Blood and Lymph Unit 4-Rheumatology Flashcards Preview

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Flashcards in Blood and Lymph Unit 4-Rheumatology Deck (48):

Explain what rheumatology is and the types of disorders rheumatologists specialize in managing.

Rheumatology: deals with pain and inflammation of MSK system and autoimmune disorders. MSK=muslcles, joints, ligaments, tendons, bones, soft tissue.

-inflammation of the joints (pain, swelling, redness, heat). can lead to joint deformity over time.
-pain may not be due to joint, may be due to periarticular pain: pain arising from structure around the joint (tendon, bursa). can be made worse with active motion compared to passive motion.
-soft tissue pain: pain perceived as arising from joint but actually comes from elsewhere (muscle, nerves, distant site)
-swelling is helpful in determining arthritis. can present as joint effusion.
-monoarticular arthritis: involves 1 joint. most seen in infections, crystal induced arthritis, trauma
-oligoarticular arthritis: arthritis seen in several joints (2-4). associated with axial arthropathies (ankylosing spondylitis, psoriatic arthritis, reactive arthritis). asymmetrical, involves large joints
-polyarticular arthritis: multiple joints, symmetric, affects small and large (RA, lupus, erythematosis, virus)

-joint hurts but there is no evidence of inflammation. may be arthritis at level not yet detectable by examination. may be caused by virus, other causes


Recognize how rheumatologists evaluate patients.

-Monoarticular disease vs. polyarticular diseases
-monoarticular: characteristic of septic arthritis, gout, pseudo gout, traumatic arthritis, mechanical derangement
-polyarticular: charachteristic of RA, lupus, psoriatic, reactive, hepatitis B,e tc.
-polyarticular that presents as monarticular: juvenile RA, reactive arthrits, sarcoid arthritis, pseudo gout, etc.

look at joint distribution:
-symmetric: same joint involved on both sides
-asymmetric: only one side involved (seen in osteoarthritis, gout, spondyloarthropathies)
-distribution: large joints (axial), small joints (RA, lupus), joints in osteoarthritis (DIP, PIP, CMC, spine, hip, knee, MTP), joints in RA (PIP, MCP, WRIST)
-migratory: rheumatic fever, disseminated gonococcemia
-additive: RA, axial arthropathies
-rapidity of onset: hours (septic joints, crystal disease), days (chronic inflammatory disease)
-response to rest and activity: worse with rest or in morning (RA, axial arthropathies), worse with use (osteoarthritis)

Look at demographic History:
-age, sex (young age is RA, lupus. elderly is gout, polymyalgia, etc.) (male=more likely gout, female=more likely RA)
-family history: RA, Axial arthropathies, systemic lupus, gout, osteoarthritis

look at synovial fluid analysis to see if non inflammatory (type 1), inflammatory (type 2), septic (type 3)

Talk to and evaluate the patient:
-pain and joint symptoms
-other symptoms, signs of inflammation (swelling, warmth, erythema, tenderness, LOF)
-inflammatory vs mechanical (inflammatory: >1 hour stiffness, fatigue, activity improves symptoms, rest worsens, systemic, corticosteroid response) (mechanical)


Recognize the major sub-groups of rheumatic diseases

Degenerative Process:
-osteoarthritis. cartilage based process. loses homogenous nature, disrupts, eventually is gone.
-increase water content of articular cartilage, type 2 shrink, loosens weave, proteoglycans drop

Mono-articular arthritis:
-bacterial infections and crystalline diseases are present often with 1 inflamed joint, may present with some others
-last longer than 6 weeks

Polyarticular Arthritis:
-H&P are key.
-acuteness of onset, inflammation, temporal pattern, distribution, age, sex
-good exam to look for skin rashes, organ involvement, tenosynovitis

-most common
-normal sed rate and CRP, cool effusions, low WBC count, asymmetric joint space loss and osteophytes

Secondary OA:
-after various metabolic diseases, occurs in strange joints-wrist and metacarpals

Avascular Necrosis:
-ischemic death of cellular bone components, long bones have tenuous blood supply. Corticosteroids can cause

-physiological factors and increased central pain, results in diffuse pain.

Inflammatory: RA, crystals, spondyloarthropathies, systemic lupus (SLE), vasculitis, polymyosititis, dermatomyositis


Appreciate that rheumatologists use a diverse arsenal of medications and other modalities to combat arthritic illnesses.

-first effective treatment was Prednisone (1949)
-therapy is now "treat to target" with low disease activity and remission as goals.

-NSAIDS: used for joint pain in almost all rheumatologic diseases. effects of inhibition of prostaglandin production : analgesia, antipyresis, anti-inflammatory
-negatives of NSAIDS: GI mucosal damage, asthma exacerbation, platelet inhibition, nephrotoxicity

-Glucocorticoid therapy: suppresses inflammatory cascade, modifies immune response through decreased neutrophil margination/migration and macrophage cytokine production (IL-1, TNF) and decreased T cell proliferation. initial therapy in almost all arthritic diseases with avoiding long term high dose use.
-Glucocorticoid toxicities: glucose intolerance, insomnia, cataracts, bruising, weight, osteoporosis, osteonecrosis

-DMARDS and other oral agents: nebulous mechanism, have own toxicities, highly teratogenic, generic and not expensive.
-hydroxychloroquine, sulfasalzine, methotraexate, azithioprine, mycophenolate, leflunomide, cyclophosphamide

Biologic agents: specific targets, injection/infusion, patented and expensive, risks and toxicities
-anti TNF agents: entanercept, adalimumab, infliximab, certolizumab pegol, golimumab. TNFalpha is key cytokine.
-others: rituximab, belimumab, toclizumab, abatacept
-toxicities and concerns such as opportunistic infections, drug induced lupus, etc.

Non pharmacologic: physical therapy, occupational therapy, cognitive behavioral therapy, podiatry/pedorthists, exercise, acupuncture, orthopedic surgery


Describe the symptoms and signs, synovial fluid analysis, and x-ray features of osteoarthritis.

-pain with use-improves with rest, stiffness, preservation of function
-rarely significant symptoms pre 40
-lack of systemic symptoms

-localized joint tenderness, bony enlargement, crepitant, restricted movement, swelling/instability
-specific patterns of deformity: heberden's and bouchard's nodes, squaring of 1st carpometacarpal joint, menu varus, hallux values, cervical/lumbar spondylosis

Synovial Fluid Analysis:
-sent for gram stain, culture, cell count, differential, crystal analysis.
->2000 WBC is indicative inflammatory arthritis
-synovial fluid: type 1 fluid has 200-2000 WBC, 25% polymorphonuclear leukocytes, normal viscocity. negative crystal exam, normal glucose

Clinical syndromes:
-6 types: primary generalized, inflammatory/erosive, isolated nodule, unifocal large joint, multifocal large joint, unifocal small joint

Lab Findings:
-no specific abnormalities
-secondary OA tests: uric acid, iron, Ca2+, phosphate, sedimentation, c-reactive protein
-cartilage degradation in serum and joint: hyaluronic acid, fragments aggecan, type 2 collagen and products, cartilage oligomeric protein
-non-specific indicators of inflammation: platelet count and ferritin
-negative acute phase reactants: albumin, hematocrit
-indirect assessment of inflammatory response: erythrocyte sed rate
-direct assessment inflammatory response: C-reactive protein

Radiographic Evaluations:
-loss of cartilage space, bony sclerosis/eburnation, cystic changes subchondral bone, osteophyte formation, altered shape, joint effusion

X ray Changes:
-gull wing in joints, medial compartment knee disease, osteophytes of spine, decreased joint space in hip, hallux valgus


Discuss the risk factors for getting OA.

-there are 12% of ppl 25-75 with symptomatic OA
-OA of hands is 32%
-relationship to aging is strong. Advanced age=strongest risk factor
-symptomatic disease seen in 25% of those with x ray evidence of OA in knees, and a stronger correlation is seen in the hip .
-pathologic changes in weight bearing joints in almost 100% people by 40 y/o
45, women have greater incidence OA
-women=more severe disease with increased Heberdens/bouchard's nodes
-miners have more OA in hips, knees, shoulders
-weavers have more OA of hands
-trauma/previous injury is increased OA risk
-obesity correlates with OA of knees/hands in women
-can be primary (idiopathic with no known inciting event) or secondary (known events induce)
-may involve single joint, often involves weight bearing joints

Predisposing factors:
-Genetics: mutations in type 2 collagen can have accelerated familial OA.
-metabolic abnormalities: hemochromatosis, wilson's disease, ochronosis associated with accelerated OA. direct chondrocyte toxicity and calcium deposition
-Trauma: mechanical instability, incongruity, load, denervation are main predisposing factors. disruptions joint mechanics leads to rapid development, leads to imbalance in anabolic and catabolic products
-inflammatory joint disease: initiated by other process
-age: 75% of people over age 70 have OA


Explain the various theories on the pathogenesis of OA.

-cartilage is main focus of pathology in OA. normally remodels over time. inflammation has significant role in OA.

Focal mechanical stress: trauma, force, instability, defects, crystal disease. can release degenerative enzymes-collagen fibrillation, type 2 degradation

Chondrocytes and synovium release pro-inflammatory substances: cytokines like IL1 (promotes degradation, decreases new matrix formation), MMP, Prostaglandins, NO, IL6. TNF. Inhibitory cytokines. complement activation. adipokines lined to cytokines.

water content changes in OA: originally increases, weakens collagen fibers, opens "weave", content decreases to 50% or less

cartilage surface disruption: disrupted and fragmented by pits/ulcers. bone develops bare areas, makes osteophytes. forms type 1 collage, and fibrocartilage caps the osteophytes


Discuss the treatment of OA as it relates to the pathophysiology

-OA is defined by symptoms and changes, so diagnosis takes a long time

-primary prevention: reduction of risk factors, reduce obesity (reduces 25-50%) and repetitive activities.
-secondary prevention: prevent progression, disease modifying OA drugs (DMOADs)
-tertiary treatment: consequence of OA treatment

-fit treatment to patient: age, comorbidity, severity, preferences, cost

-talk to patient about their concerns and what can/cannot be done
-determine if perception is disproportionate to psychosocial variables
-modalities to help prevent cartilage loss
-medications (topicals, nonopoid analgesics, anti inflammatory, opioid analgesics, nutarceuticals, intra-articular agents, adjunctive treatment)
-intra-articular agents: corticosteroids, hyaluronic acid
-nutraceuticals: glucosamine, chondroitin sulfate
-alternative therapies: used by >80% of patients (leech, SAMe, ginger, avocado, acupuncture, EM fields, magnets)

Future directions:
-blood markers: find microscopic, macroscopic cartilage loss. aggrecan, keratin sulfate, chondroitin sulfate, type 2 collagen, link protein, osteocalcin, COMP (most promising)
-therapies: metalloprotease inhibitors, synthetic proteoglycans, intra-articular injection chelators to inhibit MMP. Growth factors, biologic agents against inflammatory proteins/cytokines, experimental filler plastics for damaged areas.


describe the types of joints rheumatologists deal with

synarthrosis: bones come together and interlock-skull

amphiarthrosis: bones joined by segment flexible fibrocartilage-rib cage

diarthrosis: most common joint, bone articulations, lubricated synovial tissues

uniaxial/hinge joints: move along one plane-elbow

polyaxial joints: move multiple axes-shoulder


describe the tissues around joints that rheumatologists deal with:

ligmants: bundles of type 1 collagen. bone to bone

tendons: resemble ligaments, muscle to bone. active drivers of joint movement

entheses: ligaments and tendons insert into bone. metabolically active sites. can calcify.

bursae: synovial lined sacks/pillows of dense, regular connective tissue designed to slide and cushion. occur often btw. tendon and bone, tendon or ligament, btw tendons


Describe the following terms relating to joints as related to rheumatology:
axial arthropathy
diarthrodial joint

axial arthropathy: arthritis of spine

ankylosis: fixation of joint as result of disease process-fibrous/bony union across joint.

sacroiliitis: inflammation of sacroiliac joint

spondylitis: inflammation of 1 or more vertebrae

osteophyte: bony outgrowth

syndesmophyte: calcification of ligament or tendon at bony insertion site

synchondrosis: union btw. 2 bones formed by cartilage

diarthrodial joint: inside has articular surface covered by hyaline cartilage (type 2 collagen), pulls in water with negative charge of proteoglycans, forms gel. synovium is thin layer of cells and capsule with intra-articular surfaces. wondered. A cells (macrophage-like from bone marrow) and B cells (fibroblast-like). inflammation of synovium is synovitis. diffusely inflamed in RA=pannus. under the cartilage is subchondral bone, becomes dense in osteoarthritis, and less dense in inflammatory arthritis.


Describe the following Rheumatological biologic agents:

Rituximab - B cell depleting monoclonal anti-CD20 antibody (molecule expressed on pre-B cells but not plasma cells).

Belimumab – monoclonal antibody that targets B-lymphocyte stimulator (BLyS).

Toclizumab -anti-IL-6 receptor antibody competes for human IL-6 receptor, inhibiting binding of IL-6 to its receptor.

Abatacept - Soluble fusion protein of extracellular domain of CTLA4 and Fc portion of IgG1. It acts as a competitive inhibitor of the CD28-CD80 (B7) second signal.


Describe the following terms relating to joints as related to rheumatology:
axial arthropathy
diarthrodial joint

axial arthropathy: arthritis of spine

ankylosis: fixation of joint as result of disease process-fibrous/bony union across joint.

sacroiliitis: inflammation of sacroiliac joint

spondylitis: inflammation of 1 or more vertebrae

osteophyte: bony outgrowth

syndesmophyte: calcification of ligament or tendon at bony insertion site

synchondrosis: union btw. 2 bones formed by cartilage

diarthrodial joint: inside has articular surface covered by hyaline cartilage (type 2 collagen), pulls in water with negative charge of proteoglycans, forms gel. synovium is thin layer of cells and capsule with intra-articular surfaces. wondered. A cells (macrophage-like from bone marrow) and B cells (fibroblast-like). inflammation of synovium is synovitis. diffusely inflamed in RA=pannus. under the cartilage is subchondral bone, becomes dense in osteoarthritis, and less dense in inflammatory arthritis.



Degeneration of articular cartilage with hypertrophy of contiguous bone (lose cartilage, bone beefs up): joint space loss, subchondral cysts, sclerosis, osteophytes


OA Joint involvement

DIP (Heberden’s), PIP (Bouchard’s), 1st CMC (base of the thumb)
Hips and knees (large weight bearing joints)
Spine: cervical and lumbar
First MTP ( of great toe-not all great toe pain is THE GOUT)


OA predisposing factors


Occupational risks:
-Miners: OA hips, knees, shoulders
-Weavers: OA hands

Secondary OA (to primary inflamm. Disorders-Spondylo, RA, etc):
-Metabolic: hemochromatosis, Wilson’s disease, ochronosis

Sports: in general, no increased risk; exercise may be protective (biomechanics protect the cartilage)


OA cartilage makeup

Cartilage (avascular, no nerves-why it doesn’t repari itself)
1. Collagen: predominantly type II
2. Proteoglycans (chondroitin and keratin sulfate) linked to hyaluronic acid (hydrophilic)
3. Matrix proteins
-Metalloproteinases (MMPs): collagenase, gelatinase, stromelysin (too high concentration=degradation of cartilage)
-Tissue inhibitors of metalloproteinases (TIMPS)
4. Chondrocytes (main cell of cartillage. What’s producing proteins)
5. Water: 70% weight of intact cartilage


osteoarthritis cartilage damage and synovial fluid

-There is a hit to cartilage that cannot repair itself. Chondrocytes try to heal itself.
-Cartilage in early Osteoarthritis
increase chondrocytes
 decrease proteoglycan
 increase metalloproteinases
decrease TIMP
 increase water content
Loose weave due to MMPs and water influx. Dishrag rather than sponge.
-Lacks systemic features!
-Synovial fluid: noninflammatory, type I fluid (200-2000 WBC/mm3). Very few neutrophils
Classic of knee


osteoarthritis and cytokines

There are low levels of inflammatory cytokines even though non-inflammatory disorder

Chondrocytes and synovium produce cytokines and inflammatory mediators implicated in articular cartilage destruction:
-Interleukin-1: stimulates MMP production, PGE2, produces nitric oxide (NO), IL-6
-Nitric oxide: increases MMP production, inhibits proteoglycan synthesis, induces chondrocyte apoptosis (can’t keep up, they die, abnormal cartillage)
-Prostaglandins: ↑ production and activation of MMPs (degrade all components of cartilage)
-Other cytokines: TNF, IL-6, IL-17, and IL-18

Complement activation (in mouse models there is a terminal effect of complement activation)

-HONDA syndrome inflammatory process of adipokines may cause inflammation elsewhere in body (in hands of obese person)


OA Knees

Joint space loss
Sclerosis (whitening/ebernation of joint)
Subchondral cysts (geodes from microtrauma of joint)
Osteophytes (new bone that grows outside of joint)


RA definition and joint involvement

A systemic, inflammatory, autoimmune disorder of unknown etiology that results predominantly in a peripheral, symmetric synovitis (itis of inner lining of tissue of synovium) which can result in cartilage and bone destruction

Joint involvement:
-Bilateral, symmetric - small joints hands + feet sparing the DIPs (osteo affects DIP)
-Medium and large joints can be involved
-X-rays: marginal joint erosions and deformities


RF etiology

Etiology: Arthritogenic peptide/s in the genetically susceptible host

Disease susceptibility and severity associated with shared epitope (QKRAA; in antigen binding groove/cleft. Occurs in Beta chain of class 2 HLA) in subtypes of HLA-DR4 and HLA-DR1 (in the third hypervariable range); other genes are also involved
-Marker of severity and suceptibility to RA


RA rheumatoid factor

Rheumatoid factor (RF):
-Antibody directed against the Fc portion of IgG; RF usually IgM, can be IgG or IgA
-Own IgG, and own IgM against constant region-Rheumatoid factor!
-RF present in 85% of patients with RA
-Not specific for RA or CTDs
-Can be seen with age
-Produced locally in the synovial tissue
-Part of synovitis, not seen in liver or spleen
-RF-IgG immune complexes are pathogenic
-Etiology of forming nodules
-Vasculitis of small digits.

Remember- (+) RF doesn’t make the diagnosis!!!!


Anti-Cyclic Citrullinated Peptide Antibodies (Anti-CCP)

RF not very specific for RA

Autoantibodies reactive with synthetic peptides containing the unusual amino acid citrulline (modified arginine residues. Something our body shouldn’t normally do) are specifically present in the sera of RA patients (unique to RA patients):
-Anti-CCP: sensitivity 64-89%, specificity 88-99%
Not many other diseases give you these antibodies
-IgM RF: sensitivity 59-79%, specificity 80-84%
Found in other disease states
-RF and anti-CCP: sensitivity 30-39%, specificity 98-100%
No other disease state gives you these 2 antibodies at same time

Anti-CCP abs occur more frequently in individuals with the shared epitope; citrullination of peptides enhances binding to HLA shared epitope
-These anti-ccp antibodies may play role in propagating the disease


Synovium contents RA and extra-articular manifestations

Lymphocytes in RA synovium:
-Majority are CD4+ T cells and Th17 cells play a role; B cells and plasma cells are present (they make RF, anti-CCP); no PMNs (in synovial FLUID, not in tissue itself)
-CD4+ memory T cells: modulation and amplification of local immune response through antigen recognition (query altered proteoglycans or collagen; citrullinated peptides) (drive citrulination)
-T cell cytokines (IL-2 and IFN-) are sparse

Extra-articular manifestations:
-RF-IgG immune complex-induced vasculitis
-Rheumatoid nodule formation in tissues (extensor surfaces/digits)/organs



The result of tissue deposition of monosodium urate (MSU) crystals due to hyperuricemia (MSU supersaturation of extracellular fluids)
-If you have enough it goes into soft tissues

Joint Involvement:
-1st MTP (podagra)
-Cool, peripheral joints of lower and upper extremities

Hyperuricemia: over-production or under-excretion of uric acid; underexcretors (90%) of uric acid*****


Gout and Uric Acid purine metabolism!

Uric acid is a product of purine metabolism:
-Humans lack uricase which oxidizes uric acid into allantoin (more soluble)

Overproduction of uric acid (2 X-linked inborn errors):
-Underproducers under the age of 30, male
-PRPP synthetase overactivity
-HGPRT deficiency (complete: Lesch-Nyhan syndrome)

Crystal arthritis is diagnosed by arthrocentesis and crystal identification by polarized microscopy (MSU crystals: needle-shaped, negatively birefringent)


purine metabolism

Humans lack uricase which converts uric acid to the more soluble compound allantoin
-Gene inactivated by 2 missense stop codon

Uric acid may serve as an antioxidant
-May serve to hold onto more salt during evolution

X-linked inborn errors:
- increase PRPP synthetase
-decrease HGPRT (salvage pathway is downregulated)

Xanthine oxidase inhibited by allopurinol and febuxostat
-Purine lowering drugs
-Brings down solubility levels


Initiation of MSU Crystal-Induced Inflammation

Endogenous MSU crystals may act as a “danger signal”

Initial recognition of naked MSU crystals by TLR2 / TLR4 critical to the inflammatory response

MSU crystals engage the caspase-1 activating NLRP3 inflammasome resulting in IL-1β production
-Nalp inflammasome
-Activate enzyme caspase1 (cleaves pro-IL1 to active IL-1 which is excreted. Compensetory inflammatory mechanism)


Self-limited nature of acute gouty arthritis

Proteins coating the crystals modulate the cellular response:
-IgG-coating promotes phagocytosis by PMNs
-IgG: not specific anti-crystal antibodies
-Charge interaction. Poly’s have Fc receptors, that engage the crystal and phagocytize the gout

Apolipoprotein B-coating inhibits phagocytosis
-Switch from IgG so it quiets down and diminishes inflammatory immune response

Phagocytosis of crystals  decreases concentration

Local heat of inflammation increases MSU solubility

ACTH (cortisone) secretion suppresses inflammation
-Treat with prednisone

IL-1 and TNF are modulated by inhibitors


Calcium Pyrophosphate Dihydrate Deposition Disease

Abnormal pyrophosphate (PPi) metabolism
Not a solubility event
-PPi: metabolism of NTPs from chondrocytes
-Abnormal metabolism combines with Ca2+ to form crystals

NTP pyrophosphohydrolase (NTPPPH) hydrolyzes the phosphodiesterase 1 bond generating NMP and Ppi

Mutations of the ank gene (ANKH) resulting in a transmembrane PPi transporter protein in chondrocytes allowing excess intracellular PPi egress from chondrocytes
-Transport to the surface
-Increase egressing from the cell due to alterations in ANKH gene


Calcium Pyrophosphate Dihydrate Deposition Disease

Chondrocalcionosis (all stacked up in the cartilage)

PPi precipitates with calcium forming CPPD crystals in mid-zonal cartilage layers

Crystal release into the joint space:
-“Shedding phenomenon”
-“Enzymatic strip mining”
-Insane inflamm cascade triggered

CPPD: rhomboid, positively birefringent


Seronegative Spondyloarthropathies

A group of diseases characterized by:
-Axial arthritis: spine, SI joints (sacroiliitis); morning (am) stiffness (just like RA)
-Peripheral arthritis: small and large joints
-Enthesitis: ligamentous-, tendinous-, fibrous-osseous junctions. Inflammation of the enthesis. Junction where meet bone
-Mucocutaneous lesions: rash, conjunctivitis
-Uveitis (inflammation anterior chamber of eye)
-HLA-B27 genetic association; neg RF and ANA (seronegative)
-Synovium: increased expression of TNF

Unknown infectious trigger in the genetically susceptible individual resulting in disease


HLA B27 and Seronegative Spondyloarthropathies

HLA-B27 and Ankylosing Spondylitis (AS):
-Normal Caucasians: 6-9% are HLA-B27 +
-Not diagnostic for the disease
-Incidence of AS: 0.1% - 0.2%
-Caucasians with AS: 90% HLA-B27 +

Chance of developing AS:
-2% if HLA-B27 positive (risk of developing)
-20% if HLA-B27 positive with a first-degree relative with AS

Concordance rate in identical twins: 60%

HLA-B27: 40% of the genetic risk; at least 9 other genes involved


axial arthropathy and seroneg spondylo in rats

HLA-B27/2 microglobulin transgenic rats:
-Develop a HLA-B27-like axial arthropathy:
-Peripheral and vertebral joint involvement
-Skin, nail, and genital tract involvement
-GI tract inflammation
-Heart involvement

Disease manifestations don’t develop if the rats are raised in sterile environments


reactive arthritis

History of infectious diarrhea or urethritis
-Particularly chlamydia

Asymmetric, oligoarticular, lower ext arthritis

Dactylitis (20-50%)
-Inflammation of the digits-sausage digits

Bacterial environmental triggers transported to the joints inside monocytes (Chlamydia can be latent):
-Molecular mimicry (B27 epitope looks like actual bacteria, if make response against bacteria, respond to B27)
-Arthritogenic peptide hypothesis: unique presentation of processed peptide by HLA-B27
-HLA-B27 heavy chain theory: NK cell activation
-Express on surface without N2 globulin, triggers NK
-Unfolded protein hypothesis: ER stress response
-Th2 (IL-4, IL-10) response: ? bacterial persistence
-Might permit more of bacterial persistance that drives inflammatory response

Reiter’s syndrome: clinical triad of conjunctivitis, urethritis, arthritis
Can’t see, can’t pee, can’t climb a tree


Systemic Lupus Erythematosus (SLE)

A chronic, systemic autoimmune disease which affects multiple organ systems including the skin, joints, serosal surfaces, lungs, kidneys, CNS, and hematologic system (bone marrow)

Fundamental defect is the misdirected recognition of self as foreign, resulting in an autoimmune process; T cell and B cell process

Antibody responses toward autoantigens are antigen-driven and require CD4+ T cells
-We make selective autoantigens in lupus-not pan B cell problem

Loss of T cell tolerance permitting autoreactive B cell stimulation: ? central or peripheral abnormality in self-reactive lymphocyte deletion or anergy
-we don’t deplete auto reactive T cells in periphery, results in self reactive lymphocytes that stimulate B cells to make IgG autoantibodies


SLE genetics and environment

Genetics (polygenic):
-increased incidence of SLE among relatives (RR 2-3 fold increase)
-Concordance rate in monozygotic twins: 35%
-Association with HLA-DR3 and C4A null allele (greatest risk, most significant)
-More common in certain ethnic groups: African Americans, Asians, and Hispanic Americans

-Sex hormones: female to male ratio 9:1; increased incidence in women of childbearing age; NZB/NZW murine lupus model (mouse)
-Sun exposure: exacerbates systemic disease
Keratinocytes take hit, place snRNA on surface which stimulates Lupus


Antinuclear Antibodies (ANA)

Hallmark of abnormal antibody production in SLE

SLE: > 95% patients have + ANAs

Not specific for SLE: can occur in other CTDs

Antibodies are directed to multiple nuclear antigens:
-Anti-dsDNA antibodies: renal disease (actor)
-Anti-histone antibodies: SLE and drug-induced lupus (marker)
-Antibodies to non-DNA, non-histone nuclear antigens: (marker). SSA, SSB, Smith, Ribonuclear protein (RNP)


SLE Type 2 vs Type 3

Specific antibody-mediated disease (Type II):
-Anti-RBC antibodies (hemolytic anemia)
-Anti-WBC antibodies, anti-Plt antibodies
-Anti-phospholipid antibodies: block prothrombin activation in the clotting cascade; associated with increased clotting; ? neutralize anticoagulant effect of 2 GP1; do not cause a vasculitis
-LUPUS ANTICOAGULANT, gives you elevated PTT

Immune complex-mediated disease (Type III):
-Anti-dsDNA-DNA immune complexes
-Goes to the glomerulus
-Glomerulonephritis (lumpy-bumpy IF)



Inflammation within or through the vessel wall resulting in damage to vessel integrity/flow

-Varying degree of infiltrating lymphs, monocytes, histiocytes, eosinophils, and PMNs
-Granulomas and/or giant cells in vessel wall in some types of vasculitis
-Fibrinoid necrosis of vessel wall secondary to immune complex deposition
-Focal and segmental nature of vascular lesions common to all types of vasculitis
-Doesn’t involve whole vessel uniformally


vasculitis pathophys and sources of immune complexes

-Immune complexes: inflamm→ PAFs→ ↑vascular permeability→ IC deposition; palpable purpura
-Whatever generates immune complex first generates inflammation
-Antineutrophil Cytoplasmic Antibodies (ANCAs)
-Anti-endothelial antibodies (Don’t see in all forms)
-T cell dependent-mediated endothelial cell injury: (HLA-DR4 and giant cell arteritis; suggests antigen-driven vascular inflammation)
-Particularly giant cell since most are HLADR4 positive
-Not the shared epitope, different epitope than RA (2nd epitope)
-Infection of vascular endothelial cells

Sources of antigen for immune complexes:
-Bugs: infectious agents
-Connective tissue disease: autoimmune process


ANCA Vasculitis

Antineutrophil Cytoplasmic Antibodies (ANCAs):

Cytoplasmic ANCA (c-ANCA, cytoplasm stains):
-Proteinase-3 (PR3) in primary granules of PMNs
-Associated with generalized GPA (Wegener’s)

Perinuclear ANCA (p-ANCA, periphery of nucleus):
-Myeloperoxidase (MPO) in primary granules of PMNs
-Associated with microscopic polyangiitis (MPA)

Likely play a role in amplifying the inflammatory vascular response
-Don’t cause the vascular response


Polymyositis / Dermatomyositis (PM/DM)

Inflammatory myopathies are characterized by:
-Muscle weakness (proximal) and low endurance
-Usually idiopathic but may occur in association with neoplastic diseases (connective tissue disease) or in “overlap” with CTDs

DM presents with typical skin rashes:
Gottron’s papules
Heliotrope rash
V-sign and shawl-sign
Mechanic’s hands
Periungual changes/erythema


Anti-synthetase Syndrome**

PM or DM presenting with:
-Interstitial lung disease (ILD): 60%. Most common and critical/worst prognosis finding
-Fever: 20%
-Arthritis: 50%
-Mechanic’s hands: 30%
-Raynaud’s phenomenon: 40%

Anti-synthetase antibodies:
-Anti-aminoacyl-tRNA synthetases (cytoplasm)
-Anti-Jo-1 = due to anti-histadyl-tRNA synthetase
-Not pathologic or myotoxic antibodies



Endomysial distribution of inflammatory cells (CD8+ T cells) surrounding and invading muscle fibers; resultant muscle injury
Cytotoxic response



Perivascular (CD4+ T cells) and perifascicular inflammatory infiltrate; complement-mediated vasculopathy
around muscle fiber itself, around blood vessel. Complement mediated


Polymyositis / Dermatomyositis viral etiology

Evidence suggesting a viral etiology:
-Influenza and HIV can cause a myositis
-Viral particles by EM and viral RNA detected in muscle from PM/DM patients. NO live virus has been cultured from muscle
-Juvenile DM:  antibodies to coxsackie B
-Seasonal pattern (anti-synthetase syndrome): anti-Jo-1 antibodies and spring
-DM: microarray mRNA profiling with predominance of interferon-responsive pathways suggesting an anti-viral response