SLE

Classification Criteria rev 2002  

4/11 required

Malar Rash
Discoid Rash
Photo sensitivity
Oral Ulcers
Arthritis
Serositis

Renal disorder (cellular casts, proteinuria>0.5g)
Neurologic disorder (Seizures, Psychosis)

Hematologic disorder (Hemolytic anemica,lelukopenia, lympopenia, t'penia)

Immunologic Disorder (Anti-DNA, Anti Sm, + Lupus anticoagulant)

ANA

SLE

Pathogenesis

• Genetic Factors (HLA-DR2 or DR-3, Early complement component deficiencies ie C4 Null Alleles, Fc_gRII and RIII polymorphisms
• Loss of Immune tolerance
• Autoantibodies (Polyclonal B cell Activation, Ag driven resonse, circulating immune complexes)
• Interferon signature on gene expression profile -activates B cells,  downstream proteins upregulated that decrease w tx

+ ANA in Lupus

 In a primary care setting:

• Sensitivity-100%
• Specificity-67%
• PPV: 12%
• NPV: 100%
• Negative ANA is useful, but a +ANA present in many dz and in normals (>5%)

Autoantibody Specificity

Anti DNA (ds DNA)

Systemic Lupus  (SLE)

• Present in 50-60% of SLE
• Very uncommon in other diseases
• Assoc w severity and w nephritis
• Useful in following dz (only one) over time

 Autoantibody specificity:

Anti SM (U1, U2, U4-6, snRNP)

Specific for Systemic Lupus (SLE)

• Present in 30-40% of SLE
• Very uncommon in other diseases
• Assoc w interstitial lung dz

Autoantibody specificity

Nuclear RNP (U1 snRNP)

Specific for MCTD (100% of pts w MCTD)

• Also present in 30-40% of SLE
• Assoc w MCTD sx, overlap SLE
• Also DM/PM, PSS

Autoantibody specificity

Ro (SS-A) and La (SS-B)

Specificity: Sjogrens (60-70% of pts w Sjogrens)

• Ro also present in 25-30% of SLE. La also present in 10-15% of SLE
• Also assoc w Subacute cutaneous lupus
• Ro: neonatal lupus (congenital heart problems)

Autoantibody specificity

Histone (histone proteins)

Drug induced Lupus

• Also present in 50-70% of SLE.

 Autoantibody specificity

SCL-70 (topoisomerase 1)

 PSS (Progressive Systemic Sclerosis)

(40-70% of pts w diffuse PSS)

• Present in <5% of SLE.

Autoantibody specificity

Anti-Centromere

CREST(70-85% of pts w limited scleroderma)

• Present in <5% of SLE.
• Assoc w Raynauds phenomena

Autoantibody specificity

Jo-1 (histidyl tRNA synthetase)

DM/PM (40-50% of pts)

• Present in <5% of SLE.
• Assoc with interstitital lung dz, arthritis

B cell Surface Markers as targets for

Autoimmune Dz Therapeutics

 CD20

• CD20 :present on all pre-B cells to mature B cells but not on plasma cells
• Rituximab: anti CD20

B cell Surface Markers as targets for

Autoimmune Dz Therapeutics/Biologics

APRIL 

BlyS

 Markers:

• APRIL (B cell survival factor): Binds to TACI on B cell 
• BlyS (B Cell survival and differentiation factor)

Biologics:

• Atacicept: TACI-Ig that binds BlyS and APRIL (in SLE, RA):selectively impair mature B cells and plasma cells with less impact on progenitor cells and memory B cells.
• Belimumab (Benlysta):  anti-BlyS Ab

B cell Surface Markers as targets for

Autoimmune Dz Therapeutics/Biologics

CD22

Marker:

• CD22 (negative regulator) on B cell

Biologic:

• Epratuzumab: anti CD22 (in SLE)

Sjogrens Syndrome

Clinical Presentation

• Sicca Sx (xeropthalmia, xerostomia) w lymphoid infiltration of exocrine glands
• Sometimes kidney, CNS involved
• Arthralgia
• Increased risk of lymphoma

Sjogrens Syndrome

DX

• ANA (50+%)
• Anti-Ro, Anti-La
• RF may be high
• Fetal Heart block assoc w Anti-Ro

Scleroderma

(Progressive Systemic Sclerosis)

Diffuse

• Diffuse is always worse prognosis
• Anti-Scl-70
• Pulm fibrosis, renal disease, cardiac, rapid skin changes
• ANA + 90%

Scleroderma

(Progressive Systemic Sclerosis)

CREST variant

• Calcinosis cutis, Raynaud’s, Esophogeal dysfunction, Sclerodactyly, Teleangectasias
• Better outcome:  limited skin dz,
• Pulm Artery Hypertension is assoc w CREST variant

Idiopathic Inflammatory Myositis

General

• Proximal muscle weakness
• Elevated CPK and aldolase
• EMG abnormalities
• Muscle BX
• DDX:  thyroid dz, malignancy (+association)

Dermatomyositis

• Skin changes, malignancy association
• Anti-Mi-2 is associated w rash

Polymyositis

• Anti Jo-1, assoc w intersititial lung disease, arthritis
• Anti SRP (signal recognition particle); acute onset, more refractory

  Inclusion Body Myositis

• “Ragged Red Fibers”
• Older patients, associated neuropathy
• Less responsive to tx

Antiphosphospholipid/Anticardiolipin/
Lupus Anticoagulant (LAC) Syndrome

Clinical triad

• Recurrent Thrombotic events (arterial and venous)
• Spontaneous 2^nd trimester abortion
• Thrombocytopenia
• Other clinical manifestations:  livedo reticularis, Raynauds, transverse myelitis, hemolytic anemia, neuropathy

Antiphosphospholipid/Anticardiolipin/
Lupus Anticoagulant (LAC) Syndrome

Lab Tests 1

1. Auto antibody tests to phospholipids (anticardiolipin Ab)
2. Lupus anticoagulant tests dynamic clotting tests (autoab bind phospholipids and most clotting tests depend on phospholipids,thus they prolonged-therefore ‘anticoagulant’ in test name despite hypercoaguability clinically)

Antiphosphospholipid/Anticardiolipin/
Lupus Anticoagulant (LAC) Syndrome

Therapy

Immune Neurologic Conditions

Multiple Sclerosis

• Destruction of CNS Myelin Sheath (myelin basic protein)
• 25% twin concordance
• Women 2X Men
• Ages 20-40
• RX:  Immunosuppression, IFN beta, anti-VLA4-(Natalizumab) but associated with Progressive Multifocal Leukoencephalopathy

Immune Neurologic Conditions

Guillian Barre

Acute demyelinating peripheral polyneuropathy

Immune Neurologic Conditions

Myasthenia Gravis

Epidemiology and  Associations

• Pathogenic Ab against postsynaptic ACh receptorin 85% pts
• HLA-B-8/DR3
• Bimodal age onset
• Assoc w thymoma/thymic hyperplasia esp in younger pts
• Limited to eye in 65% pts

Immune Neurologic Conditions

Myasthenia Gravis

DX and TX

• DX:  decremental EMG w repetative stimulation, +AChesterase inhib, AntiChR antibodies
• Diff DX:  Eaton Lambert (paraneoplastic, presynaptic neuromuscular junction destruction)

Autoimmune Hemolytic Anemia

Warm (IgG)

• Can be primary or secondary to SLE, CLL, lymphoma etc
• F>M, usually <40 y/o
• IgG against red cell markers ie Rh, Kell, Kidd,A, B
• Anemia, splenomegaly, reticulocytosis, bilirubin incr

Autoimmune Hemolytic Anemia

Warm (IgG)

 DX and TX

• DX: Coombs (IgG Direct Ab test) + >95%, but + DAT in 1/14,000 normal donors
• TX:  Steroids, IVIG, splenectomy, immunosuppression, rituximab

Autoimmune Hemolytic Anemia

Cold

15-25% OF AIHA 2 types:

1.  Cold Hemagluttinin:

•    Acute/transient ie in mono, mycoplasma
•    Chronic ie in lymphoreticular dz
•    Usually IgM lambda

  2.  PCH (paroxysmal cold hemoglobinuria)

•      Children, usually sudden post infection
•      Donath Lansteiner Antibody

Autoimmune Thrombocytopenia

Types:

• ITP: IgG against platelet proteins ie gpIIb/llla, prlb/lX
• Secondary:  SLE, CLL, Hodgkins, HIV etc
• Drug-induced: heparin (auto-ab to heparin/plt factor 4 complex)

Autoimmune Thrombocytopenia

Treatment:

• Steroids
• IVIG
• Splenectomy
• Vinca-loaded plts
• RhoGam
• Danazol
• Rituximab (anti-CD-20)

TTP/HUS

Clinical Presentation and Pathogenesis

• Thrombocytopenia, microangiopathic hemolytic anemia,fever, renal, neuro sx
• Endothelial damage (infection, toxins, drugs etc) lead to secretion of large multimers of vWf which increase plt binding
• In TTP lacks vWf cleaving protease ADAMTS-13 (?autoantibody)

TTP/HUS

Treatment

• Plasma exchange,
• ?Immunosupression

Cryoglobulins

Definition

Immunoglobulin that precipitate in cold temperatures

Cryoglobulins

Types

• Type 1:  monoclonal (IgG or IgM), assoc w Multiple myeloma, Waldentroms
• Type II:   mixed mono and polyclonal usually IgM, assoc w HepC (80%), lymphoprolif dz
• Type III: polyclonal usually IgM; assoc w SLE, CA, Hep C

Cryoglobulins

Clinical Presentation

• Purpura
• Glomerulonephritis
• Arthritis
• Neuropathy

Inflammatory Bowel Disease

Markers

• Crohns:  - pAnca,  ASCA + (anti Saccharomyces ab),   smoking increases risk
• UC:   + pAnca,       ASCA -, smoking decreases risk

Cryopyrin Associated Periodic Syndromes

CAPS

Auto inflammatory Syndromes:

(Muckle Wells Syndrome, Neonatal multisystem inflam disease, Familial Cold-induced autoinflammatory syndrome)

Pathophysiology

• ‘Gain of function’ mutation in NALP3
• NALP3 inflammasomes are normally inactive.
• When they become active they are collection of proteins that activate cell to secrete inflammatory cytokines, activate capspase 1 which liberates IL-1 and IL-18

RX: 

• IL-1 inhibition with Anakira (IL-1 receptor ab) or Rilonacept (Il-1 TRAP)

 GOUT

Role of Uric Acid in inflammation

Uric Acid may act as a DAMP (Danger Associated signal) that  can drive the  NALP3 inflammasone pathway