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IMMUNOLOGY the BIG one

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Eileen Gaspar

on 13 August 2010

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Transcript of IMMUNOLOGY the BIG one

IMMUNE SYSTEM BASICS DIDN'T GET THE MEMO TO NOT ATTACK ITSELF ARMY overreacts HYPERSENSITIVE NO TROOPS HERE
INNATE ADAPTIVE Rapid acting
Nonspecific
Complement
Mphage
NK cells
#2 defense (#1 skin)
Protects body while adaptive gears up
Receptors - generic , ready made Mp
NK Complement T cell Ig Slower
Specific
Memory
T cells
B cells
Ig
#3 defense - custom made receptors-keys
TCR + Ig Act NK
Ack Mp Cell-mediated Humoral plasma cells LYMPHOID MYELOID Professional Antigen Presenting Cell Monocyte/Mp B cell T cell thymus CELLS OF THE IMMUNE SYSTEM Dendritic cell Ab Microorganism Ab Ab Ab Ab Ab Ab Ab Ab Ab Ab Ab Ab Ab Ab Ab Ab Ab Ab Ab Ab Ab Ab Mast cell Basophil Eosinophil Neutrophil Erythrocyte Platelet HEMOSTASIS GAS TRANSPORT OTHER GRANULOCYTES How does immune system know to attack or not?

HLA Antigens SELF NONSELF aka intruder aka
spy HLA antigens ~ halos I II III On most body tissues except mature RBCs
inflamed liver and muscle PRESENT TO: CD8 CD4 TNF
lymphotoxin
complement structures Class I ag present nonself stuff like
transplant rjxn
neoplasms
viruses DR2 DR3 DR4 T suppressor or T regulatory Cytotoxic CD8 CD4 CD4 -TH1 CD4 - TH2 Natural Killer cell
~Terminator IFNgamma
IL-10
TGFbeta transplant rjxn
neoplasms
viruses CELL-MEDIATED IMMUNITY HUMORAL IMMUNITY tumors
viruses CD16
CD56 IgG
IgD
Darts ~ Ig

IgG Main Antibody in serum, longest t1/2=21d, secondary response, binds to PMN, Mp

IgM First produced Ab in infxn, Largest Ab,
Secreted as pentamer


IgA Main Ab in secretions in GI, GU, & resp tract; Alternative pathway in complement activation
Dimer, Binds to eosinophils, prevents virus from binding to epithelial cells

IgE Allergic, Asthma, Triggers histamine release from mast cells, binds to basophils too, shortest
half life, and lowest serum concentration

IgD trace amounts on B cells, class switching DEFICIENCY Bruton's X-linked
Bruton's is BrutALL the Igs are low!
hypogammaglobulinemia: Lack of a tyrosine kinase
essential to B-cell multiplication.
Susceptible to pyogenics: Staph, strep, mening, H. flu
Dx: very low IgG, noIgA,M,E, or D
Check all men on mom's side
tx gamma globulin
injections.


Wiscott-Aldrich syndrome: Low IgM
High IgA and IgE
Eczema
X linked
Thrombocytopenia
tx BMT

Common variable immunodeficiency
def of G, A, M
susceptible to encapsulated S. pneumo, H. influ
bronchiectasis
giardiasis

Isolated IgA deficiency:
MOST COMMON Ig def
sinopulmonary
recurrent giardiasis
celiac

Immunoglobulin Cell-mediated Combined Complement CH50
first test to check if pt has meningococcemia
if positive, check rest of complement
+ C4 - follow SLE dz activity
C5-C9
terminal complement deficiency
increased N. meningococcal/gonoc
C3
severe pyogenic (bacterial) infxns
C1, C2, C4
decreased activation - classical
2 abnormal genes - auto. codom
recurrent sinopulmonary infxn w/ encapsulated bacteria
increased incidence of rheumatoid dz esp C3
C2 def - mc N. Amer Caucasians - early or ANA neg SLE
Decrease in C1 inhib w/ sec decreased C4
Hereditary angioedema
Autosomal dominant
Minor trauma can ppt
Laryngeal obstruction
GI - cramps n/v
does NOT respond to epinephrine
FFP given b4 trauma/surgery
dx - screen w. C4 levels --> dx by C1INH level or fcn assay
tx - androgens to increase C1 inh levels and decrease swellling episodes Severe combined immunodeficiency Lack of B-cells and T-cells.
Auto recessive or X linked
Most familiar - adenosine deaminase deficiency (dATP builds up and is toxic
to lymphocytes), the first disease cured by gene therapy.
In one X- linked SCID, the interleukin 2 receptor is absent
another form
affected "David the Bubble Boy"
tx BMT
Ataxia-telengiectasia
AR disorder causing both cellular and Ig def
sinobronchial infxns
bronchiectasis
progressive tleengiectasias
progressive neuro deterioration including cerebellar ataxia DiGeorge's thymic dysembryogenesis: No thymus, other midline defects;
often no parathyroids either -> hypocalcemic tetany
microdeletion in 22qll Immunodeficiency:
Hereditary
retroviral
iatrogenic (cancer chemotherapy, transplants)
secondary (Cushings, alcoholism,malnutrition, uremia, diabetes)
B-cell problems / complement problems / neutrophil problems: infxns w/ encapsulated bacteria and Giardia
T-cell problems: candida, later pneumocystis & intracellular, non-bacterial pathogens eg fungi,viruses, protozoa D I A B C HLAB27
Ankylosing spondylitis
Acute anterior uveitis
Reiter syndrome
Psoriatic spondyloarthropathy
Juvenile Rheumatoid Arthritis SLE SLE Severe RA CATEGORIES OF IMMUNE DISORDERS AUTOIMMUNE HOST DEFENSE AGAINST CANCER
CANCER IMMUNOLOGY TUMOR ANTIGENS Tumor associated antigens CEA Lineage-specific ag
B cell surface ag Tumor specific shared ag (not expressed in normal tissue)
Viral ag (eg HPV 16)
Overexpressed ag
Ag resulting from mutations
Differentiation antigens Increased incidence of cancer in immunosuppressed patients AIDS
Immunosuppression
X-linked immunodef
Tumors escape immunosurveillance
Loss of MHC ag
Tumor-induced immunosuppression
Tumors don't express necessary cofactors
Apoptosis of cytotoxic T cells (express fas) CANCER IMMUNOTX
IFN
cytostatic
-> severe viral syndrome, N/V, skin rash, diarrhea
myelosuppression
IFN alpha tx Hairy cell leukemia
TNF
from activated Mp
attracts PMNs
--> vasodilation
Monoclonal Ab
carrier of chemo agents or isoptopes to tumor
IL2
lymphokine that activates NK T cells
SE: capillary leak syndrome contrib to liver or kidney failure,c ardiac arrest, intestinal perforation
tx melanoma and renal cell cancer CHRONIC INFLAMMATION I



II III IV IgE mediated Immediate IgG mediated Cytotoxic Immune complex
(Ag-ab) mediated Cell-mediated ACUTE
within 1 hr after exposure
Mast cell degranulation
histamine
leukotriene C4
PGD2
cytokines
chemotactic
chymase
tryptase CHRONIC
3-12 hrs after
x hrs - days
eosiniphilic inflmmatory infiltrate
increases w/severity of acute rxn ANAPHYLAXIS
Anaphylatoxins C3, 4, 5 - nonIgE mediated eg ASA anaphylaxis
IgE mediated
if + asthma+ heart dz - greater risk of fatal anaphylaxis from insect sting
Adults w/ anaphylaxis from insect stings should subsequently get allergy shots TREATMENT
Avoidance of allergen
Antihistamines + steroids
Allergen-specific immunotherapy -> increase in T reg cell secretion of IL10 and blocking antibodies of the IgG isotype
Mild - moderate (urticaria) epinephrine 1/1000 0.1-0.5 cc IM SQ OK if mild, never IV, diphenhydramine and cimetidine, inhaled albuterol, steroids
Severe + hypotension: 1/10,000 5 cc IV q 5-10 min, NS bolus, and dopamine if needed
If epi no work can try glucagon or vasopressin injxns
IgG binds to a fixed tissue antigen or cell receptor = autoantibodies ->
complement activation --> cells to be lysed from membrane attack complex and maybe opsonization from production of C3b (Mp have C3b R),
phagocytes have R to Fc portion of ab so can attack Ab coated cells Target cell
platelets - thrombocytopenia
RBCs - autoimmune hemolytic anemia
WBCs - leukopenia

all of these occur in SLE

Fixed tissue ag
component of basement membrane - Goodpastures
Ach R on muscle cells - Myasthenia gravis Vasculitis
Autoimmune dz
Rxn to drugs Ag:Ab >>1
within 1-2 wks, slight ag excess, immune complexes interlace and become bigger and less soluble --> precipitate --> activate complement --> inflammation --> necrosis of small vesssels --> PATHOLOGIC HALLMARK SKIN SIGN = LEUKOCYTOCLASTIC VASCULITIS (hemorrhagic indurated lesions) --> Ag cleared -> Ab excess -> phagocytes remove formed immune complexes Serum sickness
Arthus rxn hepatitis - ag-associated serum sickness
tetanus and diptheria immunization
local insulin rxn SLE (ds-DNA, anti-Smith)
Hashimoto (thyroglobulin)
Pernicious anemia (intrinsic factor)
Autoimmune hemolytic anemia, thrombocytopenia, and maybe leukopenia
Rheumatoid arthritis (rheumatoid factor)
dermatomyositis (immune complexes around muscle fibrils) Type IVa
Rxn peaks in 24-72 hrs
Tuberculin sensitivity
contact dermatitis Type IVb
Cytotoxic T cells direclty destroy target cells
allograft rejection
chronic hepatitis
poison ivy
rash to jewelry Type V immune injury
antibodies bind to cells and cause them to malfunction instead of being
destroyed.

Graves' disease: Stimulatory autoantibodies against the TSH receptor.

Myasthenia gravis Ab block AchR on post synaptic jxn

Circulating anticoagulants are antibodies against a coagulation factor
(usually VIII or prothrombin activator).

Classic pernicious anemia is due to an auto-antibody which binds to intrinsic factor, rendering it unable to carry vitamin B12 through the ileal mucosa.

Celiac sprue / dermatitis herpetiformis features antibodies against reticulin, induced by exposure to gluten in wheat. Cholinergic urticaria
precipitated by heat
presents as punctate lesions that are very pruritic
RAST test measures allergen-specific IgE in serum
done when the pt has extensive skin dz, has dermatographism, has anaphylactic sensitivity to the allergen, is on antihistamines
Urticaria pigementosa is seen in cutaneous mastocytosis
three different types of mastocytosis
cutaneous - urticaria pigmentosa, formation of wheal on gentle stroking of macule
systemic increase mast cells in tissues so abdmoinal pain and fatigue
malignant mastocytosis - hepatomegaly and lymphadenopathy
tx stay away from cold, heat, alcohol asa, and opiates
oral cromolyn may help for GI sx MECHANISMS
Loss of tolerance for self-antigens
Immune response against self (auto)antigens
Release of intracellular antigens
Molecular mimcry (structural similarity between self-antigens and microbial antigens)
Polyclonal lymphocyte activation
Antibody or cell-mediated damage
Other like environmental hormones, infxn, drugs, UV radiation ORGAN SPECIFIC
AUTOIMMUNE DISEASE
Vitiligo
Thyroid
Graves
Hashimoto
Addison's
Hemolytic anemia
Myasthenia Gravis
Diabetes Type 1
Primary biliary cirrhosis
Celiac sprue
Primary Biliary Cirrhosis
Primary Sclerosing Cholangitis
Autoimmune hepatitis Non-organ specific
SLE
Systemic sclerosis
Dermatomyositis
Rheumatoid Mixed connective tissue disease
AntiU1RNP
usu NO anti-dsDNA, Sm, SSA, or SSB
Speckled pattern on ANA
Overlap with features similar to SLE, polymyositis, and systemic slcerosis
High ANA
Infrequent renal involvement
Good response to steroids SLE
DEFINITION
weeks - yrs
cells: lymphocytes, plasma cells, Mp
eosinophils in parasitic infxns
destruction and repair at same time

Different from acute:
Onset and duration
types of cells
presence of granulomas
more likey to heal by fibrosis with incomplete resolution
absence of vascular changes OUTCOME
Fibrosis and scarring
Persistent inflammation
Relapse eg Crohns CAUSES TYPES Nonspecific w/ lymphocytes, plasma cells, and Mp INFXN
Bacteria
M. tb
M. leprae
Parasites
Schistosomiasis
Fungus
Cryptococcus

FOREIGN BODIES
Silica
Berrylium
Hypersensitivity Pneumonitis Hay, birds, grain dust, A/C systems

AUTOIMMUNE
PAN

UNKNOWN
Sarcoidosis
Primary Biliary Cirrhosis GRANULOMATOUS
granuloma
Mp stim by IFN gamma
Mp stuck together to try and wall something off or because they're angry
Mp contain 1alpha hydroxylase which converts 25(OH) Vit D to active 1,25 (OH)2 Vit D w/o regln by PTH ->HyperCa Unresolved acute inflammation

Repeated acute inflammation

Low grade infection by intracellular organisms

Foreign bodies

Toxic exogenous substances

Endogenous irritants
Chronic abscess Chronic pancreatitis Chronic viral hepatitis Tuberculosis Silica
Berrylium Contents of ruptured cyst
Atheromatous lipids TNFalpha IMMUNOSUPPRESSANTS IMPORTANT CYTOKINES

Hot T-bone stEAk
IL-1 fever (hot)
IL-2 stim T cells
IL-3 stim bone marrow
IL-4 stim IgE
IL-5 stim IgA

IFNa produced by leukocytes
IFNb produced by fibroblasts
IFNg secreted by TH1 -> stim Mp, NK
TFNa secreted by Mp -> increase IL-2R syntesis, B cell proliferation, attracts and activates neutrophils, increases MHCI expression
TFNb secreted by activated T lymphjocytes. Similar to TNFa Dz with +RF (Anti-IgG antibody)
Cancers
Chronic bacterial infxns: Leprosy, Lyme dz, Subacute bacterial endocarditis, Syphilis, TB
Viral infxns: CMV, EBV, Hep ABC, HIV, Influenza, Rubella
Liver disease
Mixed cryoglobulinemia
Parasitic infxn
Pulmonary interstitial dz
Sarcoidosis If don't control rheumatoid can get amyloidosis --> nephrotic syndrome
Any anti-TNF --> annual PPDs - they are associated w/ reactivation of TB NOT increased rates of primary TB infxn

Indolent onset of sx WORSE than explosive
MTX = initial DMARD for tx of aggressive RA JOINTS
MTP, MCP, PIP
Ankle, subtalar, knee, wrist
Shoulder
Hip, elbow, AC jt
Cervical spine
LS spine NEVER primary event in RA Dry eyes (Sjorgren's), episcleritis, scleritis
Dry mouth(Sjogren's)
Cardiac: pericarditis, myocarditis, pericardial effusion, valve disease
Lungs: pleurisy, pleural effusion w/low glucose, lung nodules, pneumoconiosis, intestitial fibrosis (more in M), rarely vasculitis or pulm htn
Splenomegaly and decreased WBC (Felty's)
Kidney: drug-related renal disease and (late-onset) amyloid renal dz
Proximal myopathy
Rheumatoid nodules
Blood: Anemia of chronic dz
Nerve: Carpal tunnel syndrome, cervical myelopathy, mononeuritis multiplex usu w/ wrist or foot drop ANA sensitive not speicifc
anti-dsDNA very specific, poor prognosis, increased risk of nephritis
Anti-Sm very specific, but not prognostic
Antiphosphoplipid
Anticardiolipin
Lupus anticoagulant
False + RPR or VDRL
Arthritis is nonmutilating Drug-induced lupus
anti-histone
no CNS involvement
no renal involvement
anti-DNA seen w/ dz by anti-TNF drugs

minocycline causes ANCA+ and maybe anti-histone +
Neonatal lupus
anti SSA (antiRo)
antiSSB (antila
antiRo crosses placenta --> rash, 3 heart block, cardiomyopathy, thrombocytopenia, leukopenia
Sjogren
xerostomia
xerophthalmia
biopsy of minor glands
RF, ANA, 50% antiSSA, 30% anti-SSB
antiSSA
antiSSB Limited Scleroderma
anti-centromere
NOT associated with ILD
Hands, distal forearm, face Diffuse Scleroderma
anti-Scl 70
Wide mouthed diverticula

Fibrous thickening
Arteries
Esophagus
Skin
Lungs (cyclophosphamide), pulm htn drugs including ccb, o2, anticoag
Gut - cipro for bacterial overgrowth, H2blockers, PPI
Renal vesssels (ACEI if scleroderma renal crisis, prednisone makes this worse)
Entire extremity, trunk, face Antisynthetase
anti-Jo/anti-RNA synthetase
J0-1 in setting of polymositis => ILD ANA ANA neg lupus extremely rare <2-3% but associated with SSA/SSB Ab so order SSA/SSB if you have a neg ANA and suspect SLE! Dermatomyositis & (Ovarian) Cancer ***

Skin findings
Moderate to deep purple red papular, sometimes scaly, photosensitive rash face, neck, extensor surfaces
Periorbital edema
heoiotrope rash
Gottron papules vasculitic . Gottron papules most specific finding
papules on the extremitites Path:
Decreased circ T cells
Infiltration and destruction of salivary & lacrimal glands by CD4+ T cells
Increased circ B cells
*LYMPHOCYTIC DESTRUCTION*
primary Sjogren's has 6-40x increased risk of developing non-Hodgkin lymphoma (typically B cell or MALToma) Development of:
monoclonal protein
new-onset leukopenia
new-onset anemia
loss of previously present autoab
(ANA, Ro, La, RF) Procainamide
INH
Hydralazine
Phenothiazine
minocycline
PTU
infliximab
etanercept Subacute Cutaneous Lupus Erythematosus
10% of discoid lupus
100% photosensitive
Assoc w/ thiazides
Poor prognosis if antiDNA, butterfly rash, poor response to antimalarials, low complement 90% have ANA +
discoid lesions --> patchy alopecia ddx Dry eyes/Dry mouth
drugs
HIV
HCV
Sarcoid LARGE MEDIUM SMALL CNS LUNG KIDNEY SKIN NERVE Temporal Arteritis Takayasu arteritis PAN Churg-Strauss Hypersensitivity Vasculitis Wegener's MPAN HA
blindness
rare stroke Eye dz, stroke Stroke Stroke Rare Eye, rare stroke rare stroke rare infiltrates
asthma rare infiltrates, nodules, cavitating lesions infiltrates renovascular htn hematuria, renal failure rare glomerulonephritis glomerulonephritis glomerulonephritis rare scalp infarct rare ulcers, iscehmic digits, livedo reticularis mononeuritis multiplex,
peripheral neuropathy peripheral neuropathy peripheral neuropathy peripheral neuropathy p-ANCA p-ANCA c-ANCA VASCULITIS Ddx
Atrial myxoma
Chol. emboli
Bact endocarditis Rheumatoid
Ankylosing spondylitis
Syphilis Rheumatoid
SLE



TSHR Ab
Anti-thyroglobulin, Anti-TPO (microsomal)
Anti-thyroglobulin
Warm/Cold AIHA
Anti-AchR
Autoimmune destruction of beta cells, Anti-thyroglobulin
Anti-mitochondrial
Anti-gliadin Ab, Anti-endomysial Ab
Antimitochondrial Ab
pANCA
Anti-smooth muscle Ab
ANA, anti-dsDNA, anti-Smith,
Systemic sclerosis Anti-Scl70
ANA
Anti CCP, RF anti-Ro (subacute cutaneous lupus, Sjogren, neontal lupus)
sometimes Sjogren and polymyosiitis
T- cell immunodef:
diarrhea
recurrent viral infxns,
opportunistic,
fungal infxn Infection
Intracellular pathogens
Immune diseases
IBD Antibodies
Allergy
Asthma
Allergic rhinitis Pegylated IFNa
Tx of chronic hep B & C IFNb
Tx of MS Rheum arthritis- mol mimicry
Hyperacute rejection of an organ is mediated by already-present
antibodies (type II + type III).

Rheumatic fever features autoantibodies against streptococci which
cross-react with other tissues; nobody really understands it. In
Sydenham's chorea, a component of the syndrome, antibodies against
streptococci cross-react with basal ganglia.

Anti-neutrophil cytoplasmic antibody diseases includes Wegener's and
small-vessel polyarteritis.

paraneoplastic encephalopathies (the antigen is a cancer, the
victim is the normal cell)

Lyme neuropathy: Antibodies against the bug crossreact with the axon.

HIV infection features destruction of uninfected T-cells by anti-HIV
antibodies directed against dead viruses, which stick to the surfaces
of the unfortunate T-cells.

Type III immune injury. Caused by antigen-antibody complexes
precipitating when they're mixed in just the wrong proportions. The
"aches and pains of the viral illness" is the most familiar, and least
deadly.
In lupus, type III immune injury is a major problem.
In drug reactions, systemic infections, carcinomatosis, etc., etc.,
hypersensitivity angiitis of small arteries and small veins may be due
to drugs allergy, systemic infections, carcinomatosis, or what-have-
you.
Eosinphilic fasciitis: spares hands see above -> eosinophil
CREST: calcification of the fingerpads, Raynaud's, esophageal fibrosis,
sclerodactyly (linoleum fingers), telangiectasias (dilated vessels from
scars contracting). Defined by antibodies against centromeres.

Morphea: Localized scleroderma. Saber-cut scleroderma, etc.
Eosinophilic fasciitis, a scleroderma variant with eosinophils, is
idiopathic, and resembles the horrible eosinophilia-myalgia syndrome
from tainted "health food" tryptophan.
Anti-nucleolar antibodies; nucleolar pattern on ANA. RA
JOINT PAIN Inflammatory Noninflammatory Noncrystalline Crystalline Mono/oligo Poly Chronic Acute Chronic Acute Symmetric Asymmetric Spondylarthropathy
Rheumatoid Arthritis
SLE, Scl, MCTD
Sarcoidosis Spondylarthropathy (Reiter's, Psoriatic)
Viral (parvo, EBV, Hep, rubella, HIV)
Acute Rheumatic Fever Spondylarthropathy
TB, Fungal
Sarcoidosis
Crystalline Spondylarthropathy (Reiter's Psoriatic)
Crystalline
Septic arthrtis
Acute rheumatic fever Rheumatoid Arthritis
Seronegative Spondylarthropathies
SLE
Scleroderma
Acute Rheumatic Fever Gout
Pseudogout
Hydroxyapitite Spondyloarthropathy (Psoriatic)
Viral (parvo, EBV, Hep, rubella, HIV)
Acute rheumatic fever
Rheumatoid Arthritis
SLE, Scl, MCTD
Sarcoidosis
Crystalline Spondyloarthropathy (Psoriatic, Reiter's)
Crystalline
Septic Arthritis
Acute Rheumatic Fever
TB, Fungal
Sarcoidosis
Osteoarthritis Axial (Spine) Peripheral DIPs MCPs JOINT AREAS Spondylarthropathy
Rheumatoid arthritis (cervical spine)
OA
Infection (TB, fungus, Staph, etc) Spondylarthropathy
Crystalline
Septic Arthritis
Acute Rheumatic Fever
TB, Fungal
Sarcoidosis
OA
RA
SLE
PSS Spondyloarthropathy (Psoriatic)
Crystalline
Septic Arthritis
Acute Rheumatic Fever
Sarcoidoisis
RA
SLE
PSS
Hemochromatosis (asymmetric 2nd and 3rd MCP + PIP Spondyloarthropathy (Psoriatic, Reiter's)
OA
Crystalline (tophi-gout) Osteoarthritis
Trauma
Neuropathy
Metabolic Disease Synovial Effusions Type Color WBC/mm3

Normal Clear <200 (<25% PMN)

Noninflamm Clear - yellow 200 - 2000 (<25% PMN)

Inflamm Cloudy - yellow 2000 - 100,000 (>50% PMN)

Septic Purulent >50,000 (>75% PMN) Crystal analysis Gram stain with culture and sensitivity *Intracellular crystal* Color of the crystals same parallel to color compensator / alternate color | perpendicular
Weakly positive birefringence ~CPPD ~blue when parallel, yellow when perpendicular
Strongly - birefringence - Gout = ye=ow when parallel, blue when perpendicular
Electron microscopy or alizarin red staining (nothing on polarizing microscope) - hydroxyapitite Monoarthritis usus Staph aureus
WBC > 100,000
Pts w/ RA - polyarticular septic joints

Sickle cell
Salmonella or Staph
*Pts w/ sickle presenting w/ mono/oligoarthritis - empirically manage like septic cx come back (even if Gm neg)

IV Drug disorder
sternoclavicular
sacroiliac
MRSA or Pseudomonas

Disseminated gonococcus
Women - at menses or post menses
Jt cx positive <25%, dx by vaginal, throat, or anal cx
MCC monoarticular arthritis in sexually active <35 yo
tx - IV CTX (and empirically tx Chlamydia) Amyloidosis 2/2 long term dialysis periarticular calcification on knee xr or ulnar area of wrist
Milwaukee shoulder
Acute synovitis of wrist or knee
Hypothyroid
Hyperpara
hemochromatosis intracellular negatively birefringent crystals
if extracellular, think infxn more likely cause
increased serum uric acid doesn't dx gout
allopurinol - never stop/start in acute attack
if refractory gout, think EtOH use or noncompliance
change allopurinol dose if on azathioprine, half dose if pt has impaired renal fcn Dx criteria for RA
>=4:
AM stiff > 45 min x 6 wks
swelling MCP, wrisits, PIP x 6 wks
swelling of 3 jts x 6 wks
symmetric jt swelling x 6 wks
rheumatoid nodules
erosive synovitis x ray changes of hands
positive rheumatoid factor CPPD Crystal Disease Felty's syndrome
Rheumatoid arthritis
Selective leukopenia
Splenomegaly
Leg ulcers
Lymphadenopathy
95% RF + and HLA DR4
Tx
G-CSF if leukopenia
Splenectomy (not first choice)

Large granulocytic lymphocyte syndrome
no leg ulcers
no splenectomy unless you want them to get worse
can develop large granulocytic leukemia Factors sugestive of more severe of RA
DR4 antigen
high titer RF
constitutional sx
insidious onset
early appearance of rheumatoid nodules
radiographic erosions
progressive synovitis
vasculitis or extraarticular manifestations
anti-CCP+
No specific intervention if RA pt has 5 mm C1C2 subluxation on lateral flexion C-spine XR and no neuro deficits. Just tell them watch out and watch for sx Tx of RA
Gold
Continue tx if nonpruritic rash, mild decrease in WBCs, slight proetinuria
STOP if pruritis, moderate-to-severe stomatitis, metallic taste, proteinuria > 500 mg in 24 hours, leukopenia < 3000, or platelets < 100,000. Rare pneumoniits

SE:
Leukopenia, renal toxicity, pneumonitis: gold, pcnamine, MTX
leukopenia, sulfasalazine, biologics
diarrhea: oral gold, leflunomide
increased LFTs: MTX, leflunomide, sulfasalazine, biologics
retinopathy: jhydroxychloroquine

Sulfasalazine is broken into 2 components in the intestine:
Sulfapyridine + 5-ASA
Sulfapyridine for RA
5-ASA for UC Pregnancy rates in SLE pts - normal
Get baseline labs before pt is pregnant
Stopping meds is safe although usu continue antimalarial agents
Neonatal lupus if +SSA/SSB -> send to high risk OB and maybe ped cardiologist Eosinophilic fasciitis
Scleroderma like skin in the extremities that spares the hands
No Raynauds
Peripheral eosinophilia
High ESR
Skin bx - eosinophilia and fascial thickening
Nailfold capillaries normal Eosinophilic esophagitis
Solid food dysphagia - esp food impaction
Young males
Often hx of allergy,asthma
EGD shows "ringed" esophagus-scalloped appearance and bx eosinophilic infiltrate
Tx: PPI and ingested fluticasone or viscous lidocaine Eosinophilic granuloma
Langerhans cell granulomatosis or histiocytosis X
Smokers
Cystic lung lesions in the upper lung fields, hyperinflation, interstitial lung dz
Pneumothorax
Lytic bone lesions and diabetes insipidus
Tx - Stop smoking, trial steroids Eosinophilic - myalgia syndrome
Contaminated L- tryptophan Strongyloides
NOT Giardia If ASA-allergic use following salicyclates:
Sodium, magnesium, or choline salicyclate SNSAs Onset: Young adults
Familial
Inflamm artiritis of spine or large (hips) and peripheral joints
Peripheral arthritis, often asymmetric with sausage digits, non-nodular
Mucocutaneous manifestations: Painless oral ulcers, circinate balanitis, keratoderma blenorrhagica, psoriasis
Ocular involvement 0 Uveitis
Enthesopathy (enthesitis) - inflammation of ligaments and tendons onto bone - tenderness of posterior heel, plantar surface of foot, spinous processes, epicondyles, and sausage digits
Radiographic: sacroilitis, spinal fusion, bamboo spine, ethesitis (erosion where Achilles attaches to calcaneus)
Management
- Physical therapy
- Postural training - sleep w/o pillow - neck can fuse in neutral position
-Similar to other non-crystalline inflammatory arthroatpthies: NSAIDSs, Sulfasalazine, MTX, leflunomide, TNF inhibitors Sausage
Psoriatic
Reactive/Reiters Sx sacroilitis, chance HLA-B27 at least 60% and r/o acute anterior uveitis Reactive/Reiters
Follows infxn - rep immune rxn to infxn, NOT persistent infxn
Triad: nonspecific urethritis, conjunctivitis, asymmetric arthritis
Mucocutaneous lesions
Keratoderma blenorrhagica ~psoriasis
GI infxns that precede: Salmonella, Shigella, Yersinia, Kelbsiella, Campylobacter, Chlamydia (conjunctivitis, uveitis, arthritis, dysuria, nonbacterial urethritis) Enteropathic arthropathy
Associated with flares of inflammatory bowel dz
Erythema nodosum or pyoderma gangrenosum
Ulcerative/Crohns - arthritis usu late fidning
Whipple disease
Intestinal bypass surgery
Celiac disease Whipple disease
Arthropathy
Fever, weight loss
Neuro sx: diplopia, slowly progressive dementia
Malabsorption - osmotic diarrhea (stool volume decreases with fasting/Osm gap > 125, pH <5.6)
Lymphadenopathy
Hyperpigmentation
PAS + Tropheryma whippleii
tetracycline x 1 yr,
PCN +/- PCN +/- streptomycin +/- TMP/SMX for 6 mo - 1 yr INFECTIOUS ARTHRITIS Psoriatic Arthritis
Silvery scale plaques + pitting nails
Rx that exacerbate: beta-blockers, hydrochloroquine (Plaquenil)
Arthritis mutilans - XR looks like bone is gone ~ accordion
No pathognomic serolic test
7% of pts with psoriasis have arthritis
Can have psoriatic arthritis b4 psoriasis Inflammatory bowel disease Ankylosing Spondylitis
Cardiac: Aortic insufficiency, conduction defects, CHF
GI tract: Inflamm bowel dz
Lung: Apical fibrosis PATHOGNOMONIC Amyloidosis
Musculoskeletal: Axial with symmetric SI joint changes with minimal peripheral joint arthritis, loss of lumbar motion - Schober test- lumbar flexion
Neuro: Spine fracture dislocation, Cauda equina syndrome
Ophtalmologic: Acute Anterior uveitis in 25% of pts so need yearly eye exam
>15% of Native Americans, 0.5% 01% of Caucasians of N. Euyropean descent Chondrocalcinois with CPPD and hydroxyapitite crystals clumped in snowball shape. Severe Charcot-like resorptive process of bone and lysis of synovial capsule and ligaments, including rotator cuff Drug rxn most common type
SLE vasculitis
RA vasculitis
HSP
major hemoptysis -> increased DLCO - Anti-GBM (40% ANCA+) Goodpasture
- Hepatitis C- Cryoglobulinemia Severity of nailfold capillaries follows severity of scleroderma Polymyositis
Proximal muscle weakness and myalgias
Abnl myopathic EMG
Increased CPK
Abnl muscle bx - cytotoxic T-cell infiltrate with myonecrosis (Clostridium septicum - myonecrosis too) / immune complexes around muscle fibrils
PFTs - restrictive, low DLCO
Cancer 30% in adults > 65yo
ITIS - weakness
Anti Jo1 - pure polymyo, Raynaud , mechanics hands
AntiMi-2 only with skin involvement
Anti- PM-Scl - features overlapping with systemic sclerosis ATS says anyone on prednisons > 15 mg/day or any other immunosuppressant with 5 or more mm induration gets ISONIAZID for 9 mo tx Prednisone 60 mg/day tapered until controlled with tx 6 mo - 1 yr AORTITIS 20% of PMR PMyalgiaR
pain
Hep B
CMV
RA
Immune complex depositions
Hodgkin's
Hairy cell
HIV
Allergic rxns
Idiopathic Renal dz - mcc death Other: pericardirtis, mesenteric arteritis, monon multiplex Tx - underlying cause (usu tx HBV)
prednisone + cyclophosphamide ELISA: PR3+ ELISA: MPO+ Prosthetic Jt
1st 6 mo post-op Gm+
> 6 mo post-op Gm - & fungal Tuberculous arthritis
mildly sx
chronic knee or bony/spine-Potts Viral
Hep B
mumps
herpes
parvovirus B19 Lyme
asymmetric
stage III
few mo to 2 yrs after tick bit usu of larger jts
tx doxycycline
false + Lyme 2/2 SLE, RA, RMSF, healthy
confirm w/ Western blot Adult Still
eti unknown, infxn vs autoimmune. Sx similar to SLE
Salmon pink rash that appears with high fever and disappears with fever
mod - severe polyarthritis
ankylosis of carpal bones and cervical spine
high serum ferritin levels 10x normal
Same tx as for RA except if liver involved used MTX
Anti-TND, anakira, and maybe rituxan if yuou need to Relapsing polychondritis
Small vessel vasculitiws
Inflammation of cartilage of ear, nose, larynx, and trachea
Arthritis, slceritis, iritis
Aortic dilation and 2/2 aortic regurg
Hoarseness, saddle-shaped deformity of nose, swelling of ear's cartilage Bechet disease
Vasculitis of Middle Eastern, Japanese, or Asian
Painfull recurrent apthous stomatitis
Genital aphthous ulcers
Synovitis
variable cutaneous: erythema nodosum, vascultiis, acneiform, pathergy, dermatographism
CNS dz recurrent asceptic meningitis
Eye uveitis/optic neuritis/rretinal vascultitis
Hyperreactive to needle sticks resulting in sterile abscesses
Oral and genital ulcers respond fairly well to colchicine or pentoxifylline
tx more severe dz with corticosteroids, azathioprine, anti-TNF
Rheum-Malignancy
Hypertrophic osteoarthropathy
Amyloidosis (rectal biopsy or abdominal fat biopsy
Secondary gout
Carcinamtous polyarthritis (resembles RA - think breast CA) Villous atrophy - malabsorptive diarrhea that doesn't respond to gluten free diet
Recurrent Giardiasis (Giardia parasites or Giardia ag in the stool - tx w/ metronidazole) 2/2
low IgG Eosinophilic gastroenteritis
Form of malabsorption with problems of small bowel mucosal transport
Risk of lymphoma Trastuzumab (Herceptin)
SE: infusion rxn, CHF

Rituximab (Rituxan)
anti-CD20 mAb / B cell antagonist
B cell lymphomas
SE: infusion rxn, hypersensitivity rxn (including bronchspasm Pegylated IFNa
Tx of chronic hep B & C IFNb
Tx of MS Omalizumab
binds to IgE with high affinity
Adjunctive for severe persistent asthma
Add if symptomatic after high dose ICS + LABA to reduce or dc tx w/ oral steroids
RA med tx SE:
Leukopenia, renal toxicity, pneumonitis: gold, pcnamine, MTX
leukopenia, sulfasalazine, biologics
diarrhea: oral gold, leflunomide
increased LFTs: MTX, leflunomide, sulfasalazine, biologics
retinopathy: hydroxychloroquine

Sulfasalazine is broken into 2 components in the intestine by colonic bacteria:
Sulfapyridine + 5-ASA
Sulfapyridine for RA
5-ASA for UC - only effective in colon, for acute or maintenance azathioprine (imuran) mtx mycophenolic acid (cellcept) leflunomide (arava) Cyclophosphamide
chemo
SLE
PAN
Wegener
+ steroids for alveolitis in Scleroderma
activated in liver -> b/d product = acrolein

SE: sterility, amenorrhea, bone marrow suppression, hemorrhagic cystitis (preventable w/ hydration or mesna) , bladder cancer, SIADH cyclosporine sirolimus TNFa antagonists RA
colimumab (Simponi)
antiTNF Fab certolizuman pegol (Cimzia)
TNFa antagonists
RA
SNSA
IBD IL-1 inhibtor anakira INHIBITOR OF GENE EXPRESSION
glucorticoid CYTOTOXIC AGENTS
inhibit essential cellular processes SPECIFIC LYMPHOCYTE SIGNALING INHIBITORS CYTOKINE INHIBITION ANTIBODIES ANTIMETABOLITES ALKYLATING transplantation
autoimmune

SE: hyperglycemia, diabetes, osteoporosis, adr insuff if stressed transplantation
autoimmune
RA
poly/dermatomyositis
IPF

IBD
SE: immunosuppression
GI toxicity
hematopoetic toxicity
transplatnation
chemo
initial DMARD for RA
asthma?
psoriasis
wegener (if not that sick)
SNSA
poly/dermatomyosisirts
IBD

SE
hepatotox LFTs q 8 wks
lung tox
no etoh
transplatnation
rheumatoid

rheumatoid
wegeners
SLE
myasthenia gravis

t1/2 = 14d
increased by rifampin
tox ~ mtx (w/o lung tox)
liver avoid in ETOH, Hep B & C
bone marrow suppression

tacrolimus transplantation transplantation
atopic eczema transplantation hld
leukopenia
thromobocytopenia nephrotoxicity nephrotoxicity
neurotoxocity
hepatotoxicity soluble TNF receptor etanercept (Enbrel)
rheumatoid arthritis
psoriatic arthritis antiTNF mAb Infliximab (Remicaide) adalimumab (Humira) rheumatoid arthritis
SNSA
SE: immunosuppression
risk of TB reactivation
drug-induced lupus sulfasalazine
RA
SNSA Churg-Strauss Syndrome
Necrotizing small vessel vasculitis
Asthma and eosinophilia
Asthmatic who is not responsive to tx
Eosinophilic PNAs
Acute, benign eosinophilic PNA
-Loeffler syndrome, eos in blood and BAL
-Drugs and bugs
Acute eosinophilic PNA
r-rapidly progressive, ARDS
-Responsive to steroids
Chronic eosinophilic PNA
-subacute cough, women
-bilatearl peripheral infiltrates
-photographic mirror of pulmonary edema
butterfly pattern looks dark
-high BAL eos, not in serum
-very high ESR
-tx steroids Buerger Disease
Thrombangiittis obliterans
Medium and small arteries
Affects the wrist - Allens test: pressure over radial turns hand blue
Almost entirely associated with smoking Cromolyn sodium & Nedocromil
Stabilizes mast cells
Interfere with Cl Channels
Alternative for mild persisent asthma
Preventative prior to exercise or allergen exposure IMPORTANT PROSTACYCLINS

leukotrienes LTRA Modifiers
LTRA: alt tx for mild persistent asthma
Montelukast
Zafirlukast SE Reversible hepatitis, rare irreversible hepatiits
5-LPO inhibitor:
Zileuton SE: elevation of liver enzymes, case reports of reversible hepatitis and hyperbilirubinemia
NEVER preferred in adults
only after start LABA Hypersensitivy Pneumonitis
Immune-mediated rxn to ag
poorly formed granulomas
acute: cough, fever, fleeting infiltrates
chronic: ILD
increased incidence in non-smokers
tx: ag avoidance and steroids if superbad Rheumatoid Arthritis
Interstitial Fibrosis
Male predominance
High titers of RF and rheumatoid nodules
33% of all RA pts
Dyspneic, limited by joint dz
RA tx -> ILD: gold, PCNamine, MTX SLE
pleural involvement common
intestitial pneumonitis and fibrosis
discoid atelectasis
pulmonary hemorrhage
increased risk for PE
diaphragmatic dysfcn
hemoptysis-idiopathic pulm hemosiderosis
Scleroderma
Diffuse pulmonary fibrosis in 80%
Diffuse systemic: more severe
CREST: less severe
Pulm htn present even if ILD not that bad
ECHO if DLCO <50% predicted
Subset w/ Sys Sclerosis
-ILD rapidly progressive w/in 1st 2 yrs
-screened and follow w/ PFTs increased incidence of bronchogenic carcinoma tx Cyclophosphamide Sarcoidosis
non-infxs multisystmn dz of unknown cause
uveitis tx topical steroids
b/l hilar adenopathy
pulmonary infiltrates - honeycomb appearance on CXR
PFTs restrictive pattern
ACE to monitor dz NOT for dx
hypercalcemia and hypergammaglobulinemia
LOFGREN
Observe only if only hilar LAD w/o parenchymal involvement/pt asx
Fever
Granuloma
Erythema
Nodosum - painful rash

Scleroderma and Esophagus
Incompetent LES, poor peristalsis
At risk for severe GERD
Dysphagia can be due to esophagitis, stricture, or poor motility
W/u dysphagia: Barium swallow and EGD
Check for GERD complications
Tx: PPI, dilate if stricture
mesalamine 5-ASA
oral and enema preparations
oral forms have delayed absorption
very mild Crohn's of small bowel
UC acute or mainenance
SE: interstitial nephritis0 follow kindey fcn inhlaed budesonide
only category B for asthma

oral budesonide
mild to mod dz
ileal crohns
inducing remission UC or Crohns
Steroid-sparing
Maintenance tx
3-4 mo to start working
bone marrow suppression esp WBC so monthly CBC first yr

raises risk of lymphoma 6MP
purine analog IBD
Infliximab, adalimumab, certolizumab
Fistulous Crohn's, mod-severe active Crohn's refractory UC
Generally requires ongoing tx Celiac dz
Gluten induces autoantibodies against reticulin, which somehow flattens the villi and microvilli
dermatitis herpetiformis
risk lymphoma of gut
folate deficiency
wt loss, malabsorption, osteoporosis, infertility, unexplained increased LFTs, bacterial overgrowth, def of fe (decreased ferritin)/folic acid/calcium/VitB12
If TTG neg, check for IgA deficiency
Genetic: HLA DQ2
Associated w/ Type 1 DM
anti-tissue transglutaminase or IgA antiendomysial ab test
bone density in newly dx pts
definitive dx requires bx of proximal small bowel celiac sprue
HLA DQ2 PBC AIH
AMA (antimitochondrial) antismooth muscle (low AMA)
high alk phos normal alk phos
bili usu nl
often asx PSC
pANCA
high alk phos
bili normal
multiple strictures of intra- & extrahepatic ducts
UC & PSC - suspect colon cancer
also cholangiocarcinoma tx prednisone, azathioprine Bili>2 poor prognosis tx UDCA stricture dilation liver transplant Eculizumab
paroxysmal noctural hemoglobinuria
binds to complement protein C5; terminal complement inactivation inhibits intravascular hemolysis IFN ALKYLATING ANTIMETABOLITES ANTIBODIES PLATINUM COMPOUNDS TOPOISOMERASE INHIBITORS ANTIBIOTICS ALKALODS CHEMOTHERAPY Breast cancer that over-expresses HER2
Bonds to a transmembrane R in the family of EGDR to block the cascade that drives cell growth and division
Cardiotoxic when combined with anthracyclines DNA becomes alkylated and disrupted
Affect slowly cycling cells (stem cells)
Infertility common side effect
MDS/AML common Nitrogen mustard
Oldest
MOPP



inorganic cmpds w/ 2 amine grps and 2 cl attached
binds to DNA
can cross-link DNA
most active in cells in G1m, can act across cell phases Cisplatin Carboplatin Chlorambucil
CLL Melphalan
Myeloma ANTHRACYCLINES Bleomycin Vincristine Vinblastine
TAXANES
Bind to microtubules, preventing b/d into tubulin dimers
Disrupts mitosis

Paclitaxel
hypersensitivity rxns (prev by premed and steroids and histamine blockers
bradyarrhthmias
neuropathy, mucositis, almost universal alopecia 5-FU Cytarabine similar to metabolites in the DNA and RNA synthesis pathways
compete for a critical enzyme or substitute into backbone of DNA or RNA causing disruption
Maximally effective in cycling cells
Not associated with profound or prolonged myelosuyppresion
Not associated with risk of 2/2 lyekemia resembles pyrimidines, uracil thymidine
incorporates into RNA and disrupts transcription
toxic to GI epithelium and diarrrhea
enhanced by leukcovorin blocks DHFR
blocks DNA synthesis d/t lack of thymidine
leucovorin is the antidote providing the necessary reduced folate to overcome MTDX
Works best in cells actively cycling
careful in pts w/ effusions because drug will accumulate there and slowly leak out causing prolonged exposure and increased toxicity
ALL, Head&Neck, Breast CA mtx inhibits binding of deoxycycline to DNA polymerase; effectively blocking production of DNA
Most active in Sphase
in high doses, enters the CNS and may cause cerebellar toxicity
AML & lymphoma from periwinkle plant
binds to tubulin to interrupt microtubule formation
metaphase-specific
neurotoxic
ALL, lymphomas
SE: SIADH just like vincristine but with diff SE
myelotoxic - low blood counts
little neuropathy daunorubucin and doxorubicin
intercalates DNA and disrupts replication
mauy generate DNA breaks by creation of free radicals
active throughout the cell cycle
must reduce dosage for heaptic toxicity (increased bili - less drug cleared through liver)
cardiac toxicity w/ increasing cumulative dosage
chronic CHF diff to tx - check by regular EF and endomyocardial bx
tox reduced by dexrazoxane which inhibits free radical formation can be given IV, IM, intracavitary
fever common, occ anaphylaxis
skin rxns: eerythema and hyperpigmentation
pulmonary fibrosis with increasing doses or with hx of chest radiation parent cmpd - camptothecin
inque action, with damage occurring by interruption of normal nick and repair mxm performed by topoisomerase I enzyme
cell cycle-specific S phase Topotecan dose-limiting tox - neutropenia
nausea, fever, skin rash
Ovarian CA and lung CA cleared by kidneys
nephrotoxic
magnesium wasting 2/2 tubule damage (preventable with hydration)
peripheral neuropathy and otoxocitiy
testicular, ovarian, lung, lymphoma myelosuppression esp thrombocytopenia
less renal toxicity DDx:
Endocrine causes of proximal myopathy:
Cushing Syndrome any cause
Hyperthyroidism, any cause
Hyperparathryroidism, 1 or 2
Diabetes melllitus Urinary eosinophils common in pts who develop atherosclerotic emobolization to kidney at time of catherization Acute onset severe foot pain? -> Gout!
up to 30%
because cyclosporine increases uric acid levels IFN alfa for chronic hepatitis C silent thyroiditis which resolves after drug d/c'd be aware of celiac dz + hypothyroidism (Hashimoto's) - would need higher dose of levothyroxine irreversible damage to sperm production in young men ANA, Anti-smooth muscle >= 1:80 Ddx eos in UA:
pyelo
allergic interstitial nephritis
post infectious GN
RPGN
atheroembolic Who with HBV infxn will benefit the most from IFN?
low HBV DNA
high ALT pretx
short duration of infxn IFN beta (Avnoex) for chronic treatment
(natalizumab or Tysarbi - concern for PML - not used mcuch anymore) Decreased C3 seen in post-infxs GN Allergy Notes - Indolent systemic mastocytosis - nl life expectancy in most adults pSCott making pancakes 4 Vax for Pts at Risk

Asplenia
Hib
pneumococcal
meningococcal

Chronic liver
Hep A
Hep B

Health care worker
Hep B
Influenza
MMR

IVDU
Hep A
Hep B
Td

Lung dz
Pneumococcal
Influenza Intranasal Influenza
NONO
pregnant
>49 yo
immunosuppressed
chronic pulm dz
CKD
DM Immunization NONOs

Pregnancy no LIVE vax:
MMR, oral polio, yellow fever, typhoid, varicella, nasal influenza

HIV: Can probably give all except small pox, MMR contraindicated in pts with severe severe immunosuppression like CD4 <100
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