Vasculitis DSA and CIS Flashcards
What is Pregnancy or Neonatal Lupus?
Affects children born to mothers with
Anti Ro (SS-A) or La (SS-B)
1-2%
Maybe seen in Sjogren’s as well
What is the serology workup for Sjogren’s? Which markers are the most imporant ones and why?
(+) ANA
(+) Rheumatoid Factor (RF)
High ESR
Polyclonal Hypergammaglobulinemia
(+) Anti SSA/Ro
Presence may lead to newborn complete heart block
(+) Anti SSB/La
(never present without Ro)
Low C4 complement
Anemia of chronic disease
Pemphigus vulgaris, Goodpasture syndrome, Acute rheumatic fever, Insulin-resistant diabetes, and pernicious anemia are examples of what type of hyerpsensitivity?
Type II Hypersensitivity
Autoantibody specific for Rheumatoid Arthritis?
anti-CCP (cyclic citrullinated peptides)
Drugs to treat DM and PM
- Glucocorticoids
- Methotrexate (MTX)
- Azathioprine
- Cyclophosphamide
- Cyclosporine
- Intravenous immunoglobulin (IVIG)
- Mycophenolate mofetil
- Rituximab
- Hydroxychloroquine
What types of antibodies do you look for in scleroderma serology?
Diffuse (dcSSc)
Anti-Scl70 aka Anti-DNA Topoisomerase I
Anti-RNA polymerase III
Limited (lcSSc) or CREST
Anti-centromere
What is the basis of an immune complex-mediated (type III) hypersensitivity reaction?
What type of antigens involved?
- IgM and IgG antibodies bind antigens usually in circulation and the antigen-antibody complex deposits in vessel walls and induce inflammation (vasculitis)
- Antigens can be exogenous and endogenous
How are self-reactive T cells able to undergo apoptosis in the process of peripheral tolerance?
- Self-reactive T cells express pro-apoptotic member of Bcl family (Bim), w/o antiapoptotic members of the family like Bcl-2 or Bcl-x
- If self-antigens engage antigen receptors of self-reactive T cells, FasL and Fas are co-expressed inducing extrinsic pathways of apoptosis
What is the treatment for Wegener’s Granulomatosis?
Quit smoking
Cyclophosphamide
High dose glucocorticoids
Rituximab
Methotrexate okay only if renal fxn is normal
How does Chronic Discoid Lupus Erythematosus present?
- Skin manifestations mimicking SLE, rarely systemic involvement
- Well-defined imflammatory skin plaques w/ edema, erythema, scaliness, follicular plugging
- Localized, deep, and scarring
- Usually only involving the face and scalp
Population most impacted by autoimmune diseases?
F > M
Minority populations are at increased risk of rheumatolgoic diseases
cANCA
pANCA
What is the morphology of the blood vessels like in patients with SLE?
How about in the chronic stages?
- Acute necrotizing vasculitis involving capillaries, small arteries, and arterioles
- Chronic stages = vessels undergo fibrous thickening with luminal narrowing
MSK complications as a result of Systematic Sclerosis
Carpal tunner syndrome
Tendon friction rubs
Fibrosis and adhesion of tendon sheaths
What are the salient feautes of Neonatal Lupus?
Transient
- rashes
- thrombocytonpenia
- hemolytic anemia
- arthritis
–> risk for Permanent complete heart block
What induces the pathologic lesions of immune complex disorders?
Complement-fixing Abs (IgG and IgM) and Abs that bind to leukocyte Fc receptors
Differences between primary and secondary Raynaud
Primary: benign, exeggerated response to cold, affects more females between 15-30yo. Nailfold capillaries are normal
Secondary: unilateral, mor severe –> ischemia. Nailfolds with irregular loops, dilated lumen, and areas of vascular ‘dropout’
Episodic: pallor (vasoconstriction) –> cyanosis (ischemia) –> erythema (reperfusion)
How are antigens restricted to peripheral tissues able to be expressed in the thymus during the process of central tolerance?
A protein called AIRE
What is ANA and what is it specific for?
Anti-nuclear Ab
NOT specific Indirect immunofluorescence
1:40 is normal, higher may be of clinical significance
Centromere Pattern
30-60 Specles in the nucleus
- Localize to chromosomes in the metaphase
- CREST, systematic sclerosis
What is the earliest histological finding in both the major and minor salivary glands in patients with Sjorgen Syndrome?
Periductal and perivascular lymphocytic infiltration
What plays a role in acceptance/tolerance of a fetus while inside the placenta?
CD4+ CD25+ FOXP3 Treg cells
Some fun facts about Lupus-Like Syndrome
aka
Drug-induced SLE
Presents with SLE like symptoms but it is not a Type III hypersensitivty rxn.
T-cell DNA demethylation in older folks (Type IV)
Positive for ANA
95% will test positive for Anti-histone Abs
Affects M and F equally (unlike SLE)
No oral mucosa, CNS, or kidney involvemnt
Differentail DDx for THROMBOSIS
APS (Antiphospholipid Ab Syndrome)
Protein C deficiency
Protein S deficiency
Anti-thrombin deficiency
Factor V Leiden deficiency
Heparin Induced thrombocytopenia
Sepsis
Systemic vasculitis
DIC (disseminated intravascular coagulation)
TTP (thrombotic thrombocytopenic purpura)
What can be used to monitor disease activity of Type III Hypersensitivity?
- Complement proteins can be detected at site of injury, and during active phase of disease consumption of complement will lead to decrease in serum C3
- Serum levels of C3 can be used to monitor the disease activity
Differentail DDx for COTTON WOOL spots
- Hypertension
- Diabetes
- Immune-mediated
◦ SLE/APS
- Ischemia
- Embolic
◦ DVT
◦ Long bone fracture (white cell emboli)
◦ Traumatic pancreatitis (white cell emboli)
- Infectious
- Toxic
- Radiation-induced
- Neoplastic
- Traumatic
- Idiopathic
What group of people is most common to develop SLE?
- Women
- African American and Hispanic > White
What are the main clinical features of a patient presenting with SLE?
- Butterfly rash over the face
- Fever
- Pain but no deformity in one or more peripheral joints (feet, ankles, knees, hips, fingers, wrists, elbows, shoulders)
- Pleuritic chest pain
- Photosensitivity
Mutations in the AIRE gene cause?
Autoimmune polyendocrinopathy
Venous and arterial thromboses, which may be associated with recurrent spontaneous miscarriages and focal cerebral or ocular ischemia is characteristic of?
Antiphospholipid antibody syndrome
- Can be primary = by itself
- Or secondary = in association with lupus
Differential DDx for DLE
Discoid lupus
Tinea infection (Ring worm)
Psoriasis
Morphea (Localized scleroderma)
How do deposited antibodies in fixed tissues, such as basement membranes and ECM cause injury due to inflammation?
1) Activate complement, generating by-products, including chemotactic agents (C5a), which brings polymorphonuclear leukocytes and monocytes to tisse
2) Activate anaphylatoxins (C3a and C5a), which increase vascular permeability
What sort of renal involvement is seen in Sjorgen Syndrome vs. SLE?
- Defects of tubular function (renal tubular acidosis, uricosuria, and phosphaturia)
- Glomerular lesions are extremely rare (like those seen in SLE)
List 6 scenarios/diseases that involve immune-complex mediated (type III) hypersensitivity?
1) Systemic lupus erythematous
2) Poststreptococcal glomerulonephritis
3) Polyarteritis nodosa
4) Reactive arthritis
5) Serum sickness
6) Arthus reaction (experimental)
Which organs are most commonly involved in Systemic Sclerosis (Scleroderma)?
- Skin is most common with secondary Raynaud phenomenon
- Raynaud is typically first sx in Caucasians
- Skin pigmentation changes as the first sx are more common in African Americans than Raynaud
- GI tract
- Kidneys
- Heart
- Muscles
- Lungs
Mutations in the FAS gene cause what disease?
Autoimmune Lymphoproliferative Syndrome (ALPS)
Homogeneous Staining Pattern
Entire nucleus is diffusely stained
- Drug-induced SLE
- Sjogren’s syndrome
- SLE
What are 2 methods by which infections may induce autoimmunity?
1) Infections may upregulate the expression of co-stimulators on APCs; if these cells are presenting self-antigens result may be a breakdown of anergy and activation of self-reactive T cells
2) Molecular mimicry: microbe expresses Ag w/ same AA sequence as self-Ags
Occult malignancies in Dermatomyocytitis include…
- Ovarian - Check transvaginal US, CT abd/pelvis with IV contrast, CA-125
- Lung (CT > CXR)
- Pancreatic (Abdominal CT with IV contrast or MRCP)
- Stomach (EGD)
- Colorectal (Colonoscopy)
- Non-Hodgkin Lymphoma (CBC with diff, lymph node biopsy, bone marrow biopsy, imaging CT/MRI/PET)
- Cervical (pap smear)
- Prostate (digital rectal exam and PSA, biopsy)
- Breast (mammogram)
- Monoglonal gammopathies [multiple myeloma] serum protein electrophoresis
What do antibodies do in Myathenia gravis?
React with ACh receptors in the motor end plates of skeletal muscles and block (act as antagonists) neuromuscular transmission –> muscle weakness
Sjorgen Syndrome can occur as a primary form (sicca syndrome) or most commonly as a secondary dz to something else with systemic symptoms. Which disease is it most commonly associated with?
- Rheumatoid arthritis
- Can also be associated with SLE, polymyositis, scleroderma, vasculitis, mixed CT disease, or thyroiditis
What are some important features of Scleroderma?
No course altering tx
ONLY manage/limit organ sx and damage
Education: Quit smoking and warm clothing
Ca2+ channel blockers (Raynaud)
ACE inhibitors for HTN
Anti-refulx for esophegeal pathology
Glucocorticoids: only indicated for inflammatory myositis or pericarditis. High doses –> renal crisis
*Cyclophosphamide improves lung fxn and survival
_*Phosphodiesterase Type5 inhibito_r –> tx pulm HTN
Thromboangiitis Obliterans
aka
Buerger Disease
Medium vessels
Young males, <35yo
ONLY in smokers
Distal –> Proximal
Thrombosis –> Loss of digits –> hands/feet
Angiograph: corkscrew
TX: Quit smoking
What is the mechanism responsible for tissue injury in some forms of Glomerulonephritis and vascular rejection in organ grafts among others?
Antibody-mediated inflammation
Clinically antibody-mediated cell destruction and phagocytosis occur in what 4 situations?
1) Transfusion rxns: cells from incompatible donor react with and are opsonized by preformed Ab in host
2) Hemolytic disease of newborn (erythroblastosis fetalis): antigenic difference between mom and baby; IgG antierythrocyte Abs from mom cross placenta and destroy fetal red cells
3) Autoimmine hemolytic anemia, agranulocytosis, and thrombocytopenia: pt makes Abs to their own blood cells
4) Certain drug rxns: drug acts as a “hapten” by attaching to plasma membrane proteins of red cells and Abs are produced against the drug-protein complex
In type II hypersensitivities what are the mechanisms for which antibodies destroy cells?
- Opsonization and phagocytosis: cells opsonized by IgG recognized by phagocyte Fc receptors; IgG and IgM on cell surfaces may also activate classical pathway
- Antibody-dependent cellular cytotoxicity (ADCC): cells coated with IgG are killed by variety of effector cells, mainly NK and macrophages; cell lysis W/O phagocytosis
What are the presenting sx of inflammatory myopathies?
F>M
AA>Caucasians
Myalgias
Weakness, most often symmetrical proximal msucles (difficulty rising from chair or bathtub)
What environmental factors are involved in SLE?
- UV light: may induce apoptosis in cells and alter DNA to become immunogenic
- Gender bias: partly related to genes on the X chromosome
- Drugs: such as hydralazine, procainamide, and D-penicillamine
What are the joints like in patients with SLE?
Opposite of what?
- Non-erosive synovitis with little deformity
- Opposite of RA
Kawasaki Disease
aka
Mucocutaenous lymph node syndrome
Medium vessel
Acute Febrile illness
Worldwide, but Japan more common
1) fever
2) lymphadenopathy
3) rash on hands and feet
4) strawberry tongue
Morbidity d/2 coronary involvement may happen years later
TX: IVIG and Aspirin (typically not given if child presents with virual-like sx, this is an exception…b/c KD is not viral)
Recommended preventitive measures in SLE
- Reduce known risk factors assoicated with atherosclerosis
- Quit smoking
- Influenza vaccination - annually
- Pneumococcal vaccination - 5yrs
- Malignancy screening
- Monitor bone dz with corticosteroid use (hips, knees, etc) and osteoporosis
Antibody-mediated (type II) hypersensitivity involve what specific antibodies and can target what antigens?
- IgG and IgM
- Can be autoantibodies: specific for normal cell or tissue Ags
- Antibodies to exogenous Ags, such as chemical or microbial proteins
Diagnostic feautes of IBM?
Biopsy - endomyosial inflammation with rimmed vacuoles, and invastion of non-necrotic fibers
CK may be normal, or mildly elevated
Anti-cN1A antibodies
TREATMENT REFRACTORY version of myositis
What is the classic example of molecular mimicry?
Causes what?
- Rheumatic heart disease; Abs against streptococcal proteins cross-react w/ myocardial proteins
- Cause Myocarditis
How do you dx Dermamyositis?
Biopsy - perifascicular inlfammation and atrophy
Elevated CK and Aldolase
Anti-Jo-1, anit Mi2, and MDA5, andti Pl55/Pl40
What is Mikulicz syndrome?
Seen in what conditions?
- Enlargement and fibrosis of salivary and lacrimal glands
- Sjorgen syndrome and IgG4 related disease
What antibodies are diagnostic for Sjogren syndrome?
- anti-Ro/SS-A
- anti-La/SS-B
Pink-colored urine after a blood transfusion indicates?
Hemolysis of RBCs occuring due to antibody mediated activation of complement
What is essential for the diagnosis of Sjorgen Syndrome?
Biopsy of the lip to examine minor salivary glands
Systemic Sclerosis (Scleroderma) is characterized by excessive?
Fibrosis throughout the body
You may see:
- thinckening and hardening of the skin
- microangiopathy and fibrosis of the skin and visceral organs
- Obliteration of eccerince sweat glands –> dry itchy skin
Whats the skinny on APS?
- Pt doens’t need to have SLE to have APS (primary), but 1/3 of SLE Pts will also have APS (secondary to SLE)
- Three types of anti-phospholipid antibodies
- RPR and VRDL –> false positive for syphillis
- Lupus anticoagulatn - risk factor for venous and arterial thrombosis and miscarriage
- Anti-cardiolipin - serium cofactor Beta2GPI
- Tx is anticoagulation therapy
How does the clinical presentation of Inclusion Body Myocytitis differ from DM and PM?
Younger adults, >40-50
M>F
Caucasians > African American
Weakness is in fingers or quadriceps
What cardiovascular system effects are present with SLE?
- Symptomatic or asymptomatic pericardial involvement (50% of pt’s)
- Myocarditis
- Valvular abnormalities (mitral and aortic)
- Valvular (Libman-Sack) endocarditis (see photo)
- CAD (angina, MI) owing to coronary atherosclerosis
Polymorphisms in the genes encoding the IL-2R (CD25) and IL-7 receptor α chains are associated with what 2 diseases?
MS
Type I diabetes
What is the diagnostic work up for Systematic Sclerosis?
BLOOD PRESSUE heralding renal failure
Labs: ESR, ANA, Serology, UA
Radiographs: CXR, Barium swallow, Hand x-ray for resorption and calcinosis
Others: ECG, echo, right heart cath, PFT,
Skin biopsy?
What drugs induce lupus syndrome?
Hydralazine
Procainamide
Isoniazid (INH)
Minocycline
D-penicillamine
TNF inhibitors used to tx RA
Quinidine
Chlorpromazine
Methyldopa
Sulfa antibiotics may cause flare
What are the major causes of short- and long-term mortality in SLE?
Short-term:
- Opportunitistic infections d/2 immune system bugged and
- Kidney or CNS dzs d/2 primary dz progression
Long-term:
- Accelerated atherosclerosis leading to MI, and
- thromboembolitic events
Most chronic inflammatory diseases are caused by abnormal and excessive?
TH1 and TH17 responses
*Psoriasis, MS, and some types of IBD
Specific alleles of which HLA has been linked to production of anti-dsDNA, anti-Sm, and anti-phospholipid antibodies seen in SLE?
HLA-DQ
What is a Non-atopic allergy?
- Triggered by non-antigenic stimuli: temperature extremes and exercise
- Does NOT involve TH2 cells or IgE
- Thought to be mast cells that are abnormally sensitive to acitvation by nonimmune stimuli
Systemic Anaphylaxis is characterized by?
What is the immediate response and is then followed by?
- Vascular shock, widespread edema, and difficulty in breathing
- Within minutes: itching, hives, and skin erythema
- Followed by: striking contraction of bronchioles and respiratory distress
- Laryngeal edema –> hoarsness and further compromises breathing
- Vomiting, diarrhea, abdominal cramps, and laryngeal obstruction follow
Henoch-Schonlein Purpura
Etiology: IgA Vasculitis
Demographics: Kids
1) Palpable purpura w/o thrombocytopenia
2) Abdominal pain
3) Arthralgia
4) Renal Diseas
DX: IgA deposits
TX: supportive care + steroids
What are possible complications of Systematic Scleraderms on the Cardiovascular system?
Myocardial fibrosis
Cardiomyopathy
Pericarditis
Myocarditis
Pericardial effusion
Arrhythmia
What is the most common and also the most severe pattern of glomerular disease seen in SLE?
Characteristics/morphology?
- Diffuse lupus nephritis (Class IV)
- >50% involvement of Glomeruli
- Proliferation of epithelial cells —> cellular crescents that fill Bowmans space
- Circumferential thickening of capillary wall, forming “wire loop” strucutres on light mircoscopy (see attached photo)
What are the Clinical features of Systemic Sclerosis (Scleroderma)?
Who’s affected most often (gender and age)?
- Female-to-male ratio of 3:1
- More severe in blacks
- Peak incidence in the 50-60 yo group
- Distinctive features = cutaneous changes, skin thickening, Raynaud phenomenon
- Dysphagia, respiratory difficulty, myocardial fibrosis, mild proteinuria
Some patients with the limited form of Systemic Sclerosis (Scleroderma) also develop?
CREST syndrome
Cutaneous calcinosis
Raynaud phenomenon (ischemic ulceration may be present) often the first symptom
Esophageal dysmotility (GERD)
Sclerodactyly
Telangiectasia
Complication –> Pulmonary HTN
Good prognosis with indolent course
Autoantibody associated with diffuse systemic scleroderma?
Limited systemic scleroderma?
Diffuse = anti-DNA topoisomerase I (anti-Scl 70)
Limited (CREST) = anti-centromere
How may infections actually protect against some autoimmune diseases?
Promoting low levels of IL-2 production which is essential for maintaining Treg cells
In addition to antibody testing (whic his a must) in SLE, what others labs do you need to conisder and why?
CBC (neutropenia, and thrombocytopenia)
ESR (red blood cell distruction)
Complement (downstream affects of autoimmune dz, expect C3 and C4, CH50 low)
Antiphospholipid Ab
- Anti-cardiolipin Ab
- Lupus anticoagulant
Urinanalysis (not sure why, but I’m assuming that with Type III deposition causing renal/glomerular damange you’d see protein in UA)
What are the clinical features and presenting signs of a patient presenting with Sjorgen Syndrome?
Most common gender and age group affected?
- Women between ages 50-60
- Keratoconjunctivitis = Blurring of vision, burning, and itching, and thick secretions accumulate in the conjunctival sac
- Xerostomia = Difficulty swallowing solids, decreased taste, cracks and fissures in mouth
- Parotid gland enlargement
- Epistaxis
- Recurrent bronchitis and pneumonia
Polyarteritis Nodosa
Medium vessels - Segmental
Hepatitis B Vrius (HBV)
NO LUNG INVOLVEMENT
General: fatigue, fever, weight loss
Skin: livedo, reticularis, nodules, ulcers, digital grangrene
Neuro: Peripheral neuropathy (80% will have)
GI: posprandial abdominal pain
Renal: renin-mediated HTN, renal infarct
Behcet Syndrome
Variable vessel size
Demographic: East and Asia
Aneurysms
DVT
1) recurrent mouth ulcers
2) genital ulcers
3) eye inflammation
MSK: large join arthralgia
Neuro: MS-like sx
GI: ulcers throughout the tract (DDX Chron’s)
DX: H&P, HLA-B51 serology
TX: low dose corticosteroids
Polymorphisms in the gene for NOD2 are associated with what disease?
Chron’s disease
What are the two diagnostic antibodies in SLE?
Abs against dsDNA - correlates with dz progression
and
Abs for Smith (Sm) - will NOT correlate with dz progression
Complement activation can lead to the formation of the MAC, which disrupts membrane integrity of cells by “drilling holes,” which cells is the MOA most effective against?
Cells that have thin walls —> Neisseria bacteria
Systemic Sclerosis (Scleroderma) is characterized by what 3 things?
1) Chronic inflammation though to be result of autoimmunity
2) Widespread damage to small blood vessels
3) Progressive interstitial and perivascular fibrosis in the skin (early) and multiple organs (later)
Renal complications in Systematic Sclearderma are due to what risk factors?
malignat HTN,
hemolytic anemia, and
progressive renal insufficency
Type III Hypersensitivity preferentially involve what 3 organs/sites?
- Kidney (glomerulonephritis)
- Joints (arthritis)
- Small blood vessels (vasculitis)
*Organs where blood is filtered at high pressure to form other fluids, like urine and synovial fluid.
What organ systems are involved in SLE and how are they affected?
General: fatigue, fever, malaise, weight loss
Skin: butterfly rash, photosensitivity, vasculitis, alopecia, oral ulcers
Arthritis: inflammatry, symmetric, non-erosive
Blood: LAD, neutropenia, thrombocytopenia, splenomegaly, thrombosis
Cardio: Pericarditis*
- chest pain worse with cough, also worse when supine, better with sitting or leaning forward
- pericardial friction rub
- Diffuse ST elevation of ECG
- Libman-Sacks endocarditis
- Pleuritis, myocarditis
- Increased risk of MI due to accelerated atherosclerosis
Nephritis: no clinical signs, only histologic dx
GI: peritonitis, vascultitis
Neuro: organic brain syndromes, seizures, psychosis, cerebritis
What leads to the fibrosis in Systemic Scleroderma?
Activation of fibroblasts by cytokines produced by T cells and alternatively activated macrophages (M2)
How does Mixed CT disease typically present?
Good response to what tx?
- Synovitis of the finger
- Raynaud phenomenon and mild myositis
- Renal involvement is modest
- Good response to corticosterioid, in the short term
Polymyalgia Rheumatica (PMR)
Associated with Giant Cell Arteritis (GCA)
Proximal severe symmetrical stiffness, soreness, muscle pain. Start in the am –> lasts ALL day long
Subjecive weakness with ADL as a result of pain
No objective muscle weakness
ONLY dx is elevated ESR and CRP
TX: glucocorticosteroids
What is Sjorgren characterized by?
Result of?
SICCA Symptoms:
- Dry eyes
- dry mouth (xerostomia) with incrased incidence of candida infection,
- vaginal dryness,
- tracho-bronchial dryness
- Parotid or other slaivary gland enlargement
keratoconjunctivitis SICCA: sensation of foreing body in eye
- Schirmer test - measures tears secreted
All d/2 Immunologically mediated destruction of lacrimal and salivary glands
Strong Association with B-cell Non-Hodgkin lymphoma (MALT)
20-30% will have BOTH sicca + systemic sx
What are the three categories of inflammatory myopathies?
Dermatomyositis
Polymyositis
Inclusion Body Myositis
Nucleolar Pattern
Blobby staining of the nucleus
- Abs against RNA
- fibrillarin, RNA plymerase I and III, Th, PM-Scl and RNA helicase
- Diffuce Systematic Sclerosis - most commonly
- SLE
Autoantibodies associated with Goodpasture Syndrome?
anti-basement membrane autoantibodies
anti-type IV collagen
–> affects small vessels, such as glomerular or pulmonary capillaries (death if not treated)
TX: plasmapheresis
What are the major connective tissue diseases?
Aka “collagen vascular disorders”
SLE
Scleroderama (systematic sclerosis)
Sjogren Syndrome
Dermatomyositis (DM)
Polymyositis (PM)
Inclusion Body Myositis (IBM)
RA
Differential DDx of PROXIMAL MUSCLE WEAKNESS
Inflammatory myopathies/myositis ◦ DM/PM/IBM
HYPOthyroidism - Still can see elevated CK
Hyperthyroidism - NormalCK
Cushing disease - NormalCK
Polymyalgia rheumatic (PMR) - Pain but NO weakness, CK normal
Neurological - Multiple sclerosis, Myasthenia gravis, Amyotrophic lateral sclerosis, Lambert-Eaton Syndrome
Vasculitides (distal and asymmetric) – Polyarteritisnodosa, Churg-Strauss,Granulomatosiswithpolyangiitis
Drugs/Medication Corticosteroids,alcohol,penicillamine,hydroxychloroquine,colchicine (long term), Zidovudine, HMG-CoA reductase inhibitors
How do majority of patients with Systemic Sclerosis (Scleroderma) die?
- Renal failure –> may see hemolityc anemia during renal crisis
- Cardiac failure
- Pulmonary insufficiency
- Intestinal malabsorption
Treatment for DLE?
Photoprotection with topical anti-inflammatory agents and systematic antimalarial drugs
Tends to scar, early treatment can prevent scarring
Injury in SLE is caused by?
What type of hypersensitivity?
- Deposition of immune complexes and binding of antibodies to various cells and tissues
- Type III hypersensitivity
What is IgG4 related disease characterized by?
- Tissue infiltrates dominated by IgG4 anti-body producing plasma cells and lymphocytes (mainly T cells)
- Storiform fibrosis
- Obliterative phlebitis
- Increased serum IgG4
What disease often affects middle-aged and older men and is 1st characterized in autoimmune pancreatitis?
IgG4 Related Disease
What is the major cause of death in patients with Systemic Sclerosis (Scleroderma)?
Pulmonary disease is the major cuase of mortality.
-
Interstitial lung disease in DIFFUSE variant with chronic cough, dyspnea and ‘velcro’ crackles
- Dx: via pulm fxn test
-
Pulmonary artery hypertention (PAH) in LIMITED
- Dx: right heart catheterization
- There is also an increased incidence of bronchoalveolar carcinomal
What is absolutely essential for Sjogren’s diagnosis?
Lip biopsy
Note: parotid gland biopsy is reserved for Pts with atypical presentation (e.g. unilateral enlargement - cancer?)
Which autoantibody found in patients with Sjorgen syndrome is associated with early disease onset, longer disease duration, and extraglandular manifestations, such as diffuse pulmonary fibrosis, cutaneous vasculitis and nephritis?
SS-A
How can Dermatomyositis be differentiated from Polymyositis?
Poly has no skin involvement
Different age group: 30-50yo
subacute (weeks to months)
Patients with SLE that have the presence of antiphosphlipid antibodies will have increased?
These antibodies cause what kind of state?
- Increased PTT
- Hypercoagulable state (excessive clotting); leading to thrombosis
Churg-Strauss Syndrome
aka
Eosinophilic Granulomatosis with Polyangiitis (EGPA)
Small to medium vessels
Respiratory tracts
Asthma and eosinophilia are hallmarks of this dz
Three phases: allergic –> eosiniophilia tissue infiltration –> vasculitis with systematic necrotizing heart/lung/nerves/skin and palpable purpura
Tx: steroids, no smoking
DX: palpable purpura and Granulomatous Polyangitis
What are the 3 immune-privileged sites?
- Brain
- Eyes
- Testis
Wegener’s Ganulomatosis
aka
Granulomatosis with Polyangiitis
Small vessel involvement
M>F
>40 yo
1) oropharynx (90%), saddle nose, obstruction
2) lungs - infiltrates, alveolar hemhorrage, cavitary lesions
3) kidneys
granulomatous inflammation with necrotizing vasculitis and segmental glomerulonephritis
Important considerations in the treatment of Sjogren’s
AVOID atropinic drugs and decongestants
NO immunology drug has been proven to be helpful
Glucocorticoids are NOT effective for sicca sx
Supportive care and survaillance for mouth, dry eyes
Arthralgias may improve with hydroxychloroquine
Diagnostic workup for Polyartheritis Nodosa
Biopsy - infiltration and destruction of vessles by inflammatory cells –> fibroid necrosis
NO granulomas
Angiogram: micro aneurysm
Serology: hardly every positive for cANCA
Check for HBsAg, ABsAb, HBeAg
Tx: glucocorticosteroids
Speckled Staining Pattern
Numerous fine spots
- UI RNP, Sm, and La antigents
- Sjogren’s syndrome - more common
- Mixed Connective Tissue Dz
- Diffuse Systematic Sclerosis
- SLE
Immunofluorescence microscopy of the skin in patient with SLE will show?
Are these finding diagnostic?
- Deposition of immunoglobulin and complement along dermoepidermal junction
- May also be present in uninvolved skin
- This finding is NOT diagnostic of SLE and is sometimes seen in scleroderma or dermatomyositis
Treatment considerations for SLE
No sun (avoid and/or wear sunscreen)
NSAIDS - tame pain and inflammation
Steroids - calm immune system
Hydroxychloroquine - tx skin pigment and texture
Mixed Connective Tissue disease is characterized serologically by high titers of antibodies to?
Ribonucleotide particle-containing U1 ribonucleoprotein (anti-U1-ribonucleotide)
Some viruses like EBV and HIV cause __________which may result in the production of autoantibodies
Polyclonal B cell activation
Glomerular lesions in SLE are the result of what?
Immune Complex Deposition
Briefly describe the 3 phases of the pathogenesis of systemic immune complex disease (main players and time line of events).
- Formation of immune complex: intro of protein Ags triggers immune response resulting in formation of Abs, typically 7 days after injection of the protein. Secreted into blood where they react with Ag still present and form complexes
- Deposition of complex: Ag-Ab complex (medium sized/slight Ag excess = most pathogenic) deposit in tissues/organs
- Inflammation/tissue injury: acute inflammatory rxn, about 10 days after Ag was introduced producing fever, urticaria, arthralgia, lymphadenopathy, and proteinuria
Thyroid complication of Systematic Sclerosis?
HYPOthyroidsim d/2 fibrosis
What kind of complications does Systematic Sclerosis (diffused or limited) have on the GI system?
Entire GI can be affected
Malabsorption: Fat, protein, B12, VitD
Xerostomia
Esophagus
- GERD
- Dysphagia
- Strictures
- Barrett esophagus
Gastroparesis
Gastric antral vascular ectasi (GAVE syndrome)
Chronic diarrhea from bacterail overgrowth
Pseudo-obstruction
Primary biliary cirrhosis/cholangitis (anti-Mitochondrial Ab)
What are the defining features of Dermatomyositis?
Bimodal age distribution 7-15 and 30-60
Proximal muscle weakness w/o sensory deficits
Gottron’s patches/papules (raised violaceous lesions on DIP, PIP and MCP)
Heliotrope rash with or w/o periorbital edema
Periungual erythema
V-neck erythema (Shawl sign)
Increased risk of MALIGNANCY
Function of CTLA-4 and PD-1?
- Structurally homologous to CD28 and act as inhibitory receptors
- CTLA-4 has a higher affinity for B7 molecules on APC’s
- Act to induce anergy in a lymphocyte upon recognizing a self antigen
What do antibodies do in Graves disease?
Act as agonists on the TSH receptor of thyroid epithelial cells and stimulate the cells to make thyroid hormones —> hyperthyroidism
What are the diagnostic features of Polymyelositis?
Endomysial inflammation with invasion of non-nectrotic muscle fibers
Elevated CK
Anti-Jo-1
What other organs are involved in SLE?
CNS
Spleen (onion-skin lesions from smooth muscle cell hyperplasia)
Lungs (effusions), interstitial fibrosis and secondary pulmonary HTN
What kind of lab results do you expect to see in inlfammatory myopathies?
Serum elevation of CK
CK is normal or only mildly elevated in IBM
ESR and CRP often normal
ECG and muscle biopsy have characteristic findings
derma features in DM
Autoantibodies associated with drug-induced SLE?
anti-histone antibodies
Which cytokine is essential for the maintenance of Treg cells?
IL-2
What are the most common causes of death in patients with SLE?
- Renal failure
- Infections
- CAD
Which gene is said to be most frequently implicated in autoimmunity; encodes what?
Associated with what disorders?
- PTPN22; encodes a protein tyrosine phosphatase
- Type I DM, Rheumatoid arthritis, IBD
What are signs of renal involvement in SLE?
Hematuria, proteinuria, red cell casts, nephrotic syndrome
What occurs in the Arthus reaction?
How can it be produced experimentally and what is the end result?
- Localized area of tissue necrosis resulting from acute immune complex vasculitis, usually elicited in skin
- Experimentally by intracutaneous injection of Ag in a previously immunized animal that contains circulating Abs against the Ag.
- As Ag diffuses into the vascular wall, binds preformed Ab and large immune complexes are formed locally. Precipitate in vessel walls and cause fibrinoid necrosis
What organs are NOT affected in drug-induced SLE?
Renal
CNS
Patients with Sjorgen Syndrome are at a high risk for developing?
Dominant B-cell clone and marginal zone lymphoma
How is Subacute Cutaneous Lupus distinguished from Chronic Discoid LE?
- Skin rash is widespread, superficial, and non-scarring
- Most have mild systemic symptoms consistent with SLE
- Strong association with antibodies to the SS-A antigen and w/ HLA-DR3 genotype
*Basically an intermeditate between SLE and Chronic Discoid LE
ANA Patterns
Homogeneous - reflects Abs against chormatin, histones, and dsDNA
Speckled (very small, uniform) - most often seen, least specific. Reflects Abs against non-DNA nuclear constituents Sm, SS-A, SS-B, and ribonucleotides
Centromere (30-60 spots) - Pts with Systematic Sclerosis have Abs against centromeres
Nucleolar (few large blobs) - Antibodies for RNA, most often seen in Systematic Sclerosis
