Vasculitis DSA and CIS Flashcards
1
Q
What is Pregnancy or Neonatal Lupus?
A
Affects children born to mothers with
Anti Ro (SS-A) or La (SS-B)
1-2%
Maybe seen in Sjogren’s as well
2
Q
What is the serology workup for Sjogren’s? Which markers are the most imporant ones and why?
A
(+) 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
3
Q
Pemphigus vulgaris, Goodpasture syndrome, Acute rheumatic fever, Insulin-resistant diabetes, and pernicious anemia are examples of what type of hyerpsensitivity?
A
Type II Hypersensitivity
4
Q
Autoantibody specific for Rheumatoid Arthritis?
A
anti-CCP (cyclic citrullinated peptides)
5
Q
Drugs to treat DM and PM
A
- Glucocorticoids
- Methotrexate (MTX)
- Azathioprine
- Cyclophosphamide
- Cyclosporine
- Intravenous immunoglobulin (IVIG)
- Mycophenolate mofetil
- Rituximab
- Hydroxychloroquine
6
Q
What types of antibodies do you look for in scleroderma serology?
A
Diffuse (dcSSc)
Anti-Scl70 aka Anti-DNA Topoisomerase I
Anti-RNA polymerase III
Limited (lcSSc) or CREST
Anti-centromere
7
Q
What is the basis of an immune complex-mediated (type III) hypersensitivity reaction?
What type of antigens involved?
A
- 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
8
Q
How are self-reactive T cells able to undergo apoptosis in the process of peripheral tolerance?
A
- 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
9
Q
What is the treatment for Wegener’s Granulomatosis?
A
Quit smoking
Cyclophosphamide
High dose glucocorticoids
Rituximab
Methotrexate okay only if renal fxn is normal
10
Q
How does Chronic Discoid Lupus Erythematosus present?
A
- 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
11
Q
Population most impacted by autoimmune diseases?
A
F > M
Minority populations are at increased risk of rheumatolgoic diseases
cANCA
pANCA
12
Q
What is the morphology of the blood vessels like in patients with SLE?
How about in the chronic stages?
A
- Acute necrotizing vasculitis involving capillaries, small arteries, and arterioles
- Chronic stages = vessels undergo fibrous thickening with luminal narrowing
13
Q
MSK complications as a result of Systematic Sclerosis
A
Carpal tunner syndrome
Tendon friction rubs
Fibrosis and adhesion of tendon sheaths
14
Q
What are the salient feautes of Neonatal Lupus?
A
Transient
- rashes
- thrombocytonpenia
- hemolytic anemia
- arthritis
–> risk for Permanent complete heart block
15
Q
What induces the pathologic lesions of immune complex disorders?
A
Complement-fixing Abs (IgG and IgM) and Abs that bind to leukocyte Fc receptors
16
Q
Differences between primary and secondary Raynaud
A
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)
17
Q
How are antigens restricted to peripheral tissues able to be expressed in the thymus during the process of central tolerance?
A
A protein called AIRE
18
Q
What is ANA and what is it specific for?
A
Anti-nuclear Ab
NOT specific Indirect immunofluorescence
1:40 is normal, higher may be of clinical significance
19
Q
Centromere Pattern
A
30-60 Specles in the nucleus
- Localize to chromosomes in the metaphase
- CREST, systematic sclerosis
20
Q
What is the earliest histological finding in both the major and minor salivary glands in patients with Sjorgen Syndrome?
A
Periductal and perivascular lymphocytic infiltration
21
Q
What plays a role in acceptance/tolerance of a fetus while inside the placenta?
A
CD4+ CD25+ FOXP3 Treg cells
22
Q
Some fun facts about Lupus-Like Syndrome
aka
Drug-induced SLE
A
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
23
Q
Differentail DDx for THROMBOSIS
A
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)
24
Q
What can be used to monitor disease activity of Type III Hypersensitivity?
A
- 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
25
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
26
What group of people is most common to develop SLE?
- Women
- African American and Hispanic \> White
27
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
28
Mutations in the AIRE gene cause?
Autoimmune polyendocrinopathy
29
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
30
Differential DDx for DLE
Discoid lupus
Tinea infection (Ring worm)
Psoriasis
Morphea (Localized scleroderma)
31
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**
32
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)
33
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)
34
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
35
Mutations in the FAS gene cause what disease?
Autoimmune Lymphoproliferative Syndrome (ALPS)
36
Homogeneous Staining Pattern
Entire nucleus is diffusely stained
* Drug-induced SLE
* Sjogren's syndrome
* SLE
37
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
38
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
39
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
40
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
41
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
42
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
43
What is the mechanism responsible for tissue injury in some forms of Glomerulonephritis and vascular rejection in organ grafts among others?
Antibody-mediated inflammation
44
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
45
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
46
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)
47
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
48
What are the joints like in patients with SLE?
Opposite of what?
- Non-erosive synovitis with little deformity
- Opposite of RA
49
**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)
50
Recommended preventitive measures in SLE
* Reduce known risk factors assoicated with **atherosclerosis**
* Qui**t smoking**
* **Influenza** vaccination - annually
* **Pneumococcal** vaccination - 5yrs
* Malignancy **screening**
* Monitor bone dz with corticosteroid use (hips, knees, etc) and **osteoporosis**
51
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
52
Diagnostic feautes of IBM?
Biopsy - **endomyosial inflammation** with **rimmed vacuoles,** and i**nvastion of non-necrotic fibers**
CK may be **normal,** or **mildly elevated**
**Anti-cN1A antibodies**
_TREATMENT REFRACTORY version of myositis_
53
What is the classic example of molecular mimicry?
Causes what?
- **Rheumatic heart disease**; Abs against streptococcal proteins cross-react w/ myocardial proteins
- Cause **Myocarditis**
54
How do you dx Dermamyositis?
Biopsy - perifascicular **inlfammation** and **atrophy**
Elevated CK and Aldolase
**Anti-Jo-1**, anit **Mi2**, and **MDA5**, andti **Pl55/Pl40**
55
What is Mikulicz syndrome?
Seen in what conditions?
- Enlargement and fibrosis of salivary and lacrimal glands
- Sjorgen syndrome and IgG4 related disease
56
What antibodies are diagnostic for Sjogren syndrome?
- anti-Ro/**SS-A**
- anti-La/**SS-B**
57
Pink-colored urine after a blood transfusion indicates?
Hemolysis of RBCs occuring due to antibody mediated activation of complement
58
What is essential for the diagnosis of Sjorgen Syndrome?
**Biopsy** of the **lip** to examine **minor salivary glands**
59
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
60
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 --\> f**alse positive for syphillis**
* Lupus anticoagulatn - risk factor for **venous and arterial thrombosis** and **miscarriage**
* Anti-cardiolipin - serium cofactor **Beta2GPI** ****
* Tx is **anticoagulation** therapy
61
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
62
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
63
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
64
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?
65
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**
66
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**
67
Most chronic inflammatory diseases are caused by abnormal and excessive?
TH1 and TH17 responses
\*Psoriasis, MS, and some types of IBD
68
Specific alleles of which HLA has been linked to production of anti-dsDNA, anti-Sm, and anti-phospholipid antibodies seen in SLE?
HLA-DQ
69
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
70
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
71
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
72
What are possible complications of Systematic Scleraderms on the Cardiovascular system?
Myocardial fibrosis
Cardiomyopathy
Pericarditis
Myocarditis
Pericardial effusion
Arrhythmia
73
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)
74
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
75
Some patients with the limited form of Systemic Sclerosis (Scleroderma) also develop?
**CREST** syndrome
**C**utaneous calcinosis
**Raynaud phenomenon** (ischemic ulceration may be present) often the first symptom
**E**sophageal dysmotility (GERD)
**S**clerodactyly
**T**elangiectasia
Complication --\> Pulmonary HTN
Good prognosis with indolent course
76
Autoantibody associated with diffuse systemic scleroderma?
Limited systemic scleroderma?
****_D_**iffuse** = anti-**_D_**NA topoisomerase I (anti-Scl 70)
**Limited (**_C_**REST)** = anti-**_c_**entromere
77
How may infections actually protect against some autoimmune diseases?
Promoting low levels of **IL-2** production which is **essential** for maintaining **Treg cells**
78
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)
79
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
80
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
81
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
82
Polymorphisms in the gene for NOD2 are associated with what disease?
Chron's disease
83
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
84
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
85
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)
86
Renal complications in Systematic Sclearderma are due to what risk factors?
malignat HTN,
hemolytic anemia, and
progressive renal insufficency
87
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.
88
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
89
What leads to the fibrosis in Systemic Scleroderma?
Activation of **fibroblasts** by cytokines produced by **T cells** and **alternatively activated macrophages (M2)**
90
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
91
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
92
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**
93
What are the three categories of inflammatory myopathies?
Dermatomyositis
Polymyositis
Inclusion Body Myositis
94
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
95
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
96
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
97
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
98
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
99
Treatment for DLE?
**Photoprotection** with **topical anti-inflammatory** agents and **systematic antimalarial drugs**
Tends to scar, early treatment can prevent scarring
100
Injury in SLE is caused by?
What type of hypersensitivity?
- Deposition of immune complexes and binding of antibodies to various cells and tissues
## Footnote
**- Type III hypersensitivity**
101
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
102
What disease often affects middle-aged and older men and is 1st characterized in autoimmune pancreatitis?
IgG4 Related Disease
103
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**
104
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?)
105
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
106
How can Dermatomyositis be differentiated from Polymyositis?
Poly has **no skin** involvement
Different age group: 30-50yo
subacute (weeks to months)
107
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
108
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
109
What are the 3 immune-privileged sites?
- Brain
- Eyes
- Testis
110
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
111
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**
112
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
113
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
114
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
115
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
116
Mixed Connective Tissue disease is characterized serologically by high titers of antibodies to?
Ribonucleotide particle-containing U1 ribonucleoprotein (**anti-U1-ribonucleotide**)
117
Some viruses like EBV and HIV cause \_\_\_\_\_\_\_\_\_\_which may result in the production of autoantibodies
Polyclonal B cell activation
118
Glomerular lesions in SLE are the result of what?
Immune Complex Deposition
119
Briefly describe the 3 phases of the pathogenesis of systemic immune complex disease (main players and time line of events).
1. **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
2. **Deposition of complex:** Ag-Ab complex (medium sized/slight Ag excess = most pathogenic) deposit in tissues/organs
3. **Inflammation/tissue injury:** acute inflammatory rxn, about 10 days after Ag was introduced producing fever, urticaria, arthralgia, lymphadenopathy, and proteinuria
120
Thyroid complication of Systematic Sclerosis?
**HYPO**thyroidsim d/2 fibrosis
121
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)**
122
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
123
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**
124
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**
125
What are the diagnostic features of Polymyelositis?
**Endomysial inflammation** with invasion of non-nectrotic muscle fibers
Elevated **CK**
**Anti-Jo-1**
126
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
127
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
128
Autoantibodies associated with drug-induced SLE?
anti-histone antibodies
129
Which cytokine is essential for the maintenance of Treg cells?
IL-2
130
What are the most common causes of death in patients with SLE?
- Renal failure
- Infections
- CAD
131
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
132
What are signs of renal involvement in SLE?
Hematuria, proteinuria, red cell casts, nephrotic syndrome
133
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**
134
What organs are NOT affected in drug-induced SLE?
Renal
CNS
135
Patients with Sjorgen Syndrome are at a high risk for developing?
Dominant B-cell clone and marginal zone lymphoma
136
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
137
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
