Rheumatoid arthritis & Lupus Erythmatosus Flashcards
Know the different forms of Lupus
Discoid
Systemic lupus Erythematosus
Drug induced
Neonatal
Difference between Discoid Lupus and Systemic lupus
Discoid: Is limited to skin (Cutaneous)
-Generally does NOT involve internal organs
-10% of cases
Can evolve into systemic
Systemic: Multisystem (MORE severe) can affect - skin, joints, any organ (50% have a major organ affected)
-More symptoms = active flare
-Less symptoms = remission
-70% of cases
Drug induced lupus
-Occurs after taking prescribed drugs BUT usually fade when drug is stopped
-Most frequently hydralazine hydrochloride & Procainamide hydrochloride
-4% of people will develop Abs suggestive if lupus and ONLY small & will develop into lupus
Etiology of lupus
Cause is unclear BUT development of SLE autoantibodies is due to defective B cell tolerance for self Ags
-Primary defect in regulation of immune system is Important to pathogenesis
Genetic predisposition (BUT NO I.D. gene yet)
-Known to occur in families. 10% of Pts with lupus have Parent/sibling w/ disease
Neonatal lupus
-Condition is rare & is NOT systemic
-Rash will appear w/in first several weeks of life (may persist for 6months)
What factors affect Lupus
Gut microbes
-West Africans have lower incidence
Hormonal Influence
-Probable link w/ estrogen. Postmenopausal women who begin estrogen therapy MORE likely to develop SLE
Antibiotics (Sulfa, tetracycline-related, penicillin-related)
-Kill microbes => may trigger lupus
-African-Americans Use Abx more than West Africans => may affect lupus severity/prevalence
Vitamins
-(Vitamin D, A, & Omega-3) => modulate lupus onset or flares
Epidemiology of Lupus
-10-15x more frequent in Women than men
-2-3x more prevalent in people of color
-Highest mortality in Ppl of w/ renal involvement or CNS disease
-2 most frequent causes of death is renal failure & infectious complications
Survival at 90% AFTER 10yrs of diagnosis
Signs & symptoms of acute & chronic inflammation of Lupus
-joint pain
-arthritis
-Butterfly rash
-Fever
-weight loss
-malaise
J A B + F W M
Other characteristics of Lupus
-Elevated Abs - anti-dsDNA & anti-ribosomal P Abs
-Reduced lvls of complement & leukopenia
-Immune complex can cause clinical manifestations - photosensitive facial rash; transient diffuse arthritis; & CNS, renal, cardiac, or respiratory system
Cutaneous features of Lupus
- 20-25% develop dermal disorders (initial manifestation)
-65% with Butterfly rash (UV light will exacerbate Rash)
-Rash can also be found on arms & trunk
-Alopecia
-1/3 w/ Raynaud phenomenon
-Discoid lupus
-Uticaria, angioedema, nonthrombocytopenic, scale formation, ulcerations in mouth & genital mucus membranes.
True or False:
Treatment of lupus by steroids can lead to
a) opportunistic infections
b) interference of host defense
c) Increase host immune system
d) A & B
D) opportunistic infections & can interfere w/ host defenses
What does lupus affect the kidneys
-Immune complexes cause injury to renal system
-Acute/chronic glomerulonephritis (unpredictable progression)
True or False:
Lupus can cause lymph enlargement the lymph nodes but NOT the spleen
FALSE
Both Lymph enlargement & splenomegaly can occur
True or False:
Specific gastrointestinal issues are commonly associated w/ Lupus
False:
NON-specific GI issues are common
What is Serositis
-An inflammation of the mesothelium (thin layer of connective tissue enclosing body cavity)
-Its a cardinal finding of SLE & can lead to Peritonitis, pleuritis, or pericarditis (All associated w/ severe pain)
What are the cardiopulmonary characteristics associated with lupus
-Inflammation of myocardium => lead to tachycardia & (occasionally) congestive heart failure
-Occult diffusion & obstructive abnormalities shown by pulmonary function studies
What are musculoskeletal features of lupus
-symmetrical transient and peripheral polyarthritis of small & large joints
-Can result in chronic deformities & disabilities
-10% w/ rheumatoid hand deformities
-25% w/ osteonecrosis
What are the neuropsychiatric features of lupus
-Its secondary to central/peripheral nervous system involvement & can cause - mild confusion, memory deficiency, orientation & perception impairment
-Psychiatric disturbances like hypomania, delirium, schizophrenia
At what age does Late onset lupus typically occur?
It can occur at any age but has an Average of 62yrs
-More prevalent in Caucasians
-x8 more in women
-mild symptoms (makes it hard to diagnose)
Which specific cells are involved in the pathogenesis of lupus
B-lymphs
T-lymphs
Dendritic
What are the characteristics of pathogenesis for lupus
-Loss of tolerance to nuclear Antigens (Ags)
-Deposition of immune complexes in tissues
-multiorgan involvement
-Auto-antibodies against that react with Naive or altered self-Antigens
Demonstrable antibodies to - nuclear components, cell surface Ags, cytoplasmic Ags of PMNs, lymphocytic leukocytes, RBCs, Plts, neuronal cells, & IgGs
Characteristics of antibodies and lupus
-Antibodies will attach to their corresponding antigens and form immune-complexes => These get deposited into tissued b/c monocyte phagocyte system is unable to eliminate them.
What are the lab features of SLE
-Presence of Antinuclear antibodies (ANA)
-immune complexes
-Tissue disposition of immunoglobulins & complement
-circulating anticoagulants & other autoantibodies
-decreased complement levels
What are the cellular aspects of SLE
-SLE results form defects in the regulatory mechanism of the immune system
-Lymphocyte subset abnormalities are a major immunologic feature of SLE (variety of abberations in T-cell & B-cell function)
-T cell subsets:
1. HYPER-production of Helper T cell
2. lack/reduced Tcell suppressor
-B cells:
1. Spontaneous B lymphocyte HYPERactivity => uncontrolled production of antibodies to HOST & exogenous antigens
What are the Humoral aspects of SLE
Hallmark of SLE is circulating Immune complexes
-Autoantibodies to almost any tissue or organ
-Absence of ANAs ≠ diagnose w/ SLE Unless Pt is being chemically immunosuppressed
-ANA can also be found in other diseased (Rheumatic or nonrheumatic), like some Pts under drug therapy or older healthy ppl.
What are the diagnostic evaluations for SLE
-Histologic changes
-Hematologic finding
-Hemostatic changes
-Serologic findings
What are the Histologic changes of SLE
-Acute Vasculitis
-Supportive tissue gets infiltrated w/ neutrophils -> then plasma cells & lymphocytes
-Glomerulonephritis & membranous nephritis
What are the Hematologic finding of SLE
-Moderate anemia (normocytic & normochromic)
-Lymphocytopenia
-Thrombocytopenia (50-100 x10^ 9/L)
What are the Hemostatic testings of SLE
-Lupus anticoagulants - Inhibitor or prothrombin activator — Often see thrombosis (clot) instead of bleeding
-20% w/ antiphospholipids
-circulating anticoagulants => False POSITIVE for syphilis
-Prolonged Prothrombin time (PT) & partial thromboplastin time (PTT)
What are the serologic findings of SLE
-High lvls of Anti-DNA antibodies
-Increased gamma globulins (hyper-viscosity & renal tube acidosis)
-Serum cryoglobulins - mixed IgM & IgG types. lvl are proportional w/ severity of SLE
-Reduced complement lvls (breakdown products of C3 -> c3d & c3b)
What are Antinuclear antibodies (ANAs)
Antinuclear antibodies are autoantibodies that bind to contents of all sub-cellular structure and cell organelles
Including
-cell surfaces
-cytoplasm
-nuclei
-nucleus
Proteins recognized are mainly proteins
-macromolecular complexes
-protein nucleic acid complexes
-nucleic acids
Clinically useful target RNA-protein & DNA-protein complexes
What is the cut off for positive ANA titer dilution
31.7% (of all normal individuals were) Positive at 1:40 dilution
-13.3% @ 1:80
-5% @ 1:160
Negative cutoff titer at 1:160
Which specific autoantibodies are used to monitor SLE?
Anti-dsDNA antibodies are used
Generally ANAs
-don’t have organ or species specificity
-capable of reacting w/ nuclear material or animal tissues
ANAs in other diseases can’t be used ≠ confirm SLE
BUT can rule it out
What are the 5 subgroups of ANAs
-Antibodies to DNA
-Antibodies to centromere
-Antibodies to histone
-Antibodies to non-histone
-Antibodies to nuclear antigens
What is immunofluorescence and what is it used for?
Technique for determining the location of an antigen (or antibody) in tissues by reaction with an antibody (or antigen) labeled with a fluorescent dye.
-Extremely sensitive (uses fluorescein-conjugated antiglobulin)
-Patterns of reactivity are dependent on what the ANA reacted with
Negative reaction in normal person = no green or gold fluorescence.
Know pattern of homogeneous or Diffused
-High titers of SLE
-Characterizes anti-DNA nucleoprotein antibodies -> nDNA, dsDNA, ssDNA, DNP or histones
-Nucleus fluoresces evenly (may see Vacuoles)
-Typically seen in rheumatoid disorders
-Low titers can also indicate SLE, and RA Sjogren syndrome, mixed connnective tissue disease (MCTD).
Describe the speckled pattern
Is a grainy patterns w/ numerous round dots. W/out staining of the nucleoli
-Occurs in presence of Ab to any extractable nuclear Ag devoid of DNA or histone.
-Detected against saline extractable nuclear antigens-> Anti-RNP & anti-Sm
Anti-Sm = high specific for SLE
Anti-RNP = RA, Sjogrens & SLE, PSS, MCTD, dermatomyositis
picture show A w/ speckled staining in the nucleus of the interphase cells & B w/ speckling in the area outside of the chromosomal area
Know the nucleolar pattern
A few smooth round nucleoli w/ variation in size will fluoresce
-Reflects an antibody to nucleolar RNA (4-6S RNP)
-Present in about 50% of patients with Scleroderma (PSS), Sjogrens & SLE (Also seen in Raynaud phenomenon)
picture shows B w/ chromosomal area & A w/ staining in the nucleoli of the interphase cells
Know the Centromere pattern
Anticentromere antibody reacts w/ centromeric chromatin of metaphase & interphase cells
-HIGHLY selected for CREST variant of PSS
-discrete & speckled (46 speckles one for each set of chromosomes)
-Found infrequently in SLE MCTD, PSS
picture shows A w/ discrete speckles in the nucleus of the interphase cells = staining of the. B w/ discrete speckling seen in the chromosomal area of the metaphase mitotics
Other Assays
What autoimmune does the rapid slide test best used for?
Its the a latex slide test
Positive in SLE, RA, scleroderma, Sjogrens
Other assay
Whats the autoimmune enzyme Immunoassay (EIA)
It a Qualitative screening test & an alternative to IFA’s
Other assay
Multiplex Assay
-Rapid, sensitive & specific method
-Absence of subjective error in interpretation of result
-only limited number of antigens is tested -> can lead to FALSE Negative results
How is SLE treated
Medications: NSAIDS, acetaminophen, steroids, immunosuppressants, anticoagulants, biological disease-modifying antirheumatic drug therapy, monoclonal antibody therapy
-treatment/prevention methods will minimize symptoms, reduce inflammation & maintain normal body functions
-AVOID sun & use sunscreen to help prevent rashes
-exercise to prevent muscle weakness & fatigue
-Immunizations to prevent illnesses
Define arthritis
Arth (join) & -itis (inflammation)
-more then 100 forms (growing problem in U.S.)
-Estimated 22.7% of adults (>18) are diagnosed arthritis
-Females (24.5%) at higher incidence
-OBESITY & physically inactive = are risk factors
Etiology of RA
Oldest diseases (SLE, RA, gout) - cause is unknown
-May represent an unusual host response to one or maybe many causative agents
What are the important factors influencing RA
-Genetic
-Hormonal
-Psychosomatic
-Immunologic
Epidemiology of RA
Occurs Mr. Worldwide
-Increased frequency of local or extra-articular infections
-Cardiovascular disease = most frequent cause of death
-No specific genetic relationship (Small increase w/ 1˚relative)
-Shortened lifespan
Signs & symptoms of RA
RA is chronic, multi-system, autoimmune disorder; Progressive inflammation of joints
-Highly variable disease
-Ranges from: mild - destructive disease associated w/ vasculitis
Pathogenesis of RA. What are the three distinct phases?
- Initiation of synovitis by the primary causative factor
- Subsequent immunologic events that perpetuate the initial inflammatory reaction
- Transition of an inflammatory reaction in the synovium to a proliferative, destructive tissue process
Initial symptoms of RA?
&
when do joint symptoms appear?
Often begins w/ fatigue, anorexia, weakness & generalized aches. Strffness not localized to articular structures
Joint symptoms appear gradually over weeks to MONTHS
What are extraarticular manifestations of RA
-weight loss, fatigue
-Subcutaneous rheumatoid nodules
-ocular abnormalities
-Vasculitis
-Neuropathy
-Myopathy
-Cardia (pericarditis)
-Pulmonary (pleural effusion)
-osteoporosis
-Felty syndrome (Complex of chronic RA, splenomegaly, anemia, thrombocytopenia & neutropenia)
What is the synovium
Its the synovial membrane lined w/ synovial cells that synthesize protein & are phagocytic
What is the synovial fluid
Transparent, viscous fluid; lubricates the joind space & transports nutrients to the articular cartilage
-Inflammatory joints fluids contain lytic enzymes that interfere w/ hyaluronic acid & impairs lubrication
Routine analysis of synovial fluid
Cell count & differential crystals, gram stain & culture
-volume, appearance, viscosity, chemical analysis
What are the 2 (hypothesized) pathogenic mechanisms for RA
- The extravascular immune complex => interaction of antigens & antibodies in synovial tissues & fluid
- Alternative => Cell-mediated damage occurs b/c of accumulation of lymphocytes (mostly Tcells) in the rheumatoid synovium, resembling a delayed-type hypersensitivity reaction. (presence of cytokines which affect articular inflammation & destruction supports this hypothesis)
Diagnostic evaluation of RA
-low serum iron lvls w/ low normal iron-binding capacity
-ESR elevated to a variable degree - parallels disease activity
-Serum protein electrophoreses
1. elevation in Alpha-2 & gamma globulins
2. gamma globulin increase in polyclonal
3. mild - moderate decrease in albumin
-Rheumatoid factor, anti-cyclic citrullinated peptide (anti-CCP), immune complexes, characteristic complement lvls & ANA’s
What are Rheumatoid factors
Immunoglobulins of any Isotype w/ antibody activity directed against antigenic site on the Fc region of human or animal IgG
RF Positive correlates w/
-severity of disease (in general)
-Nodules
-Other organ system involvement (vasculitis, Felty syndrome, Sjogrens)
-Associated w/ 3 classes -> IgM, IgG, and IgA
-IgM RF = 70% of adults (NOT specific to RA)
Agglutination tests for RF
-sensitized sheep cells test & latex agglutination
-Generally detects IgM RFs
-Latex is sensitive but high number of false positives
-Presence of all three IgG isotypes (M, G, A) - specificity of 99% for RA
Immunoturbidimetric & ELISA assay - automated methods
RF also associated w/ bacterial/viral infections & old ppl
What are cyclic citrullinated peptide antibodies (CCPs)
MORE sensitive than RF
Inflammation w/ RA causes some proteins to become altered by a process call Citrullination
-modified proteins = induce autoimmune response
Anti-CCPs
-HIGHLY specific for RA (95%)
-may be present in preclinical phase - 16yrs before symptoms
Other Markers
-Antibodies to Anti-perinuclear factor (APF)
-Anti-keratin antibody (AKA)
-Soluble circulating immune complexes & cryoprecipitateble proteins - consists of Igs, complement componenst & RFs
-Complement lvls usually normal EXCEPT in VASCULITIS
-ANA’s found in 14-28% of RA patients
Juvenile idiopathic arthritis (JIA)
Caused by numerous things, like -> infection, autoimmunity & trauma
-Condition where chronic synovitis beginning during childhood
(affects = .1-1.1%/1000)
Associated w/ retroviral particle called human intracisternal A-Type particle (HIAP)
-Abs in high percentage in Pts of JIA
-(also found in Pts w/ SLE, Sjogrens, & Graves)
When is JIA typically diagnosed?
Onset before age of 16yrs
-presence of arthritis
-exclusions of conditions to cause/mimic arthritis
Immunologic features can include
-presence of RF
-immune complexes
-ANAs
How is RA treated?
-Traditional drugs -> NSAIDS (ibuprofgen, apirin/salicylates)
^mostly to reduce inflammation
-Corticosteroids (anti-inflammtory) & glucocorticoids (selective COX-2 inhibitors)
-Nonbiological disease-modifying antirheumatic drugs -> methotrexate
-Biological disease-Modifying drugs
genetically engineered proteins designed to inhibit specific components of the immune system
What the three main goals in terms of treating arthritis?
-Reduce pain & discomfort
-prevent deformities & loss of joint function
-Help Pt maintain a productive & active life
Inflammation must be suppressed & mechanical/structural abnormalities corrected or compensated for
Other treatment options for RA
-Reduction of joint stress
-physical & occupational therapy
-drug therapy
-surgical intervention
