induce keratinocytes apoptosis with subsequent epithelial destruction
EM subtypes
isolated
recurrent
persistent
HAEM
7-21 days after primary or recurrent viral infection
- HSV DNA engulfed
- migrate to epidermis to transfer these antigens to keratinocytes
- expression leads to activation of HSV specific CD41 Th1 cells, which produce IFNy
epithelial damage
isolated EM
occurs just once
- infections, drugs
recurrent EM
freq occurrence of EM over a period of years, usually >6 episodes p.a.
- infections, menstruation
persistent EM
continuous occurrence of typical and atypical lesions without interruption
- IBD, infections, malignancy
clinical forms of EM
minor
major
minor EM
skin <10% BSA
mucosa uncommon, 1 site only, usually oral
usually target lesions/bullae
major EM
skin <10% BSA
mucosa ≥2 sites
usually begins with starting a new drug or HSV
myalgias, sore head, throat and fever
spreads to mouth, upper resp tract, GIT, then kidneys and joints
HAEM cause
HSV 1 or 2
HAEM course
no/mild prodromal S+S
acute
self-limiting
recurrent
HAEM site
skin
minimal mucosal
HAEM histology
focal keratinocyte necrosis, edema, predominant mononuclear infiltration CD4+
HAEM cytokine
IFNy
DIEM cause
drugs
DIEM course
flu-like prodrome
acute
self-limiting
not recurrent
DIEM site
skin and mucosa
DIEM histology
extensive keratinocyte necrosis, less edema, prominent mononuclear infiltration CD4+
DIEM cytokine
TNFa
typical target lesion EM
central blister
edematous ring
erythematous border
atypical target lesion EM
raised, edematous lesion with two zones of colour change and a poorly defined border
oral lesions EM
small ulcers to widespread huge erosive lesions
can lead to pts not being able to eat, speak or open mouths
precede lesions in other SSE
diffuse and widespread macules - blisters - ulceration
lips swollen, cracked/crusted
usually lips and anterior mouth
EM skin lesions
commonly distal extremities of extensor surfaces (arms, legs, elbows, knees, dorsum of hands and feet)
lesions symmetric, round, slightly pruritic, may evolve into papules
some lesions may form the large annular (ring shaped) target lesions, the dark centre of it being a necrotic ulcer
EM diagnosis
no standardised criteria clinical history clinical exam biopsy (skin) - HandE, DIF lab studies - test for ESR, WCC, LFT, electrolytes - IIF to rule out AI blistering disease
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)
EM diagnosis - clinical exam
skin lesions: typical, atypical
morphology: pleomorphic appearance of oral lesions
location: lips and anterior mouth
- erythematous, erosions, fibrin, haemorrhagic
EM tx
tx underlying infection/medication
symptomatic tx - clinical severity
- prevent infections and local symptom control
mild: topical antiseptics, antihistamines, analgesics, topical CS
MM: high potency CS gel, oral anaesthetic solutions, topical ophthalmic preparations
severe mucosal: 40-60mg prednisolone, taper 2-4wks
recurrent: 6m trial of continuous antiviral therapy
