Vasculitis (LVV, MVV, SVV, MVV), PMR Flashcards
** Rheumatic diseases assoc’d w aortitis**
-Seronegative SpA
-Relapsing polychondritis
-Behcet’s
-Cogan’s
-Sarcoid
-LVV: GCA, TAK
-AAV
DDx ascending aorta vasculitis/aneurysm
Inflamm: GCA, TA, Behcet
-Noninflam: Marfan, Ehlers-Danlos type 4, familial thoracic aneurysm/dissection, loey-diatz
DDx isolated descending aorta vasculitis/aneurysm
TA (india/pakistan)
-Inflammatory abdominal artery aneurysm
DDx isolated pulm artery vasculitis/aneurysm
Behcet’s (huge’s stovin syndrome)
DDx periaortic vasculitis/aneurysm
-IgG4 related disease
-Lymphoma
-Erdheim Chester
GCA Presentation
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
Non-productive Cough in GCA Mechanisms
-Pharyngeal artery vasculitis (branch of external carotid)
-Stimulation of cough receptors in the bronchus due to aortic inflammation
Physical findings GCA
-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
What single physical exam finding has the highest likelihood of having a positive temporal artery biopsy?
Temporal artery beading
Ocular Symptoms GCA
Diplopia (Blurry vision)
-Amaurosis fugax, aura
-Painless vision loss
-AION, PION
-Iritis, Conjunctivitis
-Ophthalmoplegia (ischemia EoM)
Mech of vision loss in GCA
-1. AION caused by vasculitis of posterior ciliary artery
-2. central retinal artery occlusion
-3. posterior ischemic optic neuropathy (PION)
-4. occipital cortex ischemia
Nonvasculitis ocular symptoms in GCA patients on prednisone
Glaucoma
-Cataracts
-Central serous retinopathy
GCA vessels
Aorta
-Subclavian
-Vertebral
-Carotid
-Iliac
-Mesenteric
-Renal
-Coronary
-Rarely pulm artery
Aneurysm monitoring/management
MRA/CTA q6-12mo
-Periodic CXR, TTE, Abdo US
-
-Surgery/Endovascular repair >5cm or dissection
-
GCA Imaging - US (vessels, signs, adv, disadv)
Vessels: Temporal, axillary, subclavian
-Signs: halo sign, compression sign
-Adv: cheap, no radiation, noninvasive
-Disadv: operator dependent
GCA Imaging - MRI (vessels, signs, adv, disadv)
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
GCA Imaging - CT (vessels, signs, adv, disadv)
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)
GCA Imaging - FDG PET (vessels, signs, adv, disadv)
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
** GCA Bx Histology**
** 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)
4 reasons for negative TAB in someone you suspect GCA in
- 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
**4 clinical or lab findings that are associated with positive TAB **
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).
Layers of vessel from lumen outwards
Tunica Intima
-Internal elastic lamina
-Tunica media
-External elastic lamina
-Tunica adventitia
-Vasa vasorum
Where is vasovorum and what does it do
Located in adventitia
-Microvascular network supplies O2 and nutrients to vessel
GCA labs
Elevated ESR, CRP
-Anemia, Thrombocytosis, Transaminitis (ALP)
-
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
GCA HLA link
HLA DR4
HLA DRB1*04
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)
TA presentation phases
1: prepulseless inflammatory period: fevers, arthralgias, wt loss
-2: vessel inflammation: pain/tenderness
-3: fibrotic: bruits and ischemia
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
TA Dx
MRA > CTA, FEG-PET, US
-Biopsy NOT necessary to diagnose
TA histopath
-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)
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)
TA morbidity
Cardiac:
-Aneurysm, rupture, dissection
-LVH
-Aortic root dilatation, regurg
-pHTN
-MI
-Stroke
Infectious aortitis causes
-TB
-Syphilis (tertiary)
-Bacterial (Staph, Strep, Salmonella
-Viral
Idiopathic isolated aortitis
-Isolated idiopathic thoracic or abdo aortitis
-Giant cell aortitis: indistinguishable from GCA
-IgG4RD
-Chronic periaortitis (abdo)
-Inflamm abdo aortic aneurysm
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
** PAN organ involvement **
Peripheral nerves > skin > abdo > muscle > kidney
-Unlikely: ENT, lungs
**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
Clinical features more found in HBV assoc’d PAN vs PAN
HBV assoc’d: more orchitis, HTN, renal infarct
PAN cutaneous findings
Sam as GPA/eGPA/IC SVV
-Purpura
-Ulcers,
-Livedo,
-Nodules,
-Fingertip infarct,
-Necrotic lesions
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
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)
PAN histology
Focal & segmental transmural **necrotizing vasculitis ** of medium/small arteries (>arterioles; no vein or large vessel involvement; uncommon splenic, rarely pulmonary)
PAN purpura Biopsy histology
LCV
PAN angiogram findings
Microaneurysm (saccular aneurysm)
-Occlusion/cutoff
-Luminal irregularities
-Stenoses
-Rosary bead sign
Ddx aneurysms on abdo visceral angio
Segmental arterial mediolysis (SAM)
-FMD
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
2 imaging findings to differentiate segmental arterial mediolysis (SAM) from PAN
-SAM: NO significant vessel wall thickening. String of beads (stenosis, dissection, aneurysm, thrombosis) at multiple renal/ mesenteric arteries
1 lab finding to differentiate SAM from PAN
PAN has elevated ESR, CRP, abnormal UA
-SAM DOES NOT
PAN pathogenesis theories
Immune complex (complements / complexes seldom found)
-Endothelial injury → cytokines/inflamm (no Ag or trigger found)
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
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
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
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%
PAN Cause of death
-1 year
->1 year
1 year: uncontrolled vasculitis
>1 year: complication tx, infxn, vascular event (stroke, MI)
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
Thromboangiitis obliterans aka Buergers
-What is it
Inflamatory , obliterative, nonatheromatous vascular dz of small/medium arteries AND veins.
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
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
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
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
TO Ix
Normal: CBC, LFT, UA, BG, ESR/CRP, ANA, RF
-TTE for cardiac thrombi
-Duplex US / ABI
-Arteriogram
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
TO Tx
-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)
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)
PACNS/PCNSV DDx
-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
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
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 +
RCVS manifestations
-Acute thunderclap headache
-Seizures
-Brain edema
-SAH (lobar/convexity)
-PRES
RCVS Investigations
CSF and labs NORMAL
-Angiogram: reversible arterial narrowing of intracerebral arteries in bilateral hemispheres
Vasogenic edema
SAH
RCVS Tx
-CCB (nipodipine 60mg q6h, verapamil 80mg BID< verapamil SR 180-20 daily)
-Sometimes short course high dose prednisone
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
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)
PMR Pathogenesis
- HLA DR4 association
-Dendritic cells activated at adventitia-media border of large vessel →IL1/6 production and suppression of Treg/Th17 response
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)
Source of PMR symptoms
Tenosynovitis (biceps)
-Bursitis (subdeltoid, subacromial, trochanteric, interspinous)
-Synovitis (hip/shoulders)
PMR labs
Inflammatory markers
-Normocytic anemia
-Thrombocytosis
-INCREASED GAMMA GLOBULINS
-Elevated ALP
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
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
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
PMR poor prognostic factors
Older age
-Female
-Very high ESR/CRP
-Failure of CRP to normalize within 1 wk of pred
Pred taper in PMR
-Or tapering 1mg q2mo if flare occurs during taper
Steroid sparing agents for PMR
MTX 10-20mg/wk
Nonmedication treatment plan for PMR
ROM exercises
-Vitamin D
-Calcium supplements
-Regular DEXA scan
-Flu vaccines
** 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)
** How does pANCA stain and what does it bind? **
pANCA = perinuclear cytoplasmic staining
-Binds MPO, but also elastase, lactoferrin, catalase, lysozymes
** False positive ANCA**
-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
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
** 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
** 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
** DAH workup**
Serologies: ANCA, AntiGBM, ANA
-CT chest
-Bronchoscopy: fungal, viral, bacterial, mycobacterial cultures, PJP
-Biopsy shows hemosiderin laden macrophages
-PFT shows increased DLCO
** 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.
** Non Rheum DDX for saddle**
Trauma
-Cocaine
-Surgery
** Rheum DDX for saddle**
GPA
-Relapsing polychondritis
-Sarcoid
-IgG4 related disease
-RA
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
Renal Manifestations of GPA
Active urine: blood, WBC, protein, casts
-Acute/ chronic renal failure
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
Ear Manifestations of GPA
-Vertigo
-Hearing loss (conductive and sensorineural)
-Otitis media
-Mastoiditis
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)
MSK Manifestations of GPA
Arthralgias
-Myalgia
-Synovitis
CNS Manifestations of GPA
CNS:
- Pachymeningitis,
- Cranial neuropathy,
- Ocular palsy,
- CVA, SAH/SDH
- Seizure,
- Pituitary involvement,
-PNS: mononeuritis multiplex
Cardiac Manifestations of GPA
RARE Pericarditis, or involvement of myocardium/coronary vasculature
GI Manifestations of GPA
Intestinal perforation
GU Manifestations of GPA
Bladder/urethral vasculitis
-Orchitis
-Epididymitis
-Prostatitis
GN histology GPA
-ABSENCE of immune complex deposition
-Focal &segmental
-Necrotizing and crescentic
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
Generalized vs limited GPA
-Limited: NO Renal, pulm hemorrhage, orbital pseudotumor, progressive neuropathy, and CNS dz
What to consider if hard palate lesions seen in ?GPA
Cocaine induced
-Infiltrative Ca (NK cell or T cell lymphoma)
Bloodwork abnormalities in GPA
Anemia of chronic inflamm
-Leukocytosis
-Thrombocytosis
-ESR, CRP
-Low albumin
-Elevated globulin levels
-UA: hematuria, pyuria, casts, proteinuria
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
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
**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)
Why ritux over CYC based on evidence
-RITUXVAS: no diff in sustained remission at 12 and 24 mo (vs CYC-AZA)
CYC IV vs PO
Relapse: IV>PO
-Leukopenia: PO>IV
**PEXIVAS summary **
PLEX → no signif reduction of mortality and ESKD in pt w/ organ/life threatening AAV
**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)
Induction MMF vs CYC
MMF noninferior but higher relapse in PR3
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
Maintenance Tx trials: RTX vs AZA
RITAZAREM & MAINRITSAN showed:
-RTX = less relapse than AZA
-RTX for 36mo > 18 mo
AAV Maintenance Tx trials: MTX vs AZA vs MMF
Similar efficacy for maintenance but relapse higher in MMF vs AZA
Tx subglottic stenosis
Radial CO2 laser incision, dilation
-Intralesional steroid injxn +/- topical mitomycin C
CYC dosing
NIH: 0.5-1.0g/m2 monthly x3-6mo
GPA maintenance therapy
AZA, MTX, Ritux within 3-6 mo after CYC start, 1-3years dep resp Mx, PR3 etc
-Ritux > AZA (MAINRITSAN)
Options for treatment resistant GPA
PLEX
** 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)
MPA vessels affected
Small vessels: capillaries, venules, arterioles
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
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
MPA vs GPA
NO granuloma in MPA
MPA antibody
p-ANCA against MPO
-c-ANCA against PR3 in 15-30%
eGPA vessels involved
Small and medium vessels
eGPA patient phenotype
-Previous atopy
-Nasal polyps
-Asthma
-Eosinophilia
Cytokines involved in eGPA
IL5 and eosinophil granule protein
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
eGPA clinical features - paranasal sinus
Sinus pain/tenderness
-Rhinitis
-Polyposis
eGPA clinical features - lungs
Asthma (adult onset)
-Pulm infiltrates- patchy, shifting, nodular, NO cavitations
-Effusions
-ILD
-Pulm hemorrhage
eGPA clinical features - NS
Mononeuritis multiplex
-Asymmetric sensorimotor polyneuropathy
-Rarely CNS involvement
eGPA clinical features - joints
Arthralgias, arthritis (RARE)
eGPA clinical features - GI
Eosinophilic gastroenteritis (abdo pain, bloody diarrhea), abdo masses
eGPA clinical features - misc
Renal failure (uncommon), CHF, corneal ulcerations, panuveitis, prostatitis
eGPA lab findings
Eosinophilia with high IgE
-Anemia
-Inflamm markers
-RF in 70%
-pANCA against MPO
** 6 rheum causes of peripheral eosinophilia**
-Eosinophilic Fasciitis/ Myositis / Myalgia syndrome
-IgG4 / Sjogren
-SLE
-RA
-eGPA
-Sarcoid
** 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
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
Drugs to avoid in eGPA
Leukotriene inhibitors
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
eGPA Tx
FFS 0: GC alone
-FFS≥1: GC + CYC
-
-Resistant: Ritux or mepolizumab (IL5 AB)
Meds causing drug induced AAV
Thyroid: PTU, methimazole, carbimazole
-Hydralazine, minocycline
-Cocaine with levamisole
Drug induced AAV manifestations
Constitutional sx
-Arthralgias w/ occasionals synovitis
-Cutaneous vasculitis
-Necrotizing GN (PAUCI IMMUNE)
-DAH
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
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
**Cocaine with levamisole manifestations (labs) **
-Bone marrow suppression → leukopenia, AGRANULOCYTOSIS, Thrombocytopenia
-AB against PR3, MPO,APLA
-Human neutrophil elastase
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
**Purpura Tx **
Colchicine
-Dapsone
-AZA
-MMF
-Prednisone
-Treat underlying problem
-DC drug
**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)
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
IC mediated V causes
New meds
-Recent infxns
-Hep C
IC mediated V pathophys
Immune complex deposition in vessel wall → complement activation → PMN migration to area → lysosomal enzyme release and vessel wall damage
IC mediated V other manifestations
Constitutional (fever, malaise)
-Arthralgia (RARE arthritis)
-GI: pain, GIB
-GU: proteinuria, hematuria, renal insuff
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)
IC mediated V MIMICKERS
-APLA
-Livedoid vasculopathy
-Cholesterol emboli, Atrial myxoma, IE
-Low Plt: ITP, TTP, DIC
-Meningococcemia
-Calciphylaxis
-Pigmented purpuric dermatoses
-Scurvy
-Amyloid
SVV Ix to send
CBC, Cr, UA, Hep B/C, RF, ANA, dsDNA, complements, ANCA, CRYO, HIV, SPEP, CXR, ESR/CRP
IgA V histopath
LCV or necrotizing SVV
-Immunofluorescence shows IgA deposition in blood vessels and in glomerular mesangium
IgA V pathogenesis
-IgA binds mesangial cells in kidney → prolif & proinflamm cytokines
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
-
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
AntiGBM Tx
Concurrent PLEX, high dose GC, and CYC
Urticarial vasculitis subtypes
- Normocomplementemic - idiopathic hypersensitivity
-Hypocomplementemic (HUV) - low complement eg C1q - HUVS (HUV syndrome)
Hypocomplementemic vasculitis syndrome criteria
HUV + 2 minor criteria
– LCV
– Arthralgia/arthritis
– Ocular inflamm
– GN
– Abdo pain
– Anti-C1q AB
HUV manifestations
Urticaria
-Arthralgia
-Scleritis/uveitis/episcleritis
-Angioedema
-Obstructive pulm dz
-GN
-GI
-Cardiovascular disease
HUV associations
75% in isolation
-25% assoc’d w/ SLE or SS
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
UV assoc’d conditions
Autoimmune: SLE, SS
-Ca: Lymphoma, IgM Paraproteinemia
-Infxn: Hep B, C
-Drug rxn
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
UV Tx
-Dapsone, HCQ, colchicine
-
-MSK: NSAIDs, or pred from 10-60mg
-
-Severe: CYC, Ritux, AZA, MMF
-
-Refractory: PLEX, IVIG
Erythema elevatum diutinum biopsy
LCV w/ fibrinoid necrosis
-Nonspecific immunoflueocescence
Erythema elevatum diutinum assoc’d conditions
Same as UV: CTD, Infxn, paraproteinemias, esp IgA
Erythema elevatum diutinum Tx
Dapsone, sulfapyridine
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
What are cryo
Igs/complexes that precipitated out of serum/plasma at low temp
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
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
Type 1 Cryo assoc’d disorders
Essential
Lymphoproliferative disorders:
- MM
- Waldenstrom’s macroglobulinemia
- Chronic lymphocytic leukemia
- B cell lymphoma
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)
** 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
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,
Mixed Cryo skin manifestations
Purpura,
Urticarial vasculitis,
Digital necrosis,
Bullae,
Livedo racemosa
Mixed cryo renal manifesations
Type 1 membranoproliferative GN
-Nephrotic syndrome
-Nephritic syndrome
-HTN
-AKI/ARF
Mixed cryo neuro manifestations
Sensory polyneuropathy (symm/asymm, insidious/abrupt)
-Mononeuritis multiplex
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
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
Poor prognostic factors for mixed cryo vasculitis
Male
-Age>60
-Type 2
-GI involvement
-Chronic HCV
-Diffuse vasculitis
** 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
** 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
Mild/mod mixed cryo vasculitis manifestations
-+ Tx (induction and maintenance)
-Purpura
-Mild neuropathy
-GN w/o renal failure
-Antiviral therapy +/- steroids → antiviral for maintenance
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
Cryofibrinogenemia - what is it
Insoluble complex of fibrin, fibrinogen, fibrin split products, plasma prot and Igs that precipitate from PLASMA (NOT SERUM) w/ cold
Cryofibrinogenemia manifestations
Derm: vascular occlusion/ischemia → pupura, livedo, ulcers, gangrene, strokes, MI
-** Paradoxical bleeding ** bc clotting factors depleted
Cryofibrinogenemia assoc’d conditions
CTD, infxn, Ca, drugs (OCP), DM, advanced DLPD
Cryofibrinogenemia Tx
Avoid cold
-Smoking cessation
-Treat underlying
-Fibrinolytics (eg streptokinase)
-Low dose ASA
-GC for mild/mod
-DMARD for underlying CTD
Cold agglutinin disease - pathophys
IgM AB against erythrocytes → hemolytic anemia and complement mediated RBC destruction in reticuloendothelial system (liver) → occlusion by agglutinated RBC
Cold agglutinin disease - manifestations
Acrocyanosis
-Raynaud’s
-Ulcers over ears, nose, digits
Cold agglutinin disease - Tx
Warmth
-GC
-RTX
-Rarely PLEX
-Treat underlying
Examples of variable vessel vasculitis
Bechcet
-Cogan
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)
Behcet’s mimickers
IBD: Crohn’s
-SLE
-ReA
-Herpes
-Systemic vasculitis
-Sweet’s
-Periodic fever syndrome (PFAP, HIDS)
Behcet’s histopath
Variable: from neutrophilic vascular rxn to LCV
HLA assoc’d w/ Behcets
HLA B51
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
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
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)
Behcet’s MSK manifestations
Arthralgia > arthritis - mono, oligo, poly
-RARE erosions
-Enthesopathy
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
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
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
Behcet’s GI manifestations
Mucosal ulceration → perforation
MORTALITY RISK
Behcet’s Cardio manifestations
RARE
-Valvular lesions
-Myopercarditis
-Coronary arteritis/aneurysm
Behcet’s GU manifestations
GN is rare
-Epididymitis
-Salpingitis
Behcet’s lab findings
Inflamm markers
-Leukocytosis
-Elevated IgG/A/M
-Elevated CSF prot/cell count
** Behcet’s cause for mortality**
CNS involvement
-Valvular dz (ruptured pulm/periph aneurysm)
-Bowel dz (perf)
** 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
** 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
** Behcet’s Tx for MSK **
Colchicine
-Refractory: GC, AZA, MTX, SFZ TNFi, Interferon-a
** Behcet’s Tx for CNS **
GC
-AZA
-Interferon a
-CYC
-TNFi
-*Do not use cyclosporine unless coexisting ocular disease
** Behcet’s Tx for GI**
GC
-SFZ
-AZA
-TNFi
Behcet’s Tx for vascular thrombosis
GC and immunsuppressives
-**do not anticoag until inflamm controlled bc silent aneurysm can cause hemorrhage → death
Behcet’s Tx for aneurysm/vasculitis
GC, CYC
-Endovascular embolizatin/surgery for hemorrahge
**Biologics for Behcets*
TNFi - Infliximab, Humira, Etanercept
**Nonbiologics for Behcets*
AZA
-Cyclosporine
-Apremilast
-Colchicine
MAGIC
Mouth and genital ulcerations with inflamed cartilage
-*ie behcets and relapsing polychondritis
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
Cogan manifestations
-Ocular
-Audiovestibular
-Constitutional
-Vasculitic(large medium),
Cogan Audiovestibular manifestations
Rapid onset sensorineural hearing loss (often bilateral)
-Vestibular dysfunction (vertigo and ataxia)
-Cochlear hydrops
-Tinnitus
Cogan constitutional manifestations
Fever
-Weight loss
-LN
-HSM
-Arthritis
Cogan vasculitic manifestations
-Aortitis w/ aortic insuff/aneurysm
-Coronary vasculitis
-Aortic/mitral valvulitis
-Purpura
-Gangrene
** Cogan Ocular manifestations**
Nonsyphilitic interstitial keratitis (Red, painful, photophobic eyes)
-Scleritis/episcleritis
-Uveitis
-Chorioretinitis
-Optic neuritis
-Retinal vasculitis
Cogan lab manifestations
Low Hgb, high WBC/Plt/inflamm
-RARE: ANCA, ANA, APS, RF,
-Anti HSP70 AB
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)
Vasculitis mimic for Old guy with jaw claudication but normal CRP and test to rule it in
Atherosclerosis → carotid US
-TMJ disease → MRI
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
**Vasculitis mimic for Mechanical heart valve with active urinary sediment **
IE → TTE, cultures
Vasculitis mimic for 30 yr M with severe emphysema and ischemic digit
Buerger’s → Angio
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
Single organ vasculitidities
Cutaneous LCV
-Cutaneous arteritis
-Primary CNS vasculitis
-Isolated aortitis
Vasculitis assoc’d w/ systemic dz
SLE, RA, Sarcoid vasculitis
** 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
** 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
** eGPA Cause of Death**
MI/CHF
** 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
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)
** 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
**Neuropathic patterns seen in vasculitis **
Mononeuritis multiplex
Stocking glove distribution
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)
** 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
** 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
** ANCA disease association and % **
pANCA:
- MPA 50-60%
- eGPA 25-30%
cANCA
- GPA 75%
** Erythema nodosum biopsy**
Panniculitis involving septa in subcutaneous fat
Cryo path
Precipitated cryo on light microscopy
Diffuse IgM deposition in capillary loops in immunofluorescence
**Components found in cryoprecipitate **
Fibrinogen.
Factor VIII.
Factor XIII.
Von Willebrand factor.
** GCA how to biopsy**
Unilateral > Bilateral Within 2 weeks
Long segment >1cm preferred
** Young patient with arthritis, oral ulcer and uveitis: List 5 differential diagnosis?**
Seroneg: PEAR
Behcet
Vasculitis: GPA
SLE
Relapsing polychondritis
