Sjogren's / IgG4-RD Flashcards
SS pathogenesis models
- Lymphocytic infiltration of organs → cytotoxic cell death and apoptosis of acinar epithelium
- ABs against muscarinic R type 3,
- Cytokine breakdown of ACh
- Altered aquaporin channel expression
SS infiltrating cells:
CD4+ T lymphocytes w/ memory B lymphocytes
(Others: plasma cells, CD8+, T reg, NK cells, DCs)
** Things that can be dry in Sjogren’s **
- Skin - xerosis, pruritus
- Eyes
- Mouth
- GI tract (constipation)
- Larynx (hoarse)
- Upper airway (nonallergic rhinitis, sinusitis, bleeding)
- Vagina: dyspaurenia
Ocular sx of primary SS
-Xeropthalmia or Keratoconjuntivitis sicca → infxn, ulceration, vision loss
-Painful/itchy eyes
-Sensation foreign body
-Blurred vision
-Photophobia
-Worse at night (vs blepharitis = mornings)
Tests for dry eyes
Schirmer’s (<5mm in 5 min)
-Ocular surface staining (fluoresceine + lissamine green dye show cell disruption and damage; ≥5)
-Tear break up time (film BUT≤10s)
Dry mouth sx in SS
-Taste: metallic, salty, bitter, burning sensation
-Difficulty swallowing
-Reflux
-Lipstick sign
-Infxn: caries, candidiasis
-Cracked teeth, loose fillings, trouble with dentures
Salivary gland tests in SS
Sialometry (≤0.1cc/min)
-Scintigraphy (Tc-99m uptake/secretion)
-Sialography (anatomy; risk pain/infxn/duct rupture)
-MRI or US (parenchymal heterogeneity)
-Minor salivary gland biopsy (GOLD STD)
Biopsy requirements of MSG
4+ glands
-Minimum gland area 8mm2
Sjogren’s gland biopsy histopathology
Lymphocytic sialadenitis ( ≥1focus score ie ≥1 50 lymphocytes/4mm2)
-Acinar atrophy
-Ductal dilatation and fibrosis
-Epimyoepithelial cell islands
Meds causing dry eyes/mouth
Drugs with antimuscarinic activity:
- Antihistamines
-BZD
-TCAs
-drugs for overactive bladder, urinary incontinence
-Diuretics
Conditions causing dry eyes/mouth
-Amyloid, Sarcoid, IgG4RD
-Blepharitis
-Cystic fibrosis
-Dehydration
-Contact lens irritation
-Radiation
-DM
-GvHD
-Infxn: Hep C, HIV, TB, leprosy, mumps
-IgG4 disease
-Psychogenic: fear, depression
-Vit A def
Glandular swelling DDX
Autoimmune: sjogren’s, IgG4, granulomatous
-Infxn: bacterial, viral (influenza, HIV, CMV, mumps, coxsackie), TB,
-Ca: primary salivary gland Ca, lymphoma
-Endocrinopathy: acromegaly, DM, gonadal dysfcn
-Other: cirrhosis, pancreatitis, anorexia, bulemia, obstruction, recurrent parotitis, sialadenitis
UNILATERAL cause salivary gland enlargement
Infection (bacterial)
-Cancer: Lymphoma, primary salivary gland Ca
-Chronic sialadenitis
-Obstruction
ASYMMETRIC bilateral cause salivary gland enlargement
- Granuloma dz
-Infxn: HIV, mumps, CMV, HFlu, Coxackie A
-Recurrent parotitis of childhood
-IgG4
SYMMETRIC bilateral salivary gland enlargement
- Acromegaly
-Alcoholism,
-Chronic pancreatitis
-Hepatitis cirrhosis
-Anorexia/bulimia
-DM
-Gonadal hypofunction
-Idiopathic
** Exocrine glands involved in primary SS (and consequences)**
Skin (xerosis, pruritus)
-Upper airway (nonallergic rhinitis, sinusitis, bleeding)
-Larynx (hoarseness)
-Trachea (dry cough)
-GI (dysphagia, constipation)
-Vagina (dyspareunia)
Arthritis characteristics of primary SS
Similar to RA BUT nonerosive and mild
-Symmetric
-MCP, PIP
-AM stiffness
** Extraglandular manifestations primary SS **
- Constitutional, lymphadenopathy, lymphoma
- Neuro: CNS, peripheral neuropathy
- Autoimmune thyroid
- Lung
- GI: dysphagia, liver involvement
- Renal
- Vasculitis
- Raynaud
- MSK: arthralgia, arthritis, myositis
** Most common cryo types in SS**
Type 2 > 3 (mixed) poly IgM, poly IgG
Lung manifestations primary SS
-Xerotrachea/xerobronchitis
-ILD:NSIP, UIP, Lymphocytic interstitial pneumonitis
-Bronchiolitis (constrictive)
-Bronchiectasis
-Recurrent PNA
-Bronchial associ’d lymphoid tissue lymphoma
** Renal manifestations primary SS**
-Tubular interstitial nephritis (MC)
-Nephrogenic DI
-Type 1 RTA (hypoK, muscle paralysis, stones, high urine Ca and PO4),
-GN
** Renal Tx**
TIN: steroids alone, MMF
-GN: steroids, RTX, PLEX
GI manifestations primary SS
Celiac (think SS if diarrhea, vit D)
-PBC
-Autoimmune hepatitis
-Recurrent pancreatitis
Vasculitis of primary SS
MC: Cutaneous palpable pupura
-Infreq: necrotizing or cryo
Neuro manifestations of primary SS
CNS: sclerosis-like brain lesion, sz, encephalopathy, cog impairment, sensory/motor deficit, longitudinal extensive transverse myelitis, optic neuritis
PNS: motor (mononeuritis multiplex), sensory, or sensorimotor
- Small fiber neuropathy (burning pain w/ normal NCS) → dysautonomia (loss pinprick, temperature, w/ normal vibration/DTR)
3 types neuropathy in Sjogens
- Mononeuropathy multiplex
- Polyneuropathy (axonal sensorimotor, chronic inflamm demyelinating polyneuorpathy eg CIDP; distal sensory)
- Polyradiculopathy
- Sensorimotor polyradiculoneuropathy ie. Guillain-Barré syndrome
- Sensory (small fiber, sensory ataxic)
- Cranial neuropathy (eg Bell’s)
Neuropathy Tx
Pulse steroids + Ritux or Cyclo +/- IVIG
-Maintainence: MMF, AZA, Ritux
MC SS neuropathy
Axonal sensorimotor polyneuropathy
Tx of longitudinally extensive transverse myelitis
Induction: Pulsed steroids + ritux/CYC
-Maintenance: MMF, AZA, RItux
Small fiber neuropathy Tx in SS
-Neuropathic meds: gabapentin, pregabalin, topical lidocaine, capsaicin
-Refractory: IVIG
SS risks in pregannacy
Neonatal / Congenital heart block if Ro/La positive
Lab findings in primary SS
ANA, Ro, La, RF, (some hv ACA- high risk extraglandular, Raynaud, lymphoma)
-Hypergammaglobulinemia
-AoCD, Leukopenia, Thrombocytopenia
Cancer risks in SS
- NHL
- Mucosa-associated lymphoid tissue lymphoma (MALT)
** SS clinical risk factors for lymphoma**
-Disease duration > 10y
-Moderate/high dz activity (EULAR DAI >5)
-Persistent salivary gland enlargement
-Lymphadenopathy
-Raynaud’s
-Splenomegaly
-Palpable purpura
-GN
-Peripheral neuropathy
** SS lab risk factors for lymphoma **
-Monoclonal gammopathy (IgM kappa)
-Loss of previously positive RF
-Leukopenia
-Cryoglobulinemia
-Low C3/C4
-Presence of germinal centers or high focus score ≥3 on MSG biopsy
Bloodwork for cancer screening SS
CBC, SPEP, RF, complements, cryo q1-2y
** ACR/EULAR classification primary SS**
Positive if ≥ 4:
-Ocular staining score ≥ 5 (1)
-Schirmer <5mm/5min (1)
Unstim whole saliva flow rate ≤ 0.1/min (1)
Ro positive (3)
Labial salivary biopsy: focal score >1 (3)
** ACR/EULAR 2016 classification inclusion criteria**
One symptom of ocular or oral dryness:
– Daily, persistent, troublesome dry eyes or mouth for >3mo OR
– Recurrent sand/gravel sensation OR
– Use tear substitute >3x/d OR
– Drink liquids to aid in swallowing food
** ACR/EULAR 2016 classification exclusion criteria**
HEENT radiation
-Active Hep C or AIDS
-Sarcoid or Amyloid
-IgG4RD
-GvHd
Tx xeropthalmia
Environment:
– Reduce caffeine, smoking, computer time, celing fans, offending meds
– Increase fluids, omega 3, humidifier
– Special eyewear
-
-Eye drops: preservative free artificial tears, topical steroid, cyclosporine, autologous tears
-Lubricant ointment: at night
-Punctal occlusion: silicone collagen (delay clearance)
-Scleral contact lens
Tx blepharitis
Warm compress
-Avoid local irritant
-Topical Azithromycin
-Rare: systemic antibiotics (doxy)
Tx dry mouth SS
Regular dental visit
-Hydration
-Avoid caffeine, EtOH, nicotine, acidic beverages
-Sugar free / Xylitol gum, lozenge, candy
-Remove nasal polyps (limit mouth breathing)
-Biotene mouthwash
-Saliva substitute
-Secretagogues
Secretagogue examples & dose
Pilocarpine 5mg QID
-Cevimeline 30mg TID (muscarinic ACh R Ag)
Secretagogue side effects
Flushing
-Diaphoresis
-GI disturbances (nausea, abdo pain, anorexia, constipation, GERD)
-Pinpoint pupils (ie dont give to narrow angle glaucoma)
-Rhinitis/sinusitis (ie dont give to asthma pt)
-Bradycardia (ie avoid BBs)
-Urinary frequency
Who to avoid secretagogues in
Narrow angle glaucoma
-Asthma
-Pt on beta blockers
Retroperitoneal fibrosis H&P, Ix
H: pain (lower back, abdo, flank, scrotum), fevers, anorexia, malaise
-P: HTN, LE edema, phlebitis
-Ix: ESR/CRP, azotemia, CT (mass around abdo aorta btwn renal arteries and aortic bifurcation, hydronephrosis, ureter deviation), Biopsy - sclerosis and mononuclear cell infiltration
Retroperitoneal fibrosis 2ndary causes
Drugs: ergot, methysergide
-Malignant disease: lymphoma/sarcoma
-Erdheim Chester
-Infxn
-IgG4RD
Retroperitoneal fibrosis Tx
High dose pred (taper to 10mg/d by 3-6mo), maintenance x1-3y
-Resistant: MTX, AZA, MMF, Tamoxifen
-Stent - relieves ureteral obstruction
-Surgery/Endovascular aneurysm repair for large aneurysm
IgG4 HEENT involvement
- Constitutional: fatigue, weight loss, arthralgias, enthesopathy (no synovitis/enthesitis)
- CNS: pachymeningitis (dura inflammation), hypophysitis (pituitary involvement)
-Orbital pseudotumor, Lacrimal gland inflammation, Sicca, EoM myositis, Proptosis
-Salivary (sialadenitis, enlarged, sicca, SUBMANDIBULAR not parotid as in SS)
-Mikulicz dz - bilat painless swelling lacrimal and maj salivary glands
-ENT: allergy/atopy = rhinosinusitis, polyps, obstruction, asthma, eosinophelia, IgE
-Thyroiditis (fibrosis can infiltrate airways), hypothyroid
- LN: nontender, generalized or localized. cervical, paraaortic, inguinal, retroperitoneal, supraclavicular etc. **DONT biopsy as low yield for fibrosis
** IgG4-RD Lung involvement **
-
MC: Mediastinal and hilar lymphadenopathy
-Central airway disease
-Pleuritis, Pleural nodules, effusion, pleural thickening
-Fibrosing mediastinitis
-ILD (NSIP, GGO)
-Inflammatory pseudotumor
-Mediastinal/hilar adenopathy
** IgG4-RD GI manifestations**
-MC: Type 1 autoimmune pancreatitis (sausage pancreas) → DM
-Sclerosing cholangitis → painless obstructive jaundice
** IgG4-RD Renal manifestations**
MC: Tubulointerstitial Nephritis
Membranous GN
Prostatitis (BPH resolves after steroids)
Hydronephrosis from ureteral obstruction (from retroperitoneal fibrosis)
IgG4-RD cardiac manifestations
-Pericarditis
-Periaortitis (especially infrarenal)
- Aorta (thoracic/abdo) aneurysm. Aortitis does not affect other branches (unlike LVV)
-Involvement of infrarenal aorta and branches (esp iliac arteries) eg stenosis
** IgG4-RD Biopsy findings**
- STORIFORM fibrosis pattern
- Obliterative phlebitis(medium sized veins)
- CD4+ lymphocyte and IgG4+ plasma cell infiltration (lymphoplasmacytic infiltrate) - seen in cancer, AAV, castleman’s
- IgG4+ plasma cells > 40% of total IgG+ plasma cells. >10 IgG4+ plasma cells/hpf
- Tissue eosinophils
-**NO necrotizing vasculitis and granulomatous inflammation
IgG4 dx
Must use clinical, labs, radiology and biopsy, none in isolation enough!
Biopsy + IgG4 serum [ ] >135mg/dL confirms
IgG4 labs
Polyclonal gammopathy IgG and IgE
-IgG4 and mild eosinophilia
-Hypocomplementemia (bc IgG1 forms immune complex; present in renal dz)
-ESR high,
- CRP normal unless aortitis or retroperitoneal fibrosis)
RF, ANA can be positive
**IgG4 exclusion criteria - clinical **
-Fever
-No response to steroids (40mg/d x4wks)
IgG4 exclusion criteria - serologic
Leukopenia and thrombocytopenia w/o explanation (bc unusual in IgG4RD)
-Peripheral eosinophilia
-Cryo
-Positive antibodies! Eg PR3/MPO, Ro/La, dsDNA, RNP, Sm, Scl70, Jo1 (excludes RF, ANA, AMA, ASMA, APLA)
IgG4 exclusion criteria - radiologic
Rapid progression (w/i 4-6wks)
-Findings suspicious for infxn,cancer, Erdheim chester (multifocal osteosclerotic lesions)
-Splenomegaly >14cm w/o explanation
IgG4 exclusion criteria - pathologic
Cancer findings (atypia, light chain restriction)
-Findings of inflammation (granulomatous, neutrophilic, inflammatory myofibrobastic tumor)
-Features of macrophage/histiocytic d/o
-Necrosis, fibrinoid necrosis
IgG4 exclusion criteria - diagnoses
Multicentric Castleman’s
-IBD (if only pancreatobiliary dz present)
-Hashimoto (if only thyroid affected)
IgG4 Tx
- Steroids (0.5mg/kg for induction , taper over 3-6mo; no less than 5-7.5mg for maintenance)
- csDMARDs (MMF, LFN, AZA) still relapse
- Ritux (1g 2 weeks apart or 375mg/m2 x 4 weekly infusion, then 1g q6mo)
DC after 3 years of clinical, radiological, lab remission
-Surgical/Endovascular aneurysm repair
** Why Sjogren’s has polyclonal IgG**
Lymphocyte hyperactivitiy
Ag processed by APC activates T cells to induce proliferation of Ag-specific B cells
IL6 cause differentiation into AB-producing plasma cells that orliferate in BM, gut, LN, spleen, liver
** HIV pt gets Sjogren’s – what is it and how is it different/similar from idiopathic SS?**
Diffuse Infiltrative Lymphocytosis Syndrome (DILS)
- Predominantly CD8+ T cells (vs CD4+ in SS) in blood and visceral infiltration
- Autoantibodies: Ro/La uncommon
- More common to have extraglandular features
Similar
- B/L parotid/lacrimal gland swelling
- Sicca
What diseases can peripheral ulcerative keratitis happen in?
ie corneal melt
RA
Sjogren
Relapsing polynchondritis
GPA
PAN
Differences between Sjogren’s and IgG4RD
Sjogren’s:
- Age 40-50s (vs 60s)
- F>M (vs M>F)
- Glandular swelling recurrent (vs persistent)
- Higher rate arthralgia and lymphoma
- ANA+ (vs rare)
- Ro/La+ (vs rare)
- Normal levels IgG4 (vs high)
- Normal IgE levels (vs high)
- Mainly CD4+ T lymphocyte infiltration (vs IgG4+ plasmocytic infiltration)
- Bx: fibrosis without storiform pattern, no obliterative phlebitis, no IgG4+ plastmacytes
IgG4 Phenotypes from ACR/EULAR classification criteria
- Pancreatohepatobiliary: T1 autoimmune pancreatitis and sclerosing cholangitis
- Periaortitis, aortitis, retroperitoneal fibrosis
- HEENT limited - young asian females, orbital pseudotumors, ENT, thyroiditis, pachymeningitis, hypophysitis
- Mikulicz syndrome - Dacryoadenitis, sialednitis, ILD, pancreatitis, renal manifestations
IgG4 Imaging
Gross organomegaly
Sausage pancreas
Infrarenal periaortitis
MRCP/ERCP showing irregular narrowing of bile ducts
PET to find sites of bx
Igg4 predictors of relapse
high baseline Igg4 level
high baseline ige level
peripheral eosinophilia
mulitorgan involvement
young woman with head/neck limited dz
