Vasculitis (LVV, MVV, SVV, MVV), PMR Flashcards
1
Q
** Rheumatic diseases assoc’d w aortitis**
A
-Seronegative SpA
-Relapsing polychondritis
-Behcet’s
-Cogan’s
-Sarcoid
-LVV: GCA, TAK
-AAV
2
Q
DDx ascending aorta vasculitis/aneurysm
A
Inflamm: GCA, TA, Behcet
-Noninflam: Marfan, Ehlers-Danlos type 4, familial thoracic aneurysm/dissection, loey-diatz
3
Q
DDx isolated descending aorta vasculitis/aneurysm
A
TA (india/pakistan)
-Inflammatory abdominal artery aneurysm
4
Q
DDx isolated pulm artery vasculitis/aneurysm
A
Behcet’s (huge’s stovin syndrome)
5
Q
DDx periaortic vasculitis/aneurysm
A
-IgG4 related disease
-Lymphoma
-Erdheim Chester
6
Q
GCA Presentation
A
Cranial: H/A, scalp tenderness, jaw/tongue claudication, trismus, diploplia, visual sx
-Extracranial: abnormal pulse, stroke, dizziness, claudication, abdo pain, HTN, angina
-Systemic: fever, wt loss, UE claudication, arthritis, cough
7
Q
Non-productive Cough in GCA Mechanisms
A
-Pharyngeal artery vasculitis (branch of external carotid)
-Stimulation of cough receptors in the bronchus due to aortic inflammation
8
Q
Physical findings GCA
A
-Scalp tenderness
-Temporal artery tenderness, reduced pulse
-Visual sx: diploplia, amaurosis fugax, vision loss, optic neuritis, optic atrophy
-BP >10mmHg diff between arms
-Carotid/Subclavian bruits
9
Q
What single physical exam finding has the highest likelihood of having a positive temporal artery biopsy?
A
Temporal artery beading
10
Q
Ocular Symptoms GCA
A
Diplopia (Blurry vision)
-Amaurosis fugax, aura
-Painless vision loss
-AION, PION
-Iritis, Conjunctivitis
-Ophthalmoplegia (ischemia EoM)
11
Q
Mech of vision loss in GCA
A
-1. AION caused by vasculitis of posterior ciliary artery
-2. central retinal artery occlusion
-3. posterior ischemic optic neuropathy (PION)
-4. occipital cortex ischemia
12
Q
Nonvasculitis ocular symptoms in GCA patients on prednisone
A
Glaucoma
-Cataracts
-Central serous retinopathy
13
Q
GCA vessels
A
Aorta
-Subclavian
-Vertebral
-Carotid
-Iliac
-Mesenteric
-Renal
-Coronary
-Rarely pulm artery
14
Q
Aneurysm monitoring/management
A
MRA/CTA q6-12mo
-Periodic CXR, TTE, Abdo US
-
-Surgery/Endovascular repair >5cm or dissection
-
15
Q
GCA Imaging - US (vessels, signs, adv, disadv)
A
Vessels: Temporal, axillary, subclavian
-Signs: halo sign, compression sign
-Adv: cheap, no radiation, noninvasive
-Disadv: operator dependent
16
Q
GCA Imaging - MRI (vessels, signs, adv, disadv)
A
Vessels: Temporal, Cranial, aorta, intrathoracic/intraabdo large/medium branches
-Signs: active vessels uptake contrast, structural changes (stenosis, aneurysm)
-Adv: no radiation, noninvasive, good sensitivity
-Disadv: cost, access, procedural time
17
Q
GCA Imaging - CT (vessels, signs, adv, disadv)
A
Vessels: Aorta, intrathoracic/intraabdo large/medium branches
-Signs: active vessel uptake contrast, structural changes (stenosis/aneurysm)
-Adv: fast, noninvasive
-Disadv: radiation, cost higher than US (lower than MR)
18
Q
GCA Imaging - FDG PET (vessels, signs, adv, disadv)
A
Vessels: Temporal, axillary, subclavian
-Signs: FDG uptake
-Adv: Can look for GCA and mimickers (ca, infxn)
-Disadv: radiation, high cost, access, NOT GOOD for cranial vessels
19
Q
** GCA Bx Histology**
A
** Media thickening with TRANSMURAL GRANULOMATOUS inflammation (panarteritis)
- GIANT CELLS, lymph/macrophages, eo
-Intimal hyperplasia/fibrosis
-Fragmentation/destruction internal elastic lamina’
-SHOULD NOT SEE FIBRINOID NECROSIS (look for GPA)
20
Q
4 reasons for negative TAB in someone you suspect GCA in
A
- Previous corticosteroid use
– GCA with phenotype not associated with cranial arteritis
– Sampling error& missed lesion due to skip lesions
– Inadequate sample
– Delayed biopsy after treatment
– Biopsied temporal vein
– Patient does not have GCA, i.e alternative diagnosis
21
Q
**4 clinical or lab findings that are associated with positive TAB **
A
Limb claudication (positive LR, 6.01; 95% CI, 1.38-26.16),
-Jaw claudication (positive LR, 4.90; 95% CI, 3.74-6.41),
-Temporal artery thickening (positive LR, 4.70; 95% CI,2.65-8.33),
-Temporal artery loss of pulse (positive LR, 3.25; 95% CI, 2.49-4.23),
-Platelet count of greater than 400 (positive LR, 3.75; 95% CI, 2.12-6.64),
-Temporal tenderness (positive LR, 3.14; 95% CI, 1.14-8.65),
-Erythrocyte sedimentation rate greater than 100 mm/h (positive LR, 3.11; 95% CI, 1.43-6.78).
22
Q
Layers of vessel from lumen outwards
A
Tunica Intima
-Internal elastic lamina
-Tunica media
-External elastic lamina
-Tunica adventitia
-Vasa vasorum
23
Q
Where is vasovorum and what does it do
A
Located in adventitia
-Microvascular network supplies O2 and nutrients to vessel
24
Q
GCA labs
A
Elevated ESR, CRP
-Anemia, Thrombocytosis, Transaminitis (ALP)
-
25
GCA Pathogenesis
Ag trigger activates vascular DCs at adventitia → T cell activation, attraction of lymphocytes/macrophages → granuloma formation, proinflammatory cytokines (IL 1,6, 21, 17), injury of media and external lamina, neoangiogenesis, hyperplasia of intima, and vessel stenosis/occlusion
-DCs at adventitia
→ recruit macrophage, lymphocytes
→ produce IL12/18 for Th1 differentiation → IFNg (macrophage activation and granuloma formation)
-→ IL1/6/21 → Th17 differentiation → IL17 (vascular inflamm, MMP production to destroy internal elastic lamina)
-VEGF brings more T cells and macrophages
-Plt derived growth factor IL1 → intimal proliferation and ischemia
26
GCA HLA link
HLA DR4
HLA DRB1*04
27
GCA Tx
Pred 1mg/kg (pulse if vision threatening/loss) x1 mo or until ESR/CRP normal, then long taper
-ASA 81 daily for critical/flow limiting involvement of vertebral/carotid arteries
-MTX if diabetes, relapsing, or steroid side fx
-Toci 162mg SC weekly (if visual sx or critical cranial ischemia)
28
TA presentation phases
1: prepulseless inflammatory period: fevers, arthralgias, wt loss
-2: vessel inflammation: pain/tenderness
-3: fibrotic: bruits and ischemia
29
TA clinical manifestations
Bruits, decreased pulse, asymmetric BP
-HTN, arthralgia, constitutional sx
-
-Subclavian/Iliac → limb claudication
-Carotid/Vertebral → H/A and presyncope
-Pulm artery → pHTN
-Cardiac → angina, MI, HF, death, regurg
30
TA Dx
MRA > CTA, FEG-PET, US
-Biopsy NOT necessary to diagnose
31
TA histopath
Similar to GCA: Focal panarteritis w/ skip lesions and patchy involvement
-
-Different from GCA : cellular infiltrate in adventitia and outer parts of media (including vasa vasorum) with gamma-delta T lymphocytes, NK cells, and CD8 T cells (vs Th1/Th17 lymphocytes in GCA)
32
TA Tx
-Initial
-Adjunct
-Refractory
-Salvage
-Other
-Refractory to meds
GC + MTX/AZA/TNFi
-Adjunct: ASA (if cranial/vertebrobasilar involvement)
-Refractory: LFN, MMF, AZA, ustekinumab, infliximab, toci
-Salvage: CYC
-Other: BP control, antiplatelet, smoking cessation, lipid mx
-Surgery only if ischemic once dz quiescent (angioplasty, stenting, bypass graft surgery)
33
TA morbidity
Cardiac:
-Aneurysm, rupture, dissection
-LVH
-Aortic root dilatation, regurg
-pHTN
-MI
-Stroke
34
Infectious aortitis causes
-TB
-Syphilis (tertiary)
-Bacterial (Staph, Strep, Salmonella
-Viral
35
Idiopathic isolated aortitis
-Isolated idiopathic thoracic or abdo aortitis
-Giant cell aortitis: indistinguishable from GCA
-IgG4RD
-Chronic periaortitis (abdo)
-Inflamm abdo aortic aneurysm
36
LVV mimickers
-FMD
-Atherosclerosis
-Radiation fibrosis
-IgG4
-Sarcoid
-Inflamm aortic aneurysm
-Syphilitic aortitis
-Genetic disease (marfan, loeys dietz)
-Congenital coarctation of aorta
-Neurofibromatosis type 1
37
** PAN organ involvement **
Peripheral nerves > skin > abdo > muscle > kidney
-Unlikely: ENT, lungs
38
**Clinical features PAN **
- Classification criteria
- Other features
3+ of the following
-Weight loss
-Livedo
-Testis: pain (more w/ hep B)
-Myalgias (excluding shoulder/hip girdle) or weakness
-Nerves: Mononeuritis multiplex (motor/sensory), foot drop, polyneuropathy
-dBP>90mmHg
-Elevated BUN/Cr
-HBV
-Arteriographic abN
-Biopsy small/medium artery showing PMN
Others:
-CNS: stroke, seizure, jaw claudication
-Eye: retinal hemorrhage, optic ischemia
-Skin (LE): Purpura, ulcers, livedo, nodules, fingertip infarct, necrotic lesions
-Cardiac: MI, HF
-Abdo: pain, liver fcn, mesenteric arteritis
-Renal: infarcts, HTN, Proteinuria
39
Clinical features more found in HBV assoc’d PAN vs PAN
HBV assoc’d: more orchitis, HTN, renal infarct
40
**PAN cutaneous findings**
Sam as GPA/eGPA/IC SVV
-Purpura
-Ulcers,
-Livedo,
-Nodules,
-Fingertip infarct,
-Necrotic lesions
41
Labs PAN
-AoCD, Thrombocytosis, ESR/CRP,
-Low albumin
-Can hv elevated Cr (from renal vessel occlusion) with BLAND urine
-Classically: negative ANA, cryo, RF, ANCA
- HBV
42
Dx PAN
Biopsy symptomatic (skin, sural nerve, muscle, rectum, testicle) showing granulocytes +/- mononuclear leukocytes in artery wall
-Angiogram if cannot biopsy (usually abdo: renal, liver, spleen, stomach, large/small bowel; rarely hand/foot) showing aneruysm/occlusion of visceral arteries (not due to atherosclerosis, FMD, or other cause)
43
PAN histology
Focal & segmental transmural **necrotizing vasculitis ** of medium/small arteries (>arterioles; no vein or large vessel involvement; uncommon splenic, rarely pulmonary)
44
PAN purpura Biopsy histology
LCV
45
PAN angiogram findings
Microaneurysm (saccular aneurysm)
-Occlusion/cutoff
-Luminal irregularities
-Stenoses
-Rosary bead sign
46
Ddx aneurysms on abdo visceral angio
Segmental arterial mediolysis (SAM)
-FMD
47
Segmental arterial mediolysis (SAM)
-Pathogenesis
-What vessels
-Dx
-Tx
** Vasospasm/FMD variant**
-Nonatherosclerotic & ** noninflamm** lytic loss of medial muscle → dilation/aneurysm (muscular, splanchnic, basilar cerebral, coronary arteries)
-Dx: Angiogram, Biopsy
-Tx: Surgery, BP control
48
**2 imaging findings to differentiate segmental arterial mediolysis (SAM) from PAN**
PAN: microaneurysms at vessel branch point and vessel wall thickening
-
-SAM: NO significant vessel wall thickening. String of beads (stenosis, dissection, aneurysm, thrombosis) at multiple renal/ mesenteric arteries
49
**1 lab finding to differentiate SAM from PAN**
PAN has elevated ESR, CRP, abnormal UA
-SAM DOES NOT
50
PAN pathogenesis theories
Immune complex (complements / complexes seldom found)
-Endothelial injury → cytokines/inflamm (no Ag or trigger found)
51
**Conditions assoc’d w/ PAN or PAN vasculitis**
Viral infxn: HBV > CMV, HTLV1, HIV, parvo, EBV, Hep C,
-Hairy cell leukemia
-Genetic: loss of adenosine deaminase 2 (DADA2)
-Autoimmune: SLE, RA, childhood DM, Cogan
-Med rxn: allopurinol, sulfa
52
Tx systemic PAN
Mild (No cardiac, GI, CNS): pred 1mg/kg x4 wks, taper 6-12mo + AZA (2mg/kg) or MTX (20-25/wk)
-Mod/severe: pred 1-2mg/kg + CYC
-Organ/life threatening: IV pulse GC + CYC (2mg/kg PO or 0.5-1g/m2 /mo IV) x4-12mo. (PLEX ONLY if catastrophic)
CYC → AZA/MTX once in remission for total **18mo** (MMF if can’t AZA/MTX, Ritux if can’t CYC) + pred taper
-Adjunct: HTN control, PJP ppx, OP prevention
- PT if nerve/muscle involvement
- DADA2: TNF > GC alone
53
Tx HBV assoc’d PAN (HBsAg+ and HBeAg+)
HBV assoc’d PAN:
-Pred 60 mg/d x1 wk then taper by 50% dose daily until off by end of 2nd week
-PLEX to remove immune complex 3x/wk for 3 wks, 2x/wk for 2 wks, then once/wk until HBeAg-neg
-Antiviral agents on day of PLEX after procedure
54
5 factor score - Indications and Components w/ 5 year survival
At diagnosis to predict prognosis of PAN, MPA, eGPA
-Cardiac sx
-GI involvement
-CNS involvement
-Creatinine >140umol/L
-Proteinuria >1g/24h
0 = 88% 5 year survival
1 = 75%
2+ = 54%
55
PAN Cause of death
-1 year
->1 year
1 year: uncontrolled vasculitis
>1 year: complication tx, infxn, vascular event (stroke, MI)
56
Tx Isolated PAN
-Which organs
-How to treat
Cutaneous (nodular lesions, livedo, polyneuropathy):
-Pred 20-40mg/d w/ taper
-Steroid sparing: MTX, AZA, colchicine, dapsone
-
-Localized gallbladder, uterus, breast, appendix:
-Sugical excision
-No immunosuppression
57
Thromboangiitis obliterans aka Buergers
-What is it
Inflamatory , obliterative, nonatheromatous vascular dz of small/medium arteries AND veins.
58
TO Pathology
Acute: *hypercellular inflammatory thrombus with microabscess* within thrombus
-Subacute: microabscess surrounded by granulomatous inflamm --> organization/recanalization of thrombus
-Late: mature thrombus w/ vascular fibrosis
-*Internal elastic lamina INTACT*
59
TO etiology
Unknown
-Possible:
-Smoking (pipe, cigar, tobacco, weed)
-Autoimmune: antiendothelial cell antibodies in active dz (not remission)
-DNA fragments of anaerobic bacterial in arterial lesions and oral cavities
60
TO features
Ischemia/claudication feet > hands (distally progressing up)
-Instep/pedal claudication
-Digital ulcerations, gangrene, rest pain
-Dysesthesias
-Cold sensitivity
-Superficial migratory thrombophlebitis
-Raynaud’s, rubor, cyanosis
-Arthralgias
61
TO DDx
Collagen Vascular dz: SLE, SS, MCTD
-Vasculitis: PAN, GCA, TA, cocaine, SVV
-APLA
-Blood dyscrasias: PV, ET, hyperviscosity Occupational: vibratory tools, hypothenar hammer syndrome
-Embolic: thoracic outlet syndrome, myxoma, cholesterol emboli
-Ergot/emphetamine tox
-Atherosclerosis
-Pernio
-Frostbite
62
TO Ix
Normal: CBC, LFT, UA, BG, ESR/CRP, ANA, RF
-TTE for cardiac thrombi
-Duplex US / ABI
-Arteriogram
63
TO arteriographic findings
B/L focal segments of stenosis or occlusion with NORMAL proximal or intervening vessels (no emboli or atherosclerosis). Collaterals around occluded areas (treet root, spider web, corkscrew appearance)
-Small/medium artery AND veins involved
-Common: digital arteries fingers/toes, palmar, plantar, tibial, peroneal, radial, ulnar arteries
64
TO Tx
Discontinue any tobacco (smoking, even nicotinue replacement)
-
-Treat ischemic ulcer (wound care, CCB, pentoxifylline, iloprost, sympathectomy, bosenta, GCSF, fibroblast/hepatocyte growth factor, BM mesenchymal stem cells)
-
-Treat cellulitis (abx)
-
-Treat superficial phlebitis (NSAIDs)
-
-Angioplasty, Revascularization, Bypass graft
-
-Amputate (last resort)
65
PACNS / PCNSV manifestations
*H/A*
-Neuro sx: cog dysfcn, stroke, FND, sz, hemorrhage, encephalopathy, myelopathy, radiculopathy, neuropathy, ataxia, coma
-
-Systemic vasculitis sx ABSENT (fever, rash, mononeuritis multiplex)
66
PACNS/PCNSV DDx
Infections: Hep B/C, HIV, VZV, Syphilis, Lyme, TB, Fungal, Bartonella, Herpes
-
-Malignancy: CNS lymphoma, lyphomatoid granulomatosis
-
-Drugs: Cocaine, heroine, amphetamines (all cause vasospasm vs vasculitis)
-
-CTD: SLE, Sjogren, Behcet, PAN, AAV, APLA
-Susac: endotheliopathy w/ sensorineural hearing loss, encephalopathy, retinal artery occlusion
-
-Others: Sarcoid, CADASIL, FMD, Moyamoya, cardiac emboli
67
PACNS/PCNSV Dx
Brain biopsy (higher yield from granulomatous vasculitis vs lymphocytic vasculitis)
-Imaging:
-Angiogram (not specific: stenosis/ectasis in 1+ vascular bed) > CTA/MRA
-MRI (cortical/subcortical infarcts, white matter hyperintesity, gadolinium enhanced intracranial lesions)
-CSF: lymphocytic pleocytosis, elevated protein, occasionally high IgG and oligoclonal bands. (consider RCVS if normal CSF)
-*exclude intravascular lymphoma if LDH elevated*
68
PACNS/PCNSV Tx
High dose pred + CYC (or ritux) x3-6mo (while taper pred)
-Remission (no new sx or MRI lesion): AZA or MMF x1y +
69
RCVS manifestations
-Acute thunderclap headache
-Seizures
-Brain edema
-SAH (lobar/convexity)
-PRES
70
RCVS Investigations
CSF and labs NORMAL
-Angiogram: reversible arterial narrowing of intracerebral arteries in bilateral hemispheres
Vasogenic edema
SAH
71
RCVS Tx
-CCB (nipodipine 60mg q6h, verapamil 80mg BID< verapamil SR 180-20 daily)
-Sometimes short course high dose prednisone
72
MVV mimickers
-Cholesterol emboli
-Atrial myxoma
-FMD
-Lymphomatoid granulomatosis
-Angioblastc Tcell lymphoma
-Thomboembolic disease
-Ergotism
-Type 4 EDS
-Segmental arterial mediolysis
-Grange syndrome
-Pseudoxanthoma elasticum
73
PMR clinical features
SECRET
-Stiffness/pain (prox muscles, NO weakness, >2wks)
-Elderly (>50, mostly >60, mean age onset 70)
-Constitutional, Caucasian
-Rheumatism (arthralgias/arthritis - NONEROSIVE, asymmetric distal joint, Knee/wrist/SC joint; MTP/ankle RARE)
-ESR>40 +/- high CRP
-Temporal arteritis
-Absence of RF/CCP
-Rapid GC response
-AM stiffness >45min
-Nocturnal
-Constitutional sx (fever, wt loss, sweats, fatigue)
74
PMR Pathogenesis
- HLA DR4 association
-Dendritic cells activated at adventitia-media border of large vessel →IL1/6 production and suppression of Treg/Th17 response
75
PMR ACR/EULAR classification criteria
Required:
-- Age >50,
-- Bilateral shoulder discomfort,
-- Abnormal inflamm markers
-Points (at least 4 required or 5 if optional US criteria used)
-AM stiffness >45min (2)
-Hip pain/ROM limitation (1)
-No RF/CCP (2)
-Absence of other joins (1)
- Shoulder bursitis, biceps tenosynovitis, or glenohumeral synovitis AND at least one hip w/ synovitis and/or trochanteric bursitis (1)
- Bilateral shoulder w/ subdeltoid bursitis, biceps tenosynovitis, or GH synovitis (1)
76
Source of PMR symptoms
Tenosynovitis (biceps)
-Bursitis (subdeltoid, subacromial, trochanteric, interspinous)
-Synovitis (hip/shoulders)
77
PMR labs
Inflammatory markers
-Normocytic anemia
-Thrombocytosis
-INCREASED GAMMA GLOBULINS
-Elevated ALP
78
Indications for TAB in PMR
Sx of GCA:
-- Fever, HA, Claudication (jaw, tongue) scalp tenderness
-- Visual changes,
-- Tender/enlarged arteries, bruits,
-- Decreased pulsation or discrepant BP
-- Failure of prednisone 20mg/d to improved symptoms or normalize ESR/CRP within 1mo
79
PMR DDx
-Chronic pain, depression
-Hypothyroid
-Polymyositis (weakness w/o pain)
-Malignancy (esp lymphoma, myeloma)]
-Occult infxn (TB, HIV, SBE)
-Late onset spondyloarthropathy
-RA
-Shoulder OA, Rotator cuff, Frozen shoulder
80
PMR Tx
12.5-25mg pred daily x1-2yrs
OR
-IM methylpred 120mg q3wks
OR
-MTX 7.5-10mg/week + GC (if DM, OP, or can’t taper GC)
-NEWLY FDA APPROVED SARILUMAB (IL6Ra blocker)
-Exercise
-NO TNFi or CHINESE HERBAL SUPPLEMENTS
81
PMR poor prognostic factors
Older age
-Female
-Very high ESR/CRP
-Failure of CRP to normalize within 1 wk of pred
82
Pred taper in PMR
Decrease by 2.5mg q2-4wks until 10mg/d, then taper by 1mg q1-2mo
-
-Or tapering 1mg q2mo if flare occurs during taper
83
Steroid sparing agents for PMR
MTX 10-20mg/wk
84
Nonmedication treatment plan for PMR
ROM exercises
-Vitamin D
-Calcium supplements
-Regular DEXA scan
-Flu vaccines
85
** How does cANCA stain and what does it bind? And what disease **
C Anca = diffuse staining of neutrophil cytoplasm
-Binds PR3 (serine protease in neutrophilic granules)
-GPA (cANCA 90% Sens/spec)
86
** How does pANCA stain and what does it bind? **
pANCA = perinuclear cytoplasmic staining
-Binds MPO, but also elastase, lactoferrin, catalase, lysozymes
87
** False positive ANCA**
Usually pANCA and atypical ANCA (pattern not clearly c or pANCA)
-
-CTD: RA, SLE, SS, SSc, PM, RP
-Goodpasture
-Autoimmune GI: IBD, Autoimmune liver, PSC, PBC
-Cystic fibrosis
-Infxn: HIV, HBV/HCV, TB, IE, leprosy, malaria, Parvo B19, Mono
-Meds: PTU, methimazole, carbimazole, hydralazine, minocycline, cocaine with levamisole
88
GPA / MPA pathogenesis
1) Infxn → cytokine release (IL1, TNF) →
neutrophil/monocytes to transport PR3/MPO to cell surface.
2) ANCA bind to surface PR3/MPO activating neutrophils/ monocytes →
- degranulate ROS + lysosomal enzymes
- upregulate adhesion molecules on endothelial cells so activated neutrophils bind/transmigrate into vessel wall → vasculitis
- NETs damaging endothelium and causing more AB production
Activation of alternative complement pathway (by infxn/injury) → C5a release to further prime neutrophils for activation and promote NET formation and more PR3/MPO
89
** 5 causes of DAH with capillaritis**
Primary SVV: GPA, MPA, eGPA, anti-GBM, HSP/IgA
-2ndary vasculitis: SLE, RA, APLA, MCTD, DM, behcet, UC, APLA, SSc
-Cryo vasculitis
-Lung or autologous BM transplant rejection
-Drug induced (chemo, PTU, hydralazine, TNF)
-Infxn: IE, leptospirosis
90
** 5 causes of DAH without capillaritis**
-Idiopathic pulmonary hemosiderosis
-Coagulopathy (DIC, anticoag, antiplatelets, thrombolytics)
-Mitral stenosis
-Pulmonary veno occlusive disease
Diffuse alveolar damage
- Anything causing ARDS
- PNA
- Drug associated: amio, penicillamine, nitrofurantoin
- Toxin or inhalation injury (crack cocaine)
- PM, SLE
- Radiation therapy
- PE
91
** DAH workup**
Serologies: ANCA, AntiGBM, ANA
-CT chest
-Bronchoscopy: fungal, viral, bacterial, mycobacterial cultures, PJP
-Biopsy shows hemosiderin laden macrophages
-PFT shows increased DLCO
92
** DAH tx**
O2 supplementation +/- mech vent
-+/- ECMO
-GC (methylpred 1g IV daily x 3d → 1mg/kg PO)
-CYC IV 15mg/kg q2wk x 3, then q3wk x 3 mo or
-Rituximab 375mg/m2 x 4;
-PLEX.
93
** Non Rheum DDX for saddle**
Trauma
-Cocaine
-Surgery
94
** Rheum DDX for saddle**
GPA
-Relapsing polychondritis
-Sarcoid
-IgG4 related disease
-RA
95
Resp Manifestations of GPA
Upper
- Sinusitis, discharge, ulcers, septal perforation, epistaxis
- Saddle nose
- Laryngeal granuloma --> subglottic stenosis, stridor & hoarseness
Lower
- Granuloma (vessel, airway walls, interstitium →
- Nodules +/- cavitation → post-obstructive PNA
- Capillaritis → DAH
- Resp insuff from fibrosis
96
Renal Manifestations of GPA
Active urine: blood, WBC, protein, casts
-Acute/ chronic renal failure
97
Eye Manifestations of GPA
- Proptosis from orbital inflamm disease
-Episcleritis/scleritis
-Peripheral ulcerative keratitis (risk of corneal melt)
-Uveitis
-Conjunctivitis
-Optic neuritis
-Lacrimal duct obstruction
-Retinal artery thrombosis
98
Ear Manifestations of GPA
-Vertigo
-Hearing loss (conductive and sensorineural)
-Otitis media
-Mastoiditis
99
Skin Manifestations of GPA / eGPA / IC SVV
-Purpura, petechiae
-Ulcers , infarctions
-Subcutaneous nodules
-Vesicles
-Livedo reticularis
-Urticarial lesions
-Erythema multiforme (more eGPA and IC SVV)
100
MSK Manifestations of GPA
Arthralgias
-Myalgia
-Synovitis
101
CNS Manifestations of GPA
CNS:
- Pachymeningitis,
- Cranial neuropathy,
- Ocular palsy,
- CVA, SAH/SDH
- Seizure,
- Pituitary involvement,
-PNS: mononeuritis multiplex
102
Cardiac Manifestations of GPA
RARE Pericarditis, or involvement of myocardium/coronary vasculature
103
GI Manifestations of GPA
Intestinal perforation
104
GU Manifestations of GPA
Bladder/urethral vasculitis
-Orchitis
-Epididymitis
-Prostatitis
105
GN histology GPA
-ABSENCE of immune complex deposition
-Focal &segmental
-Necrotizing and crescentic
106
GPA histology
-Necrotizing vasculitis of small arteries/veins
-Extravascular & vascular wall granulomas
-Fibrinoid necrosis in vessel walls
- Infiltration of soft tissue by neuts, lymphs, macrophages, giant cells
107
Generalized vs limited GPA
Generalized: all 3 sites: upper respiratory tract, lungs, kidneys
-
-Limited: NO Renal, pulm hemorrhage, orbital pseudotumor, progressive neuropathy, and CNS dz
108
What to consider if hard palate lesions seen in ?GPA
Cocaine induced
-Infiltrative Ca (NK cell or T cell lymphoma)
109
Bloodwork abnormalities in GPA
Anemia of chronic inflamm
-Leukocytosis
-Thrombocytosis
-ESR, CRP
-Low albumin
-Elevated globulin levels
-UA: hematuria, pyuria, casts, proteinuria
110
How to differentiate GPA/MPA, Goodpastures, and SLE on imunofluorescence
Immunofluorescence:
-Goodpasture: linear deposition of anti-basement membrane AB binding epitopes in glomeruli/alveoli in basement membrane
-
-SLE: granular/lumpy deposition of Ig in glomerulus (immune complex deposition)
-
-GPA/MPA: NEGATIVE, scant Ig deposition in area of necrosis
111
Mimickers of GPA (and how to tell)
eGPA (atopy, eosinophilia)
-MPA (NO granuloma, cavitary pulm nodules, or destructive upper airway dz)
-Lymphomatoid granulomatosis (NO GN)
-Goodpasture (antiGBM positive, linear deposition)
-SLE (ANA, dsDNA, Sm, granular deposition)
-Granulomatous infxn: mycobacterium fungi syphilis, actinomycosis
-Cocaine: anti neutrophil elastase antibody, nasal septum pathology
-Atrial myxoma: TTE
-IE: blood cultures
-CHolesterol emboli: TEE, angio, skin bx
-Lethal midline granuloma: NK T cell lymphoma, nasal/palate destruction
112
**GPA induction therapy **
Pulse steroids
-CYC - IV (more relapse) = PO
-Ritux > CYC for induction/ relapsing dz
-CYC if severe (ARF Cr >4.0mg/dL)
-
-PLEX not recommended (consider if high risk ESRD PEXIVAS showed nonstatistically signif decrease in ESRD; not for DAH)
-
-Limited: MTX can be considered as steroid sparing agent
-
-** PPX SEPTRA 1DS MWF if >15-20mg/d pred (or dapsone, atovaquone, pentamidine if allergic)
113
**Why ritux over CYC based on evidence**
RAVE: RTX noninferior to CYC-AZA for induction and SUPERIOR to CYC-AZA for relapsing AAV. no diff in adverse events
-
-RITUXVAS: no diff in sustained remission at 12 and 24 mo (vs CYC-AZA)
114
**CYC IV vs PO**
Relapse: IV>PO
-Leukopenia: PO>IV
115
**PEXIVAS summary **
PLEX → no signif reduction of mortality and ESKD in pt w/ organ/life threatening AAV
116
**RTX + GC tx 0.5mg/kg vs Ritux + GC 1mgkg **
Noninferior but excluded severe renal/pulm involvement
-Most in study were MPO (lower relapse risk)
117
**Induction MMF vs CYC**
MMF noninferior but higher relapse in PR3
118
**Avacopan when and how to use**
Avacopan 30mg BID for induction of new or relapsing GPA/MPA treated w/ CYC or RTX
-For induction: continue for one year
-DC GC by end of week 4
-**caution if GFR<15 and DAH req mech vent
119
**Maintenance Tx trials: RTX vs AZA**
RITAZAREM & MAINRITSAN showed:
-RTX = less relapse than AZA
-RTX for 36mo > 18 mo
120
**AAV Maintenance Tx trials: MTX vs AZA vs MMF**
Similar efficacy for maintenance but relapse higher in MMF vs AZA
121
Tx subglottic stenosis
Radial CO2 laser incision, dilation
-Intralesional steroid injxn +/- topical mitomycin C
122
CYC dosing
NIH: 0.5-1.0g/m2 monthly x3-6mo
123
GPA maintenance therapy
AZA, MTX, Ritux within 3-6 mo after CYC start, 1-3years dep resp Mx, PR3 etc
-Ritux > AZA (MAINRITSAN)
124
Options for treatment resistant GPA
PLEX
125
** Preventing complication of GPA Tx **
CYC:
- Malignancy screening (esp >36g),
- Ovarian/sperm protection
- Decrease dose based on WBC
- Mesna for hemorrhagic cystitis
Infection:
- PJP ppx : septra 1ds mwf (or dapsone, atovaquone, pentamidine if allergic)
- Vaccinations
-IVIG if hypogammaglobulinemia
-OP prevention
-Nasal irrigation w/ mupirocin, budesonide, shampoo (as surfactant)
126
MPA vessels affected
Small vessels: capillaries, venules, arterioles
127
MPA presentation & histology
RPGN: Focal segmental necrotizing GN w/ crescents w/ NO immune deposits
-DAH/hemoptysis: Pulmonary capillaritis w/ NO immunofluorescence
-
-Fever
-Arthralgias
-Purpura
-PNS/CNS disease
128
MPA vs PAN
Vessels involved
Pulm/Renal
Lab data
Angio results
Relapse
PAN:
- Small/medium sized muscular arteries
-NO RPGN or DAH
- HBV and RARE ANCA
- Necrotizing vasculitis
- Microaneurysm with vessel occlusion/stenosis of kidney, liver, spleen, stomach, small bowel
- Rare relapse
MPA:
- Capillaries, arterioles, or venules
-RPGN and DAH
- NO HBV
- MPO, pANCA
- Necrotizing vascultiitis (NO Granulomas)
- Angiography normal
- Rare relapse
129
MPA vs GPA
NO granuloma in MPA
130
MPA antibody
p-ANCA against MPO
-c-ANCA against PR3 in 15-30%
131
eGPA vessels involved
Small and medium vessels
132
eGPA patient phenotype
-Previous atopy
-Nasal polyps
-Asthma
-Eosinophilia
133
Cytokines involved in eGPA
IL5 and eosinophil granule protein
134
eGPA 3 phases
Prodromal: allergic sx of rhinitis, asthma, polyposis, recurrent fevers
-Peripheral blood/tissue eosinophilia: shifting pulm infiltrates and eosinophilia, chronic eosinophilic PNA, eosinophilic gastroenteritis, myocarditis, fevers
-Life threatening systemic vasculitis: asthma STOPS, myocarditis, valvular insuff, neuro sx (vasculitis peripheral neuropathy), eosinophilic gastroenteritis, pupura, testicular pain
135
eGPA clinical features - paranasal sinus
Sinus pain/tenderness
-Rhinitis
-Polyposis
136
eGPA clinical features - lungs
Asthma (adult onset)
-Pulm infiltrates- patchy, shifting, nodular, NO cavitations
-Effusions
-ILD
-Pulm hemorrhage
137
eGPA clinical features - NS
Mononeuritis multiplex
-Asymmetric sensorimotor polyneuropathy
-Rarely CNS involvement
138
eGPA clinical features - joints
Arthralgias, arthritis (RARE)
139
eGPA clinical features - GI
Eosinophilic gastroenteritis (abdo pain, bloody diarrhea), abdo masses
140
eGPA clinical features - misc
Renal failure (uncommon), CHF, corneal ulcerations, panuveitis, prostatitis
141
eGPA lab findings
Eosinophilia with high IgE
-Anemia
-Inflamm markers
-RF in 70%
-pANCA against MPO
142
** 6 rheum causes of peripheral eosinophilia**
-Eosinophilic Fasciitis/ Myositis / Myalgia syndrome
-IgG4 / Sjogren
-SLE
-RA
-eGPA
-Sarcoid
143
** 6 nonrheum causes of peripheral eosinophilia**
Leukemia, lymphoma
-Infection: parasitic, helminth (eg strongyloides), fungi (histo, coccidiomyocosis, aspergillosis), viral (HIV)
-Allergic bronchopulmonary aspergillosis
-Asthma/atopy
-Eosinophilic PNA
-Drugs (NSAID, nitrofurantoin)
-IBD
-Idiopathic hypereosinophilic syndrome
-Cholesterol emboli
-Radiation exposure
144
eGPA histopath
-Necrotizing granulomas (extravascular) with central EOSINOPHILIC core (not basophilic) surrounded by macrophages and giant cells
-Eosinophils > PMN and lymphocytes
-Necrotizing vasculitis of small arteries/veins
145
Drugs to avoid in eGPA
Leukotriene inhibitors
146
FFS what is it for and what are they
5 features w/ poor prognosis in eGPA:
-Cr > 1.58
-Proteinuria >1g/d
-CNS
-GI
-Myocardial involvement
147
eGPA Tx
FFS 0: GC alone
-FFS≥1: GC + CYC
-
-Resistant: Ritux or mepolizumab (IL5 AB)
148
Meds causing drug induced AAV
Thyroid: PTU, methimazole, carbimazole
-Hydralazine, minocycline
-Cocaine with levamisole
149
Drug induced AAV manifestations
Constitutional sx
-Arthralgias w/ occasionals synovitis
-Cutaneous vasculitis
-Necrotizing GN (PAUCI IMMUNE)
-DAH
150
**Cocaine with levamisole manifestations (clinical)**
Constitutional: fevers, sweats, weight loss
-ENT: sinusitis, septal cartilage necrosis and perforation
-Derm: Purpura, digital abscess, necrotic lesions, ecchymotic bullous skin lesions
-MSK: arthralgia
-Pulm: DAH
-Renal: GN
-Heme: leukopenia, neutropenia
151
**Levamisole cocaine vasculitis etiology**
-Cocaine induces B cell activating factor secretion from neutrophils that produce more ANCA and cause more NETosis → mitochondrial DNA (immunogenic)
-Cocaine acts as haptan to trigger immune response an increase Ig formation and IC deposition → 2ndary hypercoag, tissue/skin thrombosis
152
**Cocaine with levamisole manifestations (labs) **
-Bone marrow suppression → leukopenia, AGRANULOCYTOSIS, Thrombocytopenia
-AB against PR3, MPO, APLA
-**Human neutrophil elastase**
153
**Differential for purpura and LCV on biopsy**
Infection: meningococcemia, gonococcemia, IE
-Cancer: paraneoplastic, lymphoproliferative dz
-Drugs: glucocorticoid induced,
-CTD, RA, EDS,
-Cholesterol emboli
-Idiopathic
-Thrombocytopenia: ITP, TTP, DIC, HITT
-Vasculitides: MPA, GPA, eGPA, IgAV, PAN, urticarial vasculitis, cryo vasculitis
154
**Purpura Tx **
Colchicine
-Dapsone
-AZA
-MMF
-Prednisone
-Treat underlying problem
-DC drug
155
**Erythema nodosum causes - 4 families w/ 3 examples each **
Idiopathic
-Pregnancy
-Systemic: Sarcoid, IBD, Celiac, SLE, APLA, RA, Ank Spond, TA, PAN, GPA, Sweet, SS,
-Infectious: TB, fungal (coccidiodo/ blasto/ histo), IE, viral (herpes), strep, leprosy, list any bacteria (E coli, staph, strep, campylobacter)
-Drugs: OCP, antibiotics (amox, penicillin, cipro, cephalosporin)
-Cancer: HL, NHL, leukemia, solid (GI/GU)
156
IC-mediated SVV histopath / LCV features
- Infiltration w/ PMN and mononuclear cells
- FIBRINOID NECROSIS of vessel wall
- Leukocyte fragments (leukocytoclasis)
- Vessel wall destruction
- Endothelial cell damage
-*eosinophils on biopsy suggest drug induced
157
IC mediated V causes
New meds
-Recent infxns
-Hep C
158
IC mediated V pathophys
Immune complex deposition in vessel wall → complement activation → PMN migration to area → lysosomal enzyme release and vessel wall damage
159
IC mediated V other manifestations
Constitutional (fever, malaise)
-Arthralgia (RARE arthritis)
-GI: pain, GIB
-GU: proteinuria, hematuria, renal insuff
160
IC mediated V causes
Hypersensitivity vasculitis (idiopathic or drug rxn)
-Urticarial vasculitis
-IgA vasculitis
-Cryo vasculitis (hep B, C, Ca, rheum dz)
-Rheum d/o (RA, SLE, SS, crohns)
-Infxn (SBE, Flu, Mono, HIV, Hep B/C)
-Ca (Leuko, lymphoma, myeloma, solid tumor, MDS, hairy cell)
-Anti GBM (NO SKIN)
-Erythema elevatum dilutinum (LCV limited to skin of extensor surfaces - knuckles, knees, butt)
161
IC mediated V MIMICKERS
-APLA
-Livedoid vasculopathy
-Cholesterol emboli, Atrial myxoma, IE
-Low Plt: ITP, TTP, DIC
-Meningococcemia
-Calciphylaxis
-Pigmented purpuric dermatoses
-Scurvy
-Amyloid
162
SVV Ix to send
CBC, Cr, UA, Hep B/C, RF, ANA, dsDNA, complements, ANCA, CRYO, HIV, SPEP, CXR, ESR/CRP
163
IgA V histopath
LCV or necrotizing SVV
-Immunofluorescence shows IgA deposition in blood vessels and in glomerular mesangium
164
IgA V pathogenesis
IgA deficient in galactose which is recognized by antiglycan antibodies → IC formation and deposition in tissue → alternative complement pathway activation (galactose deficient IgA not seen in SLE LN)
-
-IgA binds mesangial cells in kidney → prolif & proinflamm cytokines
165
IgAV manifestations
TETRAD:
-GI: abdo pain, intussusception, hemorrhage, ileal perforation
-Renal dz (proteinuria, hematuria, ARF)
-Rash: macular erythema, urticarial lesions → purpura
-Arthritis: transient oligo, ankle/knee
-
166
IgAV/HSP Tx
Mild: supportive,
-Arthritis: NSAID
-GI: pred 1mg/kg
-Renal: ACE+ARB + pulse steroids w/ high dose PO after if proteinuria >1g/d, nephrotic syndrome, >50% crescentic GN
-Resistant: AZA, CYC, Ritux
167
**AntiGBM Tx**
Concurrent PLEX, high dose GC, and CYC
168
Urticarial vasculitis subtypes
- Normocomplementemic - idiopathic hypersensitivity
-Hypocomplementemic (HUV) - low complement eg C1q
- HUVS (HUV syndrome)
169
Hypocomplementemic vasculitis syndrome criteria
HUV + 2 minor criteria
-- LCV
-- Arthralgia/arthritis
-- Ocular inflamm
-- GN
-- Abdo pain
-- Anti-C1q AB
170
HUV manifestations
Urticaria
-Arthralgia
-Scleritis/uveitis/episcleritis
-Angioedema
-Obstructive pulm dz
-GN
-GI
-Cardiovascular disease
171
HUV associations
75% in isolation
-25% assoc’d w/ SLE or SS
172
Urticarial vasculitis vs urticaria differences
Duration: >24-48h w/ residual hyperpigmentation vs <24h w/o trace
-Pain vs Pruritus
-0.5-5cm vs >10cm
-Systemic sx (fever, MSK, LN, active urine) vs rare in allergic urticaria
-Histology: LCV vs edema of upper dermis
-Distribution: Trunk/prox extremities > distal in other LCV
173
UV assoc’d conditions
Autoimmune: SLE, SS
-Ca: Lymphoma, IgM Paraproteinemia
-Infxn: Hep B, C
-Drug rxn
174
UV pathophys
IgG2 antiC1q AB (C1q precipitins) bind collagen like regions of C1q → IC → deposit in blood vessel to activate complement → inflamm
-Lung involvement if antiC1Q AB binds collagen like regions of surfactant in alveoli
175
UV Tx
Supportive with H1/H2 blockers
-
-Dapsone, HCQ, colchicine
-
-MSK: NSAIDs, or pred from 10-60mg
-
-Severe: CYC, Ritux, AZA, MMF
-
-Refractory: PLEX, IVIG
176
Erythema elevatum diutinum biopsy
LCV w/ fibrinoid necrosis
-Nonspecific immunoflueocescence
177
Erythema elevatum diutinum assoc’d conditions
Same as UV: CTD, Infxn, paraproteinemias, esp IgA
178
Erythema elevatum diutinum Tx
Dapsone, sulfapyridine
179
SVV mimickers
-Cholesterol emboli, IE, Mycotic aneurysm w/ emboli
-APLA
-Sepsis (gonoccoccal , meningococcal)
-Ca (lymphoma, solid tumor, myeloprolif)
-Ecthyma gangrenosum (Pseudomonas)
-TTP
-Drugs: Cocaine, Amphetamines, Minocycline, Hydralazine,
-HIV, Hep C
-Amyloid, sarcoid
-SLE, RA, SS, IBD
-Immunodef
-Calciphylaxis
-Livedoid vasculopathy
180
What are cryo
Igs/complexes that precipitated out of serum/plasma at low temp
181
Cryo classification
Type
-1: SINGLE MONOclonal Ig
-2 (MC): MIXED MONOclonal Ig w/ RF activity against POLYclonal Ig
-3: MIXED POLYclonal Ig w/ RF activity against POLYclonal Ig
182
How to collect cryo
At 37C: Collect blood, let clot x1 hr, centrifuge
-At 4C: incubate serum and centrifuge. Qualitative screen visually for cryoprecipitate vs quantitative using Wintrobe tubes
-
-If present: electrophoresis and immunofixation for isotypes and clonality
183
**Type 1 Cryo assoc’d disorders**
Essential
Lymphoproliferative disorders:
- MM
- Waldenstrom’s macroglobulinemia
- Chronic lymphocytic leukemia
- B cell lymphoma
184
**Mixed cryo assoc’d conditions: ie Type 2/3**
Essential
-CTD: ** SS **, SLE, RA, APLA, Behcet’s, AAV, IBD
-Infxn: ** HCV **, HIV, TB, IE, HBV, EBV, CMV, Parvo, brucellosis
-Heme Ca (waldenstrom, NHL, CLL)
185
** Mech of tissue injury in cryo vasculitis and manifestations: Type 1 and 2/3
Type 1: Cryo aggregation and precipitation → vascular occlusion → Raynaud, arterial thrombosis, distal ulceration/necrosis, hyperviscosity
-Type 2/3: HCV protein binds CD81 on B cells → stim and B lymphocyte expansion → Igs w/ RF activity bind HCV components form cryoglobulin immune complex → vasculitis, Raynaud's, pupura, arthritis, renal dz, neuropathy
186
Cryo clinical manifestations: Type 1, 2/3, 6 MC
Type 1: Raynaud, arterial thrombosis, distal ulceration/necrosis, HYPERVISCOSITY (bleeding vision changes, neuro symptoms
-Type 2/3: arthritis (poly, nonerosive), raynaud’s, renal dz, neuropathy, skin manifestations
6 MC: cutaneous, liver dz, arthralgia, renal dz, raynauds, neurologic,
187
Mixed Cryo skin manifestations
Purpura,
Urticarial vasculitis,
Digital necrosis,
Bullae,
Livedo racemosa
188
Mixed cryo renal manifesations
Type 1 membranoproliferative GN
-Nephrotic syndrome
-Nephritic syndrome
-HTN
-AKI/ARF
189
Mixed cryo neuro manifestations
Sensory polyneuropathy (symm/asymm, insidious/abrupt)
-Mononeuritis multiplex
190
Lab findings mixed cryo vasculitis
ELEVATED RF AND HYPOCOMPLEMENTEMIA
-C4 reduced MORE than C3
-Polyclonal hypergammaglobulinemia or monoclonal gammopathy
Other tests to order:
- Ana, ANCA, ENA, CH50, HCV RNA, SPEP
191
Mixed cryo vasculitis Dx
High RF, low complements, and presence of monoclonal gammopathy
-LCV on biopsy and intravascular hyaline thrombi
-Immunofluorescece: Ig and C3 deposition
-Liver/BM biopsy may show clonal expansion fo B cells
192
Poor prognostic factors for mixed cryo vasculitis
Male
-Age>60
-Type 2
-GI involvement
-Chronic HCV
-Diffuse vasculitis
193
** Mixed cryo vasculitis Tx options **
GC (high dose if neuro/renal/diffuse vasculitis)
-PLEX if hyperviscosity, high cryo [ ], or signif renal insuff
-CYC for severe WITH PLEX
-Colchicine - for pain, weakness, pupura, leg ulcers
-Low antigen diet
-Antiviral (interferon based or direct acting) + RTX > either alone
194
** Severe mixed cryo vasculitis + Tx (induction and maintenance) **
Ulcers/ischemia
-DAH
-Severe neuropathy
-GN w/ renal failure or nephrotic syndrome
-GI involved
-
-**Ritux + Steroids → antiviral for maintenance**
195
Mild/mod mixed cryo vasculitis manifestations
-+ Tx (induction and maintenance)
-Purpura
-Mild neuropathy
-GN w/o renal failure
-Antiviral therapy +/- steroids → antiviral for maintenance
196
Life threatening mixed cryo vasculitis manifestations
+ Tx (induction and maintenance)
-RPGN
-CNS involved
-Intestinal ischemia
-DAH
-PLEX + GC pulse + Ritux or CYC → antiviral for maintenance
197
Cryofibrinogenemia - what is it
Insoluble complex of fibrin, fibrinogen, fibrin split products, plasma prot and Igs that precipitate from PLASMA (NOT SERUM) w/ cold
198
Cryofibrinogenemia manifestations
Derm: vascular occlusion/ischemia → pupura, livedo, ulcers, gangrene, strokes, MI
-** Paradoxical bleeding ** bc clotting factors depleted
199
Cryofibrinogenemia assoc’d conditions
CTD, infxn, Ca, drugs (OCP), DM, advanced DLPD
200
Cryofibrinogenemia Tx
Avoid cold
-Smoking cessation
-Treat underlying
-Fibrinolytics (eg streptokinase)
-Low dose ASA
-GC for mild/mod
-DMARD for underlying CTD
201
Cold agglutinin disease - pathophys
IgM AB against erythrocytes → hemolytic anemia and complement mediated RBC destruction in reticuloendothelial system (liver) → occlusion by agglutinated RBC
202
Cold agglutinin disease - manifestations
Acrocyanosis
-Raynaud’s
-Ulcers over ears, nose, digits
203
Cold agglutinin disease - Tx
Warmth
-GC
-RTX
-Rarely PLEX
-Treat underlying
204
Examples of variable vessel vasculitis
Bechcet
-Cogan
205
Behcet’s criteria (revised international criteria for adamantiades - behcent’s disease)
Recurrent oral ulcers at least 3x in one 12mo period
+ 2 of following:
- Recurrent genital ulceration
- Eye lesions (anterior/posterior uveitis, hypopyon (cells in vitreous)**, retinal vasculitis
- skin lesion: pseudofolliculitis, papulopustular, erythema nodosum like, acneiform, pyoderma gangrenosum like
- **Positive pathergy (2mm erythema 1-2d after needle prick to 5mm)**
206
Behcet’s mimickers
IBD: Crohn’s
-SLE
-ReA
-Herpes
-Systemic vasculitis
-Sweet’s
-Periodic fever syndrome (PFAP, HIDS)
207
Behcet’s histopath
Variable: from neutrophilic vascular rxn to LCV
208
**HLA assoc’d w/ Behcets**
HLA B51
209
Aphthous stomatitis differential
Idiopathic
-Metabolic deficiency: B12, folate, Fe
-Autoimmune: IBD, Behcets, SLE, ReA, Celiac, Autoinflamm (PFAPA, HIDS)
-Drug: MTX, SJS
-Infxn: HIV, HSV
-Recurrent (complex) apthosis
-Menstrual related
-Cyclic neutropenia
-Derm: pemphigoid, pemphigus, lichen planus
210
Genital ulcers differential
Infxn:
-- Venereal: HSV, syphilis, chancroid, LGV, granuloma inguinale
-- Nonvenereal: pyogenic, yeast,
Inflamm:ReA, Crohn's, Behcet
Trauma (mech, chem),
Cancer: BCC, SCC
Drug reaction
211
Behcet’s eye manifestations
Ant/Post/Pan uveitis (bilateral, episodic)
-Conjunctivitis
-Corneal ulceration
-Papillitis
-Retinal vasculitis
-Optic neuritis
-Hypopyon (inflamm cells in anterior chamber of eye)
212
Behcet’s MSK manifestations
Arthralgia > arthritis - mono, oligo, poly
-RARE erosions
-Enthesopathy
213
Behcet’s Derm manifestations
Erythema nodosum
-Superficial thrombophlebitis
-Acneiform skin eruption or pseudofolliculitis
-Pyoderma gangrenosum like lesions
-Sweet’s
-Cutaneous SVV and pustular vasculitic lesion
-Pathergy
214
Behcet’s Vascular manifestations
-Thrombosis: SVC, IVC, portal or hepatic veins, pulm arteries, DVT
-**Arterial aneurysm of pulm arterial tree** MORTALITY RISK
-Superficial thrombophlebitis
-Small artery vasculitis
-*Hughes Stovin = DVT + pulm artery aneurysm w/ hemoptysis
215
Behcet’s Neuro manifestations
B/A
-Meningoencephalitis
-CN palsy
-Seizure
-Cerebellar ataxia
-Hemiplegia/Paraparesis
-Pseudobulbar palsy
-Extrapyramidal signs
-Intracranial HTN from dural sinus thrombosis
CNS MANIFESTATIONS MORTALITY RISK
216
Behcet’s GI manifestations
**Mucosal ulceration → perforation**
MORTALITY RISK
217
Behcet’s Cardio manifestations
RARE
-Valvular lesions
-Myopercarditis
-Coronary arteritis/aneurysm
218
Behcet’s GU manifestations
GN is rare
-Epididymitis
-Salpingitis
219
Behcet’s lab findings
Inflamm markers
-Leukocytosis
-Elevated IgG/A/M
-Elevated CSF prot/cell count
220
** Behcet’s cause for mortality**
CNS involvement
-Valvular dz (ruptured pulm/periph aneurysm)
-Bowel dz (perf)
221
** Behcet’s Tx for skin lesions**
Topical triamcinolone / sulcrafalate
-Dexamethasone swish and spit
-Oral Colchicine (for eyrthema nodosum and genital ulcers)
-GC - topical, intralesional, PO
-**Apremilast if fail topical, colchicine, and can’t taper pred **
-AZA > MMF
-**TNFi (WITH AZA)**
-Interferon alpha
-Dapsone, cyclosporine, IL1i
222
** Behcet’s Tx for eye dz**
Topical (anterior uveitis), intraocular, and systemic GC (posterior)
-AZA + GC for posterior (uveitis, retina, optic nerve)
-**TNFi (INFLIXIMAB best) WITH AZA or other DMARD +/- Cyclosporine (can worsen CNS behcet) or tacro**
-Interferon alpha (NOT with AZA bc myelotox)
-Salvage: CYC, chlorambucil
-Others: MTX, MMF, Anakinra, Toci, Ritux
223
** Behcet’s Tx for MSK **
Colchicine
-Refractory: GC, AZA, MTX, SFZ TNFi, Interferon-a
224
** Behcet’s Tx for CNS **
GC
-AZA
-Interferon a
-CYC
-**TNFi**
-*Do not use cyclosporine unless coexisting ocular disease
225
** Behcet’s Tx for GI**
GC
-SFZ
-AZA
-**TNFi**
226
Behcet’s Tx for vascular thrombosis
GC and immunsuppressives
-**do not anticoag until inflamm controlled bc silent aneurysm can cause hemorrhage → death
227
Behcet’s Tx for aneurysm/vasculitis
GC, CYC
-Endovascular embolizatin/surgery for hemorrahge
228
**Biologics for Behcets*
TNFi - Infliximab, Humira, Etanercept
229
**Nonbiologics for Behcets*
AZA
-Cyclosporine
-Apremilast
-Colchicine
230
MAGIC
Mouth and genital ulcerations with inflamed cartilage
-*ie behcets and relapsing polychondritis
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Behcet’s pathogenesis
Infectious trigger in genetically predisposed host
-Heat shock protein release → interact w/ TLR → Cytokine release (IL1/8/12/17) → neutrophil and T helper 1 cell hyperactivity
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Cogan manifestations
-Ocular
-Audiovestibular
-Constitutional
-Vasculitic (large medium),
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**Cogan Audiovestibular manifestations**
Rapid onset sensorineural hearing loss (often bilateral)
-Vestibular dysfunction (vertigo and ataxia)
-Cochlear hydrops
-Tinnitus
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Cogan constitutional manifestations
Fever
-Weight loss
-LN
-HSM
-Arthritis
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Cogan vasculitic manifestations
-Aortitis w/ aortic insuff/aneurysm
-Coronary vasculitis
-Aortic/mitral valvulitis
-Purpura
-Gangrene
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** Cogan Ocular manifestations**
**Nonsyphilitic interstitial keratitis** (Red, painful, photophobic eyes)
-Scleritis/episcleritis
-Uveitis
-Chorioretinitis
-Optic neuritis
-Retinal vasculitis
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Cogan lab manifestations
Low Hgb, high WBC/Plt/inflamm
-RARE: ANCA, ANA, APS, RF,
-Anti HSP70 AB
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Cogan Tx
-Anterior ocular eg keratitis: topical steroids, topical CNI
-Posterior ocular: high dose GC
-Audiovestibular or Systemic: High dose GC
-Resistant or failure to taper GC: MTX, AZA, MMF
-Others: CYC, cyclosporine, TNFi, Toci
-Cochlear implants
-Vascular surgery (AoV replacement or aneurysm repair)
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**Vasculitis mimic for Old guy with jaw claudication but normal CRP and test to rule it in**
Atherosclerosis → carotid US
-TMJ disease → MRI
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**Vasculitis mimic for Polyneuropathy, cardiac involvement, pulmonary infiltrates, and eosinophilia but no asthma**
Sarcoid → ACE, CXR, biopsy
-IgG4rD → biopsy
-Lymphoma/heme malignancy → biopsy/flow cytometry
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**Vasculitis mimic for Mechanical heart valve with active urinary sediment **
IE → TTE, cultures
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**Vasculitis mimic for 30 yr M with severe emphysema and ischemic digit**
Buerger’s → Angio
243
**arthritis in Lyme vs Behcet vs Sarcoid vs HSP, and additional features**
L: Migratory arthralgia → late episodic knee mono or asymmetric oligoarthritis
CN palsy, meningitis, AV block, myopericarditis
-B: mono/oligo/poly nonerosive distal medium joints (ankle, knee, wrist, elbow), with ulcers and enthesopathy
-S: symmetric (can be erosive), distal medium + PIP;
LN, granuloma, dactylitis.
Loftren’s (nodosum, LN, MSK),
Heerfordt (parotid, uveitis, facial nerve palsy)
-H: lower extremity large oligo (nondeforming). periarticular swelling
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Single organ vasculitidities
Cutaneous LCV
-Cutaneous arteritis
-Primary CNS vasculitis
-Isolated aortitis
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Vasculitis assoc’d w/ systemic dz
SLE, RA, Sarcoid vasculitis
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** SVV causes**
- AAV: GPA, eGPA, MPA
- IC: Cryo, IgA, Hypocomplementemic Urticarial (Anti C1q)
2ndary:
- Infection: Hep B/C, HIV, IE
- Drugs: Levamisole, penicillin, cephalosporin, diuretics, phenytoin, allopurinol
- CTD: SLE, RA, Sjogren
- Malignancy: lymphoma, leukemia, myeloma
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** Best time to biopsy LCV**
<24h = PMN infiltration w/o fibrinoid necrosis
24-48 = most likely to demonstrate LCV
>48h = inflamm cells --> lymphocytic and macrophages (vs PMN) and clear quickly leaving fibrinoid necrosis and nothign else
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** eGPA Cause of Death**
MI/CHF
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** GPA of larynx Tx**
Steroids +/- CYC
Endoscopic tx:
- Bronchoplasty (airway dilation)
- Airway stents
- Intralesional GC injxn into granuloma
- Dilation of subglottic lesion
- Carbon dioxide laser
- Tracheostomy
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eGPA classification criteria
Apply only when SVV or MVV diagnosis made
Clinical:
-Obstructive airway disease (+3),
-Nasal polyps (+3),
-Mononeuritis multiplex (+1)
Lab/Biopsy criteria
- Eosiniophilia >1E9 (+5)
- Extravascular eosinophil predom inflamm on bx (+2)
- cANCA or PR3+ (-3)
- Hematuria (-1)
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** Conditions assoc'd w/ mononeuritis multiplex**
Inflamm: RA, SS, SLE, GPA, PAN, Cryo, HUVS
Infxn: leprosy, sarcoid, lyme, HIV, EVC, CMV, Hep B/C
Metabolic: DM, Lead neuropathy
Infiltrative: sarcoid, amyloid, malignancy
Trauma
Ischemic: sickle cell, cholesterol emboli, livedoid vasculopathy
Wartenburg's relapsing sensory neuritis
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**Neuropathic patterns seen in vasculitis **
Mononeuritis multiplex
Stocking glove distribution
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GCA Classification Criteria
Apply only when SVV or MVV diagnosis made
REQUIRES Age 50 or more
Positive if 6 or more points
Clinical:
-AMS neck/shoulder (+2),
-Sudden vision loss (+3),
-Jaw claudication (+2)
-NEW temporal headache (+2)
-Scalp tenderness (+2)
-Abnormal exam of temporal artery(+2)
Lab/Imaging/Biopsy criteria
- Maximum ESR >50 or CRP >10 (+3)
- Positive TAB or halo sign (+5)
- Bilateral axillary involvement (aneurysm, stenosis, occlusion on angio, CT, MR, US, or PET) (+2)
- FDG PET activity throughout aorta (+2)
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** Techniques to look for ANCA**
Indirect immunofluorescence
- Serum mixed w/ neutrophils fixed on slide
- ANCA from serum attaches to neutrophils and is detected w/ AB
- Titre reported and staining pattern (perinuclear or cytoplasmic)
ELISA with plate coated w/ PR3, MPO
- Incubate patient serum w/ ANCA
- Enzyme added with radiolabel that targets ANCAs
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** Stroke in Young DDX **
Inflamm/Infection
- SLE, APS
- Vasculitis (PACNS, GPA, TAK, Behcet, Cogan)
- Relapsing polychondritis
- RA, Sjogrens
- Neurosarcoid
- HIV, VZV, Neurosyphilis, TB
Nonatherosclerotic angiopathy:
- Amyloid
- Moyamoya
- FMD
- Susac
- Sneddon
- RCVS
Heme:
- Hypercoag from deficiency of Prt S/C/AT, Factor V mutation
- Acquired hypercoag: preg, OCP, steroids, nephrotic syndrome
- Sickle cell
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** ANCA disease association and % **
pANCA:
- MPA 50-60%
- eGPA 25-30%
cANCA
- GPA 75%
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** Erythema nodosum biopsy**
Panniculitis involving septa in subcutaneous fat
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Cryo path
Precipitated cryo on light microscopy
Diffuse IgM deposition in capillary loops in immunofluorescence
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**Components found in cryoprecipitate **
Fibrinogen.
Factor VIII.
Factor XIII.
Von Willebrand factor.
260
** GCA how to biopsy**
Unilateral > Bilateral Within 2 weeks
Long segment >1cm preferred
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** Young patient with arthritis, oral ulcer and uveitis: List 5 differential diagnosis?**
Seroneg: PEAR
Behcet
Vasculitis: GPA
SLE
Relapsing polychondritis
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