BL 02-18-14 8-9AM RHEUM COURSE OVERVIEW-Janson_Hirsh Flashcards
Arthritis
= inflammation in joints
= pain, swelling, redness, or heat
- Over time, inflammation can lead to deformity
Arthralgia
= joint hurts but no evidence of inflammation
= may represent early forms of arthritis not yet detectable by exam or may be due to a viral syndrome or other causes
Periarticular pain
= When pain actually NOT due to pain in a joint
= Instead, pain arises from structures around the joint such as tendons or bursae
Distinguished from true arthritis by:
- lack of effusion
- often point tenderness over immediate area of inflammation
- pain worse w/ active compared to passive motion
Soft Tissue pain
= Pain which may be perceived as arising from the joint, but which actually arises elsewhere (in muscle, adjacent nerves, or referred)
ARTHRITIS - joint swelling, signs of inflammation, & ROM
Joint swelling can be esp. helpful in determining if pt has arthritis:
- Joint = potential space
- S, swelling can present as a joint effusion (important objective finding)
- Cool swelling in non-inflammatory disease (OA)
- Joints are usually not red, unless infected or involving crystals
- B/c problem is in joint itself, both passive & active motion causes pain
Monoarticular Arthritis
= involvies only one joint
a. Infections, crystal-induced arthritis, or trauma.
b. –> aspirate to rule out infection
c. Untreated septic joint can destroy joint in 6 days
Oligoarticular Arthritis
= in several joints (2-4)
a. Axial arthropathies (ankylosing spondylitis, psoriatic arthritis, or reactive arthritis)
b. Often asymmetrical
c. Often involves large joints (but not invariably)
Polyarticular Arthritis
= Involves multiple joints, often symmetrically
a. Usually affects both small & large joints
b. RA, SLE, certain viral syndromes
Types of Joints:
A. Synarthrosis = interlocked bones (skull)
B. Amphiarthrosis = bones joined by fibrocartilage (rib cage w/costal cartilage)
C. Diarthrosis = synovial joint
Types of Diarthosis joints (based on movement / axes)
(1) Uniaxial or hinge joints (one plane of movement)
- – EX: elbow, knee
(2) Polyaxial joints (multiple axes of movement)
- – EX: ball & socket joint of shoulder
Ligaments
= bundles of parallel Type I collagen connecting bone to bone
—> prevent inappropriate motion (passive restraints)
*Hinge joints are commonly bordered by collateral ligaments to limit flexion & extension of the joint
Tendons
= resemble ligaments but connect muscle to bone
–> active drivers of joint motion (while ligaments are passive restraints)
Entheses
= where ligaments & tendons insert into bone
- Metabolically active (different from tendon or bone)
Important in seronegative spondyloarthropathies
- – can inflame, erode, & eventually calcify
- –> “enthesopathic type” arthritis
Bursae
= synovial lined sacs w/ dense regular CT support
a. Designed to slide & cushion tissues that are less forgiving during movement
b. Contains lubricating film of synovial fluid
c. Btwn tendon & bone, ligament, or tendon
Diarthrosis
= aka synovial joint The bone... - articulartes - is cushioned by hyaline cartilage - is stabilized by ligaments - is actively moved by muscles & tendons - is nourished & lubricated by synovial tissues
Ankylosis
Disease process causes fibrous or bony union across joint leading to fixation of joint
Axial Arthropathy
Arthritis involving the spine.
Sacroiliitis
Inflammation of sacroiliac joint
Syndesmophyte
Calcification of ligament/tendon at site of bony insertion
Synchondrosis
= Union btwn 2 bones formed by cartilage Examples: - Pubic symphysis - Manubriosternal joints - Costosternal joints
Internal Structure of a Diarthrodial Joint
- Bone’s articular surface covered by hyaline cartilage
- Synovium
- Subchondral bone
Hyaline cartilage - overview
- covers articular structures of bone in diarthrodial joints
- firm & resilient & dynamic
- turgid gel (water + collagen + proteoglycans)
- Contains no vessels or nerves
- Gets nutrients from synovium via synovial fluid
Composition of Hyaline cartilage
Water (major component of cartilage)
Collagen (esp. Type II), an extremely strong protein
Proteoglycans (esp. chondroitin sulfate & keratin sulfate)
- – hooked by link proteins to hyaluronic acid
- – high density of fixed negative charge —> coiled spring —> gives cartilage its elastic properties
Embedded in the hyaline cartilage are…
Chondrocytes
–> produce both collagen & proteoglycans
Enzymes —> can digest these structures
Synovium
= thin layer of cells + capsule that covers all intra-articular surfaces other than articular areas of cartilage
Spondylitis
Inflammation of one or more vertebrae of the spine
Synovium - 2 cell types
Synovial cells are divided morphologically into 2 types:
- Type A cells = macrophage-like (w/HLA-DR) & derived from bone marrow
- Type B cells = fibroblast-like
Osteophyte
A bony outgrowth of bone
Pannus (and RA)
- When synovium becomes diffusely inflamed & thickened, as in RA
- Early erosions in RA occur where synovium inserts into bone b/c pannus slowly destroys bone
Subchondral bone (and arthritis: osteo- vs inflammatory)
= Area under cartilage
In OA, commonly dense or sclerotic
In inflammatory arthritis, inflammation/increased blood flow to this area
—> periarticular bone becomes less dense (osteopenic)
Synovium composition
Well-ordered matrix of microfibrils & proteoglycan aggregates with synovial cells
Arthritis: Diseases which characteristically present as Polyarticular Diseases
- rheumatoid arthritis
- systemic lupus erythematosus (SLE)
- Psoriatic arthritis
- reactive arthritis
- hepatitis B
Synovitis
= Inflammation of synovium
—> can lead to pannus
Symmetric Joint Distribution - Diseases
- rheumatoid arthritis
- systemic lupus erythematosus
Asymmetric Joint Distribution - Diseases
- osteoarthritis
- gout
- spondyloarthropathies
Arthritis: Diseases which characteristically present as Monoarticular Diseases
- septic arthritis
- gout
- pseudogout
- traumatic arthritis
- mechanical derangement of joint
- osteochondritis dissecans
Small Joint Distribution - Diseases
- rheumatoid arthritis
- systemic lupus erythematosus
Joints involved in Osteoarthritis
- Distal interphalangeal joints (DIP)
- Proximal interphalangeal joints (PIP)
- 1st carpometacarpal joint (CMC)
- Cervical & Lumbosacral spine
- Hips
- Knees
- 1st metatarsophalangeal joint (MTP)
Migratory Joint Distribution - Diseases
- rheumatic fever
- disseminated gonococcemia
Arthritis: Polyarticular Diseases which characteristically present as Monoarticular Diseases
- Juvenile rheumatoid arthritis
- Reactive arthritis
- Sarcoid arthritis
- Psoriatic arthritis
- Pseudogout
Large Joint Distribution - Diseases
axial arthropathies
Additive Joint Distribution - Diseases
- rheumatoid arthritis
- axial arthropathies
Arthritis - Rapidity of Onset
- Hours - septic joints & crystal diseases (gout & pseudogout)
- Days - most chronic inflammatory diseases
Response to rest and activity in Arthritis
Worse with rest or in the morning:
- rheumatoid arthritis
- axial arthropathies.
Worse with use:
- osteoarthritis
Arthritis: Presentation at a young age
- Rheumatoid arthritis
- Axial arthropathies
- SLE
Family Hx & Rheumatoid Arthritis
HLAS-DR4
Family Hx & Axial Arthropathies
HLA-B27
Family Hx & Systemic Lupus Erythematosus
HLA-DR2
HLA-DR3
C4A null allele
Degenerative Joint Disease (Osteoarthritis, OA)
= cartilage-based process (primary abnormality)
- Mostly affects big weight bearing joints, mostly
Articular cartilage loses its homogeneous nature
- –> disrupted / fragmented with pitting, clefts, & ulcerations
- -> uneven histochemical stain for proteoglycans in cartilage
- -> w/ advanced disease, no cartilage remains & bare areas seen of exposed underlying bone
Biochemical changes in Osteoarthritis
- ↑ Water content of articular cartilage
- Smaller than normal small Type II collagen fibers
- Normally tight weave of collagen in mid-zone is slackened & distorted
- Sharply diminished [Proteoglycan] - 50% or less
- Less & less aggrecans present
- Shorter & shorter glycosaminoglycan chains
- Increased Type I collagen in cartilage covering osteophytes
Metabolic changes in Osteoarthritis
Great increase of synthesis & secretion of matrix-degrading enzymes by the chondrocyte
= mainly acid & neutral proteases, esp. neutral metalloproteinases
—> Able to degrade all components of ECM
Arthritis: Presentation in elderly
- gout
- polymyalgia rheumatica
- pseudogout
Etiologic factors in Osteoarthritis
- greatly increases w/age
May be caused by
- significant trauma in which joint is excessively incongruent (ex: hip disolcation)
- unstable joint
- impulsive loading over a lifetime
- inflammatory arthritis (its end stage)
- obesity
- hereditary forms
Clinically in OA…
NO systemic symptoms like morning stiffness, easy gelling (stiff w/sitting), unusual evening fatigue
Asymmetric joint involvement & cartilage loss
- ex: hip loses cartilage more superiorly than medially
- ex: knee more medially than laterally
- Mild inflammation may occur, but secondary to loss of cartilage & typically later in disease course
Non-inflammatory diseases causing secondary OA
- Avascular necrosis
- Fibromyalgia
Arthritis: Presentation in Males
- gout
- axial arthropathies
- hemochromatosis
Arthritis: Presentation in Females
- rheumatoid arthritis
- scleroderma
- systemic lupus erythematosus
Metalloproteinases
- Collagenase
- Stromelysin
- Gelatinase
Theories for why Inflammation occurs in Joints in RA
- Abundant blood supply & rich capillary network
- – Immune complexes might concentrate in synovium based on physical properties of vessels - Joint has no epithelial tissue (different than other body spaces)
- Synovial lining is discontinuous w/occasional gaps & lacks formal basement membrane
- Joint contains some unique cell types such as synoviocytes & chondrocytes that could be targeted as privileged antigens
Gross pathology of synovium in RA
- Proliferation in pattern of villus fronds (proliferate like fern branches from common stalk to maintain contact w/synovial fluid)
- Rheumatoid knee may have synovium that weighs 10x a normal synovium
Synovium in RA
- absolute ↑ in both Type A & Type B synovial cells
- diverse lymphocytes (B & T), NK cells, & mast cells —> cytokines, serine proteases, histamine, rheumatoid factors
- PGs, metalloproteases, oxygen radicals (superoxide), activated complement in synovial fluid
- pannus —> invades & destroys adjacent cartilages / bone
Inflammatory joint diseases - symptoms / distribution
Systemic symptoms such as
- morning stiffness > 1 hr
- easy gelling
- unusual fatigue in afternoon & evening
Joint involvement can be
- symmetric (RA)
- asymmetric (axial arthropathies, septic joints)
Cartilage lost in symmetric pattern
Typically has one or more signs of inflammation
Metabolic joint disease - Types
- gout (monosodium urate disease)
- pseudogout (calcium pyrophosphate dihydrate disease)
- hydroxyapatite deposition disease (basic calcium phosphate deposition disease)
Metabolic joint disease - process
- Metabolic process causes crystals to form & deposit in joints
- –> intermittent signs of inflammation
- –> systemic symptoms
- –> bone erosions w/out cartilage loss
Gout
- occurs after prolonged period of supersaturation of monosodium urate in serum & synovial fluid
- Complex mechanism whereby crystals ppt in joints & induce inflammation
- Episodic & very painful arthritis w/ swelling, redness, warmth
- Often in lower extremities
- May form tophi (crystalline deposits of uric acid in cartilage, joints, skin)
Regulation of urate crystal formation in Gout
i. lower intraarticular temp
ii. presence of proteoglycans
iii. changes in pH
iv. reduced binding of urate to plasma protein
v. trauma
vi. aging
vii. connective tissue turnover
Acute inflammatory response to crystals in Gout
- Not fully understood
- High level of uric acid, supersaturation & inflammatory response to crystals
- Neutrophils appear necessary to invoke response
Synovium in acute gout
- can have clumps of crystals (tophus-like deposits) in synovium, neutrophil infiltration & some lymphocytes
- In chronic disease, large number of lymphocytes & plasma cells are seen
Inflammatory Joint Diseases
Rheumatoid Arthritis
Axial Arthropathies
Septic Joints
Site of Inflammation in Inflammatory Joint Diseases
Inflammation primarily in synovium —> secondary destruction of cartilage & bone
Rheumatoid arthritis (RA)
= classic example of an inflammatory arthritis
- Can involve variety of major organ systems, but primarily a disease of the joints
- Primarily small joints
Acute-phase response (APR)
- a large number of systemic & metabolic changes that occur with inflammation
- may represent early defensive mechanisms or adaptations to stress of inflammatory stimulus
- participants in innate immune response
- can measure via ESR or CRP
Cytokines stimulate liver to produce acute phase proteins (w/ consequence of decreased albumin production)
Spondyloarthropathies - types
Ankylosing spondylitis
Reactive arthritis
Psoriatic arthritis
Inflammatory bowel disease arthropathy
C-Reactive Protein (CRP)
= pentameric protein that behaves as primitive Ig
- -> can activate classic complement pathway & bind to Fcγ receptor
- Rapidly rises 2-3 days after acute inflammatory stimulus
Antinuclear Antibodies (ANA)
- AutoAbs against cell nuclear antigens (commonly against DNA & small nuclear ribonucleoproteins - snRNPs)
- Associated w/ SLE & others like it
Fluorescent antinuclear antibody tests
- to measure for antinuclear antibodies
- also pick up cytoplasmic antigens
- NONSPECIFIC - just tells pt is making autoAbs to nuclear components
ANA profile (specific autoantigen tests)
Measures more specific cellular Abs
- Originally used immunodiffusion assay
- Includes Smith (Sm), nuclear ribonucleoprotein (snRNP), Ro/Sjogrens Syndrome Antigen (SS-A), La/SS-B, & anti-double stranded DNA (anti-ds-DNA)
More useful b/c can find specific antigens more characteristic of some diseases
EX: anti-Sm & anti-ds-DNA are relatively specific for SLE
Organ specific autoimmunity
- Immune response directed against single autoantigen or restricted group of autoantigens
- –> destruction of specific organ or cell type
- EX: Thrombocytopenia <— autoAbs to platelets
- EXs: Myasthenia gravis, Type I diabetes, Pernicious anemia, Addison’s disease, & Autoimmune thyroid disease
Spondyloarthropathies - manifestations
Spinal arthritis & enthesitis
Inflammatory low back pain
- insidious onset (months)
- prolonged morning stiffness
- pain improves w/ exercise
- no neurologic sequelae
Organ damage in SLE
Organ damage can come about by both:
- Organ specific (type II)-mediated immunologic damage (direct Ab binding to specific cells /tissues)
OR
- Systemic autoimmunity (type III) - mediated immunologic damage (immune complexes)
Systemic lupus erythematosus (SLE)
= classic autoimmune disease affecting multiple organ systems
Categories of Vasculitis
- Large vessel vasculitis affecting aorta (giant cell (or temporal) arteritis & Takayasu’s arteritis)
- Medium vessel vasculitis (polyarteritis nodosa & Kawasaki’s disease)
- Small vessel vasculitis (granulomatosis w/ polyangiitis (GPA; formerly known as Wegener’s) & in leukocytoclastic vasculitis)
Erythrocyte Sedimentation Rate (ESR)
= most widely used measure of an APR (acute phase rxn)
Process:
- Anticoagulated blood in vertical tube –> measure rate of fall of RBCs (usually over 1 hr)
- increased acute phase proteins —> increased aggregation of RBCs (rouleaux) —> fall more rapidly
“Pauci-immune” mechanism for vasculitis
<–Abs to cytoplasmic Ags found in neutrophils (antineutrophil cytoplasmic antibodies (ANCA))
- ANCAs may be directly involved in pathogenesis of pauci-immune types of vasculitis
Defined by immunofluorescent staining of ANCAs
- Cytoplasmic staining (C-ANCA) binds to proteinase 3 (PR3) & is commonly seen in GPA
- Perinuclear staining (P-ANCA) binds to myeloperoxidase (MPO) & is seen in microscopic polyangiitis and other diseases
Systemic autoimmunity
- Immune response against multiple autoantigens or antigens seen in most cells & not to a specific organ or cell type
- –> affects multiple organs due to circulating immune complexes or direct immune attack
- Seen classically in SLE
Inheritance of MHC genes
Inherited co-dominantly:
- Receive 1 allele at each locus from each parent
- Located on short arm of chromosome 6
Vasculitis
- Heterogenous group of diseases usually categorized by size of vessels involved
2 most common immune mechanisms to explain cause of vasculitis
- Immune complexes
2. “Pauci-immune” mechanism associated w/ antineutrophil cytoplasmic antibodies (ANCA)
Class II region of MHC locus
Has HLA-DR, DP, & DQ gene loci
= only expressed in B-cells, DCs, macrophages, and thymic epithelium
= primarily involved in presentation of “exogenous” extracellular antigens (bacterial, fungi, other)
Major Histocompatibility Complex (MHC) (Human Leukocyte Antigen [HLA] System)
= thought to be important hereditary component to predisposition of an autoimmune disease
= set of closely-linked genes whose products regulate recognition of foreign antigens by T cells
Contents of MHC locus
Contains 3 major immunologically-important regions
- Class I region (~universal, endogenous Ags)
- Class II region (restricted to APC, exogenous Ags)
- Class III region (complement, TNF, etc.)
Many autoimmune diseases are associated w/a particular MHC Class I or II allele
Class I region of MHC locus
Has HLA A, B, C, & other gene loci
= expressed on all nucleated cells
= thought to be involved in presentation of “endogenous” cytoplasmic antigens (viral, tumor, etc)
Class III region of MHC locus
Has gene locus for…
- various components of complement (C4a, C4b, C2, Bf)
- tumor necrosis factor
- other proteins
