SLE Flashcards
2019 EULAR/ACR classification
Only if ANA ≥1:80 and had ≥10pts
-Class 3/4 nephritis (10), class 2/5 (8), proteinuria ≥0.5g/d (4)
-Anti Sm/dsDNA (6)
-AIHA/thrombocytopenia (4), Leukopenia (3)
-Low C3 AND C4 (4), C3 or C4 (3)
-Any APLA AB (2)
-ACLE (6), SCLE/DLE (4), alopecia/ulcers (2)
-Arthritis (6)
-Pericarditis (6), effusion 5
-Seizures (5), Psychosis (3), delirium (2)
-Fever (2)
SLE risk factors
-DR2 and DR3 histocompatibility complex → present self Ag to self reactive T/B cells
-Complement deficiency: C1q, C2, C4 → less clearance of apoptotic debris and IFNa production
-Hormones: childbearing years, XXY, XO, DHEA as Tx
-Enviro: smoking, EBV, CMV, Silica, UV light, pesticides, demethylating drugs, gut microbiome
Acute cutaneous lupus manifestations
-Malar rash
-Bullous lupus
-Toxic epidermal necrolysis variant
-Maculopapular
-Photosensitive
-ulcers
Chronic cutaneous lupus manifestations
-Classic discoid, hypertrophic
-Lupus pannicullitis/profundus
-Mucosal
-Lupus tumidus
-Chilblains
Chilblain’s Tx
-Cold avoidance
-Smoking cessation
-Topical steroids
-Oral nifedipine
APLA positivity definition
+ LAC
-Medium/high titer ACA (IgG/M/A)
-Positive anti-B2-glycoprotein (IgG/M/A)
SCLE (subacute cutaneous)
vs DILE (drug induced)
vs DLE (discoid)
-Manifestations, antibody, prognosis
SCLE: skin only , SSA/SSB+ (can be ANA-), 5-10% –>SLE
DILE: systemic (no CNS/renal), Histone+, improve when DC drug
DLE: skin only, ANA-, rarely become SLE
ANA staining patterns: rim, speckled, nucleolar
-Rim = AB to deoxynucleoprot (most spec for SLE)
-Speckled = MC in SLE and other dz (least spec for SLE)
-Nucleolar = think scleroderma
Situations where ANA is negative
-Severe proteinuria (no Igs in serum to bind HEp-2 cells); ANA turns + after tx
-After cytotox therapy
-In dz remission
CNS SLE - diffuse vs focal differences
-Diffuse: transient, reversible w/ therapy, not assoc’d w/ pathologic abN
-Focal: acute in onset, PERMANENT w/ therapy, assoc’d w/ pathologic changes on autopsy
CNS SLE manifestations
Diffuse:
– Confusion, Coma
– MCI/Dementia
– Psychosis, A&D
– Headache, pseudotumor cerebri
– Aseptic meningitis
Focal:
– Stroke syndromes
– Seizures
– Chorea
– Ataxia, hemiballismus
– Demyelinating syndromes
– Transverse myelopathy
SLE CNS pathogenesis
Endothelial disfunction:
- SLE complement activation → microvasculopathy and BBB disruption → influx autoAB, cytokines → diffuse manifestations
-Procoagulant factors (APLA etc) activate endothelial cell → thrombosis/emboli → stroke/focal manifestations
SLE CNS manifestations autoantibodies
Diffuse:
– Antineuronal
– Ribosomal P → psych (esp psychosis)
– NMDA → cog dysfcn
Focal
– Anti-aquaporin 4/ neuromyelitis optica (NMO) → transverse myelitis +/- optic neuritis
– APLA → transverse myelitis, strokes
SLE pt w/ GTC seizure and hypertensity on MRI with normal LP
Posterior reversible encephalopathy syndrome
** Posterior reversible leukocencephalopathy risk factor **
-HTN
-Immunosuppression (esp CYCLOSPORINE)
-Autoimmune dz: SLE, PAN, Cryo, GPA
-Acute/chronic renal failure, TTP, HUS, sepsis, blood transfusion, contrast
PRES clinical manifestations and Ix and Tx
-HTN
-Seizures
-H/A, Confusion, ALOC, N/V, visual change, ARF
-MRI: vasogenic edema over cerebral hemispheres = increased T2 signals: cerebellum, brainstem, anterior cortex
-LP: normal, but can hv elevated protein
TX:
- Manage HTN w titratable agent (eg labetolol)
**PRES DDX **
-Diffuse NPSLE: seizure + increased T2 signals with LP that can be normal w/ elevated dsDNA, IL6, immune complex, B cell activation, and BAFF
-Aseptic meningitis
-CNS vasculitis
-APLA stroke
-Autoimmune encephalitis
SLE pt w/ bizarre behavior and delusions - DDX and Ix
-NPSLE
-Prednisone induce psychosis
-Causes of delirium
Ix:
- SLE labs,
- CNS AB (riosomal P, NMO),
- LP for CSF cell count/diff, prot/gluc, Cx, viral studies, IgG index, oligoclonal bands,
- Antineuronal AB,
- MRI brain/spine, EEG
Lung manifestations SLE
-Bilateral pleuritis
-Acute lupus pneumonitis +/- DAH
-ILD/fibrosis (usually in overlap SLE, but r/o drugs)
-pHTN (r/o CTEPH, OSA)
-Shrinking lung
-Cryptogenic organizing PNA (highly responsive to steroids; r/o antisynthetase)
-Infxn (r/o aspiration, atypical w/ tree/bud)
Shrinking lung pathogenesis
-Phrenic neuropathy
-Diaphragm myopathy
-Pleural fibrosis
Cardiac manifestations SLE
-Myocarditis (HF or tachy)
-Pericarditis (L sided pleural effusion if symptomatic)
-Coronary vasculitis (RARE)
-CAD and MI
-HTN (steroids or renal insuff)
-HCQ induced cardiomyopathy
-Valvulopathy (in APLA), Libman–Sacks usually on ventricular side of posterior MV leaflet or AV
SLE GI manifestations
-* Esophageal dysmotility (upper 1/3)
-* Pancreatitis
-* Serositis
-* Mesenteric vasculitis
-* Hepatitis
-* Intestinal pseudo-obstruction
-* Protein-losing enteropathy (positive stool fecal alpha-1 antitryspin or transferrin)
** Indication for renal biopsy **
-* Increasing Cr w/o another cause
-* Proteinuria ≥ 1 g/24 hours
-* Proteinuria ≥ 0.5 g/day plus hematuria or cellular casts
LN Classes
I/Minimal mesangial
-II/Mesangial proliferative:
III/Focal (A = active lesions C = chronic lesions)
IV/Diffuse (IV-S = segmental IV-G = global, A = active lesions C = chronic lesions):
V/Membranous:
VI/Advanced sclerosing:
LN Class 1 manifestations
None
LN Class 2 manifestations
Microscopic hematuria +/– proteinuria;
Rare HTN
LN Class 3 manifestations
Hematuria and proteinuria
+/– HTN, Decreased GFR, Nephrotic syndrome
LN Class 4 manifestations
-Hematuria, proteinuria (frequently nephrotic), cellular casts,
-Decreased GFR
-HTN,
-Hypocomplementemia
-Elevated dsDNA
LN Class 5 manifestations
Extensive proteinuria
-MINIMAL hematuria or renal function abnormalities
LN Class 6 manifestations
Chronic kidney disease
LN Pathology - features of activity
-Cellular proliferation
-Cellular crescents
-Fibrinoid necrosis
-Hyaline thrombi
-Intersititial inflammation
-Neutrophils
-Hypercellularity
LN Pathology - features of chronicity
-Glomerular SCLEROSIS
-Fibrous crescents
-Fibrous adhesions
-Interstitial fibrosis
Risk factors for LN –> ESRD
-* Black and Hispanic (especially males)
-* Lower SES
-* Poor med compliance
-* Comorbidities (DM, HTN)
-* Failure to normalize Cr or serum Cr of >2mg/dL on therapy
-* Failure to decrease proteinuria to <1 g/day within 6 mo of tx
-* Renal bx showing high disease activity (cellular crescents) & chronicity (interstitial fibrosis)
First line for LN
- Induction: Class 3/4, Class 5
Induction for Class 3/4
– IV Solumedrol 0.5-1g x3d then 1mg/kg prednisone (if crescents) or 0.5mg/kg (without crescents). Taper after few weeks
– MMF: 2-3g/d for 6 mo (MMF>CYC in blacks/Hispanic) OR CYC high dose (500-1000mg/m2 monthly x6mo) or low dose (Eurolupus 500mg IV q2wks x6 doses)
– Can switch btwn MMF and CYC if no effect, or to Ritux, CNI if no effect with either
-Class 5: pred 0.5mg/kg/d x6 mo PLUS MMF: 2-3g/d for 6 mo (CNI can be added to MMF, careful if renal insuff/HTN)
– Triple therapy: Belimumab + GC + MMF or reduced CYC if repeat renal flare or high risk kidney failure
First line for LN
-Adjunct therapies
- HCQ (<5mg/kg/d)
- ACE, ARB if proteinuria >0.5g/24h (BP target <130/80)
- Statin if LDL >100mg/dL
- Stop smoking
- Counsel against pregnancy if active nephritis or Cr> 2mg/dL
- Ritux controversial
Cyclo dosing
– Dose: high vs low
– Route: IV vs PO
– Resistant
High dose: Monthly 0.5–1.0 g/m2 IV × 6 months
-Low dose (less infxn/infertility): 500 mg IV q2wk × 6 doses
-Total exposure less with IV vs PO
-Recalcitrant –> Add Ritux 1g at day 1 and day 14
Cyclo Side effects
-Fertility,
-Bladder toxicity (hemorrhagic cystitis)
-Premature ovarian failure (>10-15g total dose and age >30)
Cyclo Protocol
– Prior
– Dose
– Monthly changes
– Adjuncts
– Post Infusion
A) Prior to CYC
– Premedication 15–30 minutes prior to CYC: dexamethasone 10 mg, lorazepam 1 mg, Zofran 8 mg
– Mesna (25% of CYC dose in milligrams) in 250 cc normal saline CYC infusion
-B) CYC 0.5–1.0 g/m2 of BSA mo x6 (0.5g/m2 if CrCl<35–40 cc/min; or if on IHD 0.4-0.5g/m2 8-10h before or after IHD)
-C) Adjusting monthly dose based on WBC 10-14d post CYC: reduce by 0.25g/m2 if nadir <3, or increase to 1g/m2 if nadir >4
-D) Consider GnRH (Lupron) 3.75 mg IM 10d pre-CYC dose or testosterone (200 mg IM every 2 weeks) for men to prevent premature gonadal failure from longstanding therapy
-E) Post CYC infusion
– Mesna (25% of CYC dose in mg)
– Compazine SR 15mg BID prn or compazine 10 mg TID prn for 2–3 days
LN Maintenance therapy
– Duration
– Options
-
> 1-2years post induction
-* AZA (up to 2 mg/kg/day) (or 6-mercaptopurine if nausea on AZA) or MMF generally preferred (1–3 g/day)
-* No AZA if on allopurinol or warfarin (warfarin resistance)
-* CYC IV q3mo s/p induction if can’t tolerate AZA/MMF.
-* Prednisone is tapered over time to dose that controls renal and extrarenal manifestations
-Other:
-* Rituximab: limited data
-* CNI (cyclosporine, tacro): alone or combined with low-dose MMF
LN recommendations in pregnancy
Early preg: Therapeutic abortion or early immunosuppression to avoid teratogenicity
-Late: HCQ, Pulse steroid, AZA, Tacro
CYC if life threatening
Tx for Young SLE with proteinuria 2g/day and Bx with class 3/ 4
HCQ. Induction with MP and MMF (3 g po daily) followed by MMF (2 g po daily) maintenance for at least 3 years.
**SLE with casts, Cr 300 and Bx with 3 /4 **
HCQ. MP + IV CYC or MMF
SLE with class 3/ 4 but pregnant 4 months
- HCQ
- IV MP (ideally nonfluorinated GC eg betamethasone or dex) + TAC for induction
If severe, consider RTX.
Followed by either TAC or AZA for maintenance.
** SLE with membranous nephritis and proteinuria 2.5g Tx **
HCQ. ACEi or ARB for proteinuria.
-GC + MMF / AZA / CYC / CNI / RItux based on extrarenal mx or if nephrotic syndrome (>3g)
Trial for RItux in LN
LUNAR - no difference btwn Ritux and Placebo for renal response but may hv role in MMF incomplete responder
Trial for MMF vs AZA
ALMS and MAINTAIN
-MMF> AZA
Heme manifestations in SLE
-* Cytopenias (AIHA, AoCD, leuk/lymph/neutro-, thrombocytopenia)
-* APLAS
-* TTP
-* MAS (R/O EBV or CMV infection as a trigger)
MAS clinical/lab manifestations
-Fever,
-Splenomegaly,
-Organ dysfunction,
-Cytopenias,
-Low ESR - liver inability to synthesize proteins such as fibrinogen,
-High TGs, ferritin, IL-2 receptor [CD25])
Hemolytic anemia W/U
-LDH, bili, hapto, CBC, smear, retic count
-DAT
Thrombocytopenia Tx
– When
– How
Tx if Plt <30 or bleeding with:
– GC (Dex/Pred or pulse if severe)
– IVIG 2g/kg (400mg/kg/d x5d) in prep for splenectomy or if bleeding
– Splenectomy (NOT 1st line → clot/sepsis)
– Ritux
– Thrombopoeitin R Ag (romiplostin, eltrombopag, avatrombopag) if failed GC
– For Rh+ nonsplenectomized: anti-D (RhD)
-2nd line: AZA, MMF, Cyclosporine, tacro, Danazol (androgen), CYC, fostamatinib, dapsone, vincristine
TTP clinical and lab manifestations
-Fever,
-Anemia (microangiopathic hemolytic),
-Thrombocytopenia,
-Renal,
-CNS
-SCHISTOCYTES (vs spherocytes in Coombs + AIHA)
TTP PathoPhys
AB against ADAMTS13 → vwF NOT cleaved → large multimers binding glycoprot R → plt adhesion and microthrombi
TTP Tx
– 1st line
– 2nd line
– Refractory
PLEX followed by FFP (replace ADAMTS13)
-Less effective: antiplatelets, GC, immunosuppressive
-Refractory: Eculizumab (Monoclonal AB to C5)
SLE MSK manifestations
Tenosynovitis
-Nonerosive arthropathy (Jaccoud)
-Deformities (reversible but fixed late) 2/2 lax joint capsule, tendons,ligaments → MCP subluxation, ulnar deviation, swan neck
-Rhupus: erosive symmetric polyarthritis (RF, CCP +)
TNFi for IA in SLE - why and why not
Maybe for erosive IA (rhupus)
Why not:
– Concern for DILE
how does TNFi cause lupus
TNFi suppress Th1 cytokines driving immune response towards Th2 cytokine production, IL10 and IFN alpha
SLE Tx w/o organ involvement
-HCQ
-MTX, LFN, AZA, MMF
NSAID caution in SLE - which and why
-COX2 specific inhibitors: increase thrombotic risk in APLA+
-Celecoxib is sulfa based → rash in pt w/ SLE
-Ibuprofen can cause aseptic meningitis
SLE rash pathology and immunofixation findings
-Interface dermatitis
-Biopsy shows Igs deposited at dermal epidermal junction on IF
MC Mucocutaneous SLE lesions and description
MC:
– Oral ulcers - painless and on hard palate
– Malar rash - erythematous plaques sparing nasolabial folds
– Discoid - hyperkeratotic rash w/ mucus plugging, causing scarring alopecia
– SCLE - annular (red, raised, irregular edges, central clearing, nonscarring (sun exposed area)) vs papulosquamous (eczema/psoriasis)
Less common SLE rashes
- Bullous lesions
– Purpura
– Urticaria (SVV - test anti c1q)
– Panniculitis w/ subcutaneous nodules (lupus profundus)
– Livedo reticularis (in APLA)
– Perniosis (distal vasculopathy)
SLE mucocutaneous Tx
Nonpharm: photoprotection
-Pharm:
– HCQ (or chloroquine),
– Dapsone (if vesicular),
– Thalidomide (severe mouth ulcerations; must be on OCP)
– Belimumab (recalcitrant discoid/subacute rash)
– MTX, MMF, AZA, Ritux
Discoid lesion Tx
-HCQ
-Topical CNI
-Corticosteroid: topical, oral, intralesional
-Belimumab if recalcitrant
SLE alopecia causes
-Active disease → diffuse stress alopecia (reversible)
-CYC → diffuse (reversible)
-DLE → patchy in distribution of discoid lesions (permanent bc follicles damaged)
-Vasculitis/AB against follicles → focal patchy alopecia areata like presentation
-
Skin lesion topical steroid therapies
Face = low/medium potency NONfluorinated (eg hydrocort)
-Trunk/arm: medium FLUorinated (eg betamethasone valerate, traimciniolone)
-Hypertrophic: high FLUorinated (betamethasone, clobetasol)
-Topical tacro (alternative to topical GC)
SCLE Tx:
Non pharm: Stop smoking (impairs HCQ)
-HCQ (best for tumid LE>SCLE>DLE)
-GC <30mg/d
-Belimumab (takes 4-6mo)
SLE Tx for
– Bullous
– SCLE
– DLE
– Lupus profundus
– Chronic lesions >50% body
– Vasculitis
– Hyperkeratotic lesions
– Bullous lesions: dapsone (measure G6PD first)
– SCLE: MMF, retinoids, CNI, dapsone
– DLE: HCQ+/- quinacrine, thalidomide (beware neuropathy), cyclosporine. Ritux
– Lupus profundus: Dapsone
– Vasculitis: immunosuppressives
– Hyperkeratotic lesions: oral retinoids
SLE Indications for high dose GC (>1mg/kg/d)
-CNS lupus (eg transverse myelitis)
-Pneumonitis, DAH
-Serious complications from pleuritis, pericarditis, peritonitis
-Severe nephritis
-Vasculitis w/ visceral organ involvement
-MAS
-Thrombocytopenia w/ Plt <30
-AIHA
**AVN risk factors **
- CYC, GC use (eg pred 20mg/d >30d)
- Vasculopathy: APLA AB, Raynaud’s
- Disease activity: CNS, renal, cytopenias
- Comorbidities: HTN, DM
- Smoking
AVN Tx
Core decompression if >25% femoral head involved w/o bony collapse
Nonpharm Tx of SLE
Photoprotection: sunscreen (SPF 30+), avoid smoking (affects HCQ), camouflage cosmetics
-Avoid triggers: sun, sulfa abx, high estrogen OCP, alfalfa sprouts, echinacea
-Prevent atherosclerosis: control BP (target <130/80), LDL<100, no smoking, treat high homocysteine lvls
-OP prevention: Ca 1000mg, Vit D 800, minimize GC, bisphosphonate if >20mg pred daily for 3+ mo (controversial for premenopausal)
-Immunizations: HPV<26yo, flu, shingrix, hep b, pneumococcal
-*NO live attenuated if pred 20/d or DMARDs (MMR, polio, HSV, smallpox, yellow fever)
-Prevent infxn: IE ppx if APLA+mumur, TBST or quantiferon if pred >15/d, PJP if CYC or GC >15-20mg/d
-Prevent renal progression in LN: avoid NSAID, BP target 130/80, ACEi/ARB to decrease proteinuria by 30%
-Prevent clots in APLA: ASA if LAC+, HCQ, avoid unnecessary surgery/catheters, tx infxns, avoid COX2i, avoid exogenous E2 (OCP, HRT, SERM)
-Tx fatigue: R/O hypothyroid metabolic, A&D, OSA, meds. Can tx w/ HCQ, modafinil, DHEA
-Cancer screen
-Birth control: low/medium exogenous E2 OCP ok if mildmod SLE w/o clot risk (APLA, nephrotic syndrome, severe renal dz, clot hx, migraines), if clot risk → Prog IUD/OCP
-Screen for low vit D (target >30-40ng/mL) - r/o celiac
**Conditions w/ increased incidence in SLE but not directly related to SLE **
-Cardiovascular disease
-Anxiety and depression
-Steroids related issues: osteoporosis, AVN, metabolic syndrome (HTN, obesity, DM)
SLE Tx approach
– Mild (list symptoms)
–Mild (fatigue, arthritis, rash, serositis)
– NSAID (**worsens Cr, photosensitivity, aseptic meningitis)
– HCQ
– Low dose pred <20mg/d
– MTX or LFN / AZA
SLE Tx approach
– Mod
-
–Mod (minor unresponsive esp low C3/4, and high dsDNA)
– Same as low: HCQ, GC (20-40), MTX/AZA
– MMF, AZA,
– Belimumab
– CNI
**Evidence for Belimumab **
BLISS showed better response when combined w/ standard therapy (MMF or CYC-AZA) vs standard therapy alone in AUTOANTIBODY POSITIVE SLE
- more renal response (UPCR <0.7, GFR no worse than <20% preflare, no rescue therapy), less renal related death
-Post hoc analysis howed best in MSK and mucocutaneous domains (less worsening in Heme, immunological, renal)
Belimumab in pregnancy
-Discontinue at conception
-Discontinue during pregnancy
-Minimal transfer during breastfeeding
MoA anifrolumab
IgG1-kappa monoclonal AB blocks Type 1 interferon R preventing inflamm/immunological response from IFN a,b,e, k, omega
SLE Tx approach
– Severe
Severe (nephritis, CNS, pneumonitis, vasculitis, severe cytopenia
– Pulse steroids then high dose PO
– Induction: CYC or MMF
– Maintenance: AZA, MMF, CNI, combo
– Ritux
– Additional: PLEX, IVIG (autoimmune cytopenias, APLAS), stem cell transplant (refractory)
SLE Tx target
Remission
– SLEDAI = 0
– HCQ
– No GC
-Or
-Low disease activity:
– SLEDAI <4
– HCQ
– Pred <7.5
– Immunosuppressives
When to use PLEX in SLE
-DAH,
-TTP,
-Anti-NMO,
-APLAS
Reasons for high CRP in SLE
-Vasculitis
-Serositis
-Infection
Why is ESR always high in SLE even if dz quiescent
Persistent hypergammaglibulinemia
Signs of infection vs SLE
-Complement rises
-WBC “normalizes” from usual low; LEFT shift
-Elevated procalcitonin or lactate
How does stem cell transplantation work in SLE
Eliminates autoreactive lymphocytes and replaces them w/ undifferentiated cells
MC cause of death SLE
Infxn: bacterial, fungal, TB, nonTB, mycobacterial, viral
-Active disease: LN, CNS, vasculitis, pneumonitis
-Cardiovascular: CAD, stroke, PAD
-Cancer: HPV (from poor viral clearance), NHL, Lung Ca, SCC (from discoid)
MC Biologics in SLE, MoA and indication
Belimumab - monoclonal AB inhib BAFF/BLyS to prevent B cell survival. (BAFF/BLyS normally promotes B cell survival and prevents apoptosis)
- Indication: MSK or mucocutaneous manifestations (renal, CNS excluded from trials)
-RItux - antiCD20 monoclonal AB
– For recalcitrant dz, CAPS, or combined w/ CYC for B cell depletion
Factors less likely to respond to belimumab
-Cytopenias
-Serologically inactive
Black box warning for belimumab
Depression
Belimumab dose
-10mg/kg IV monthly
-200mg SC weekly
Drug induced lupus erythematosus classification
-Systemic DILE: arthralgia, myalgia, serositis, constitutional sx s/p 1mo of drug . +ANA and one other SLE critieria
-Drug induced SCLE - similar to idiopathic SCLE: photosensitivity, cutaneous lesions (vasculitic/bullous) **suspect if SCLE >50yo
-Chronic cutaneous DILE - discoid lesion s/p fluorouracil
** Systemic DILE Drugs (high, mod, low risk) **
High: Procainamide, Hydralazine
-Mod: Quinidine, Penicillamine
-Low: Isoniazid, Methyldopa, Minocycline, AntiTNFalpha, IFN alpha, chlorpromazine
-Possible: anticonvulsants, PTU, SSZ, Li, HCTZ, amio, anti-PD-L1 immunotherapy , statins
Drugs causing SCLE
-HCTZ, CCB, ACEi
-Statin
-AntiTNFa
-Leflunomide
-PPI
-Bupropion
-Docetaxel, Hydroxyurea, anti PDL1
Systemic DILE manifestations
-SLE sx (Fever,arthritis/arthralgia, myalgia, serositis)
-Hepatomegaly
-Derm: Erythematous papular rashes (discoid and malar UNCOMMON)
-RARE: severe manifestations eg cytopenias, renal, CNS,
-dsDNA, low C3/4 ONLY if TNFi and interferon alpha
DILE pathogenesis
-Genetics: slow acetylator phenotype
-Epigenetic: methylation changes → certain peptides overexpressed (eg LFA1) → autoreactivity
-Activated neutrophils → ROS release + oxidation → cytotoxicity
-NETs → autoantigen exposure stimulate autoreactive T/B cells
Procainamide vs hydralazine induced lupus
-Procainamide: pleuritis +/- pericarditis; antihistone H2A-H2B-DNA complex
-Hydralazine: rashes; antihistone H3/4 complex
-Both: arthralgia/arthritis, myalgia, fever
Minocycline induced lupus serologies
-Anticardiolipin AB
-pANCA
-Antihistone
IFNalpha DILE manifestations and Tx
Typical SLE:
– oral ulcers
– alopecia
– nephritis
-Require GC and SLE Tx
TNFi DILE manifestations
-Arthralgias,
-Rash
-Heme: leukopenia, thrombocytopenia
-** dsDNA AB **
-Hypocomplementemia
-Less likely antihistone
Antibodies seen in DILE
-ANA (more common than symptoms)
-Antihistone (not specific to DILE; rare in TNFi) - IgG
-dsDNA (** only w/ anti-TNFa or IFNa **)
-APLA (with procainamide, quinidine, chlorpromazine) - rarely assoc’d w/ clots ; IgM
Drug induced SCLE vs idiopathic SCLE
-Cutaneous SCLE more widespread, bullous or vasculitic
-SSA+ disappears when drug stopped
DILE Tx
-Stop Drug
-NSAID for arhtralgia
-GC for severe pericarditis/pleuritis
-HCQ if prolonged
-AZA/CYC ONLY if drug induced vasculitis
MCTD vs Overlap vs UCTD
MCTD: RNP+ w/ manifestations seen in SLE, SSc, and IIM
-Overlap: features of >1/6 SARDs (SLE, SSc, PM, DM, RA, SS)
-UCTD: some features of 1+ SARD w/ +ANA but doesnt meet criteria for any
**MC MCTD manifestations **
-Raynaud
-Swollen hands w/ puffy fingers
-Synovitis (Jaccoud’s, erosions)
-Myositis
-Acrosclerosis
-LACK of renal/CNS
-Fever
-Lymphadenopathy
-Serositis
-RARE: myocarditis, HTN crisis, aseptic meningitis
MCTD Derm manifestations
-Scleroderma,
-Skin rash,
-Oral ulcers
MCTD GI manifestations
-Esophageal dysmotility
-Esophageal sphincter hypotension
-GERD
-HSM
-Hepatitis, pancreatitis
-Intestinal vasculitis
MCTD Pulm manifestations and Ix (imaging, PFT)
-PAH (highest risk if nailfold abN)
-Pleuritis / Effusions
-ILD - NSIP
-PFT: restrictive, DECREASED DLCO, pHTN
MCTD mortality cause
pHTN
MCTD lab findings
-Lupus labs (anemia, Leuko/lymphopenia)
-ANA, RNP, hypocomplements
-RF
-Hypergammaglobulinemia → high ESR
MCTD CNS manifestations
-Trigem neuralgia
-Sensorineural hearing loss
-Headache
-aseptic meningitis,
-seizure,
-peripheral neuritis,
-cerebrovascular disease
- psychosis
Role of RNP in pathogenesis of MCTD
Molecular mimicry:
-HLA-DR4 mounts response against CMV glycoprotein that cross reacts with RNP 70kD polypeptide modified during apoptosis
MC dz in Overlap syndrome * what dz are assoc’d
Sjogren’s = MC in overlap
-Seen with RA, SLE, SSc, PM, MCTD, PBC, necrotizing vasculitis, autoimmune thyroiditis, chronic active hepatitis, mixed cryoglobulinemia, hypergammaglobulinemic purpura
Other overlap syndromes
-SLE w/ IIM
-SLE w/ RA
-SSc w/ IIM
-Limited SSc w/ PBC
-SSc w/ AAV
-Myositis overlap syndromes (antisynthetase)
-RA w/ SSc, SLE, MCTD, SS
UCTD clinical manifestations
(SLE without organ involvement)
-Arthralgia/arthritis
-Raynaud’s
-photosensitivity,
-oral ulcers
-SICCA
-Serositis
-RARE Maj organ involvement
UCTD lab manifestations
-ANA+
-Occasional SSA or RNP
-Usually no Sm, dsDNA, centromere
UCTD classification criteria
-Signs/symptoms of CTD ≥3y but not fulfilling any criteria
-ANA+ on 2 occasions
** Raynaud primary vs secondary**
Primary:
- Young F>M,
- ANA negative,
- NORMAL nailfold capillaries
- No peripheral vascular disease,
- No digital ischemia/ulcers/pitting/fissuring/gangrene,
Secondary:
-Older (>40), M, Asymmetric,
- ANA+ (or ENA/SSc ABs)
- ABNORMAL nailfold capillaries
- Ischemia proximal to fingers/toes, ulcers, pits, gangrene
- Other CTD findings (rash, sclerodactyly)
Raynaud labs to send to work up
-Cryo
-Hypercoagulable workup
-TSH (for hyPOthyroid)
-SSc AB
Raynaud reason for imaging
-Asymmetric
-Suspicion for thromboembolism, Buerger’s
-Abnormal Allen’s test
-Severe disease resistant to Tx
Raynaud imaging options
-Brachial finger index measurement (>20mmHg gradient suggest prox fixed obstruction)
-Doppler
-Finger photoplethysmography
-Invasive angio or MRA for prox vessel dz (eg vascular thoracic outlet syndrome)
Primary Raynaud pathophys
-Increased basal sympathetic adrenergic tone and increased alpha2 adrenoR activity at neutral temp → heightened fx in cold
-Nutritional bloodflow diminished but preserved = NO ulcerations
Secondary Raynaud pathophys
-Reflex cold induced sympathetic constrictor nerve activity
-Dysfunctional endothelium: releases endothelin (constrict) and reduced vasodilators (NO, prostacyclin)
-SSc: intimal prolif and abN PLT adhesion → reduced lumen size & less flow through distal capillary loops → ulcers
Raynaud’s nonpharmTx
Nonpharm:
-Avoid cold,stimulants (decongestant, amphetamines, diet drugs),BB
-Stop smoking,
-Stress management,
-Core warming, Mittens
Raynaud’s Pharm Tx
Mild/mod:
– DHP-CCB (nifedipine XL 30mg/d, amlodipine 5mgd),
– NonDHP: Dilt 120mg/d
– Topical nitrate (¼-½ inch BID/TID, rest for 12hr to prevent refractory)
– ARB (losartan),
– PDE5i (sildenafil or tadalafil),
– SSRI (fluoxetine)
Severe or ulcers:
– Combo therapy w/ PDEi or ASA (81mg)
Recurrent severe/ulcers:
– Add prostaglandin (epoprostenol or iloprost) or botox or both.
– Start endothelin-1 inhibitor (bosentan) for scleroderma w/ recurrent digital ulcers
Raynaud meds - which reduce new ulcer formation
Endothelin -1 ANT
-Statins (inhib rho kinase pathway that regulates alpha2 adrenoR expression)
RP Drugs and their side fx / contraindication
CCB: edema, constipation, presyncope, H/A, GERD; AVOID in preg; use DHP if PH or LV dysfcn
-Symphatolytic (eg prazocin): postural hypotension
-Topical nitrate: H/A; use alternative if HF or PH, dont’ use with PDE5i
-Endothelin ANT (bosentan): LFT abN, H/A, flushing, edema
-Prostacyclin analogue: flushing, jaw pain, H/A, diarrhea, nausea
Raynaud Tx for refractory
-Gangrene/amputation
-Digital sympathectomy
-Chemical sympathectomy via digital lidocaine block for pain
** Causes of Raynaud**
Systemic: SLE, MCTD, IIM, SS, RA, Burger, Vasculitis, pHTN,
-Trauma: rock driller, lumberjack, CTS, hammer operator, frostbite, hypothenar hammer syndrome
-Drugs/Chemical: BB, cocaine, amphetamine, methylphenidate, IFNa, cisplatin, bleomycin, ergot
-Occlusive artery disease: postembolic/thrombotic arterial occlusion, thoracic outlet syndrome
-Hyperviscosity syndrome: polycythemia, cryo, paraproteinemia, thrombocytosis, leukemia, cold
-Endocrine disorders: carcinoid, pheo, hypothyroid
-Infection: IE, lyme, mono, hepatitis
Misc: CRPS, peripheral AV fistula,
-Cancer: ovarian, angiocentric lymphoma, paraneoplastic, hypothyroid
Why triphasic RP
Vasospasm → pallor (most definitive)
-Static venous blood deoxygenates → cyanosis
-Rewarming → rubor
Raynaud’s precipitant
-Cold (esp when accompanied by pressure)
-Sympathetic stimulation (pain, emotional distress, meds)
-Trauma
-Hormones (eg estrogen)
-Medication
-Smoking
Sites of vasospasm in RP
Primary: acral (finger, toes, ear, nose, nipple)
Secondary: acral but also coronary arteries and vasculature supplying internal organs
Give 3 Names for B cell receptors and their function
BLyS receptor 3 (BAFF-R) –> induces survival and activation of B cells via NFkB
Transmembrane activator and calcium modulator and cyclophylin ligand interactor (TACI) –> inhibits B cell expansion and enables class switching
B cell maturation antigen (BCMA) –> plasma cell survival
Contraindications or indications that are not approved for Belimumab
- Anaphylaxis
- Ongoing infxn
- Live vaccine w/i 30d
- Preg
- Avoid use w/ Ritux or CYC
Not approved:
- Severe active LN or NPSLE
- Not approved for RA
2 methods to measure antidsDNA
- Difference in results
- How to increase specificity
Farr assay - radiolabelled DNA incubated w/ serum. Ammonium sulphate precipitates out immune complexes. Limited to high affinity AB, and is SPECIFIC for SLE but not highest sensitivity. GOLD STD
ELISA - DNA on solid phase support exposed to serum amd antiDNA AB binding detected w/ enzyme labelled AB to human Ig. Higher sensitivity than Farr assay.
Crithidia luciliae assay - circular dsDNA of parasite exposed to antibody w/ increasingly dilute concentrations until no more reactivity. Circular DNA less likely denatured = more specific than ELISA but less sensitive
Diseases assoc’d w/ positive ANA
Rheum: RA, SS, SSc, MCTD, PM/DM, SLE, DIL
Infxn: HIV, HCV, IE, syphilis, EBV, Parvo, TB, Mono
Autoimmune: Hashimoto, Grave, Autoimmune hepatitis, PBC, IBD, UPF
Cancer: lymphoprolif, paraneoplastic
Inteferon in SLE:
Role? MC family? Cell type associated?
What is an interferon signature?
MC: Type 1 IFN
Associated cell type: plasmacytoid dendritic cells
IFN signature: pattern of increased IFN gene expression (type 1 signature in SLE)
Stimulating factors for IFN1
- Inteferogenic immune complexes: autoantibodies + nucleic acid binding proteins via;
- NETs: not degraded in SLE bc reduced extracellular DNase 1 –> more exposure of nucleic acid/prot to autoAB and autoreactive B cells
- UV light: induce ROS to cause DNA damage –> recognized by autoantibodies to form immune complex to induce pDC production of T1 IFN.
Role of NETs in SLE?
NETs: cell death pathway where neuts extrude nuclear material (histones, chromatin, cytoplasmic prot) in web structure.
Increased NET in SLE bc not degraded due to reduced extracellular DNase 1 –> more exposure of nucleic acid/prot to autoAB and autoreactive B cells
Reasons to choose MMF over CYC
- Better outcomes in African american and Hispanic
- No fx on fertility, risk of hemorrhagic cystitis/bladder cancer
- Less risk of infection
- Convenience, taken PO
- Can be taken with renal dysfunction
Reasons to choose CYC over MMF
- IV ensures compliance
- Intolerance to MMF
- Caucasian
Headache DDX in SLE patient
Neuropsychiatric lupus
Aseptic meningitis (from ibuprofen or SLE)
Venous sinus thrombosis
Migraine
Tension headaches
Cluster headaches
Secondary CNS vasculitis
PRES
Thrombocytopenia DDX in SLE
TTP
Sepsis
ITP
Splenic sequestration
APS
Drug reaction
SLE flare
NPSLE PNS manifestations
Autonomic disorder
Myasthenia gravis
Neuropathy: cranial, mononeuritis, poly
Plexopathy
GBS
Difference between cutaneous DM and SLE skin biopsy
Both are vacuolar interface dermatitis
DM inflammation limited to upper dermis
Main difference is depth of infiltrate/mucin deposition
Weakness DDX in SLE (Ix, and Tx)
Steroid myopathy (CK, EMG, NCS, Pathology –> Taper steroids, PT/OT)
Plaquenil neuromyotoxiciity (CK, biopsy –> stop Plaquenil)
Myalgia/Myositis (BW, Bx –> steroids)
Discoid lesion biopsy
Hyperkeratosis,
Interface dermatitis w/ lymphohistiocytic infiltrate
Epidermal vacuolation
SLE with accelerated atherosclerosis
Give 4-5 factors in SLE which aggravate this
GC –> DM, Obesity, and vessel injury
Renal disease –> HTN
Smoking
APS AB
Inflamm (from Type 1 IFN) –> vessel injury
How antimalarials help in atherosclerosis
- Decrease production of IL1,6, PG
- Increase low-density lipoprotein receptors lowering lipid levels.
- Decrease insulin degradation (help prevent DM)
- Inhibit plt aggregation/adhesion (help to prevent thrombosis)
SLE vs RA hand clinical deformities
SLE:
- Nonerosive arthropathy
- Reversible deformities that can become fixed
- Pain/tenderness > swelling
- Predominant tendinitis/tenosynovitis (vs synovitis in RA)
SLE vs RA XR deformities
SLE:
- No erosions
- No deformities
- Normal joint spaces
- AVN
- Enthesitis more common than in RA
SLE vs RA synovial fluid
SLE:
-Lymphocyte predominance,
-Fluid only mildly inflammatory,
-Presence of LE cells: neut/macrophages that have engulfed nuclear material
4 disease associations with anti-Ro and the frequency of positivity in each disease?
SLE (40%), RA (5%), MCTD (Rare), dSSc (10-20%), Primary Sjogren’s (75%)
List the disease association with anti-Jo and the frequency?
Myositis – Anti-synthetase syndrome ~20-30%
Disease associated with anti-histone antibodies and the frequency?
Drug-induced lupus –between 90-95%
