Rheumatology/disorders

the study of arthritis and allied conditions including connective tissue disease and other inflammatory, degenerative & metabolic disorders of the musculoskeletal system

It describes a type of inflammatory response at a joint level

One of the most prevalent diseases
Rate is greater for women than men
Fl has highest incidence
Risk factors- age, overweight
Kills few, but major impact on daily life of patient, debilitating.

Bones and joints
-3 types of joints
a. Synarthroidial or fibrous- little or no movement ex. skull bones, lack a joint cavity
b.Cartilaginous or amphiarthroisis-bones joined by cartilage ex. intervertebral disk
c. Synovia or diarthrodial- most freq. affected by rheumatoid diseases. Freely movable joint

Joint capsule lined by synovial tissue (synovium)
There is no blood or nerve supply to the articulation cartilage, but there is a good blood supply to the synovial membrane. No pain fibers but it is innervated by autonomic fibers.
Synovium is made up of 2 layers
1) Subintimal-vascular, has mast cells and macrophages
2) Intimal- has A cells that remove bacteria and B cells that secrete hyaluronic acid

Produces synovial fluid which creates a cushion btwn bones and provides material for the articulating cartilage to survive

-Clear, Straw colored
-Thick- viscosity 50-200 X water
-Thickness is due to hyaluronic acid which provides lubrication and nutrients
and has a consistency of egg whites.
- Lubricates joints and reduces friction
-Provides a source of nutrients for articulating cartilage
-WBC<200 cells/mm3

Acetic acid is added to synovial fluid. Forms a ppt with hyaluronic acid. A poorer clot is formed with more inflammation since hyaluronic acid is reduced by lysosomal action
-Color of the fluid become more cloudier with an increase in inflammation

Covers surface of bone, constantly being rebuilt and destoryed. Layer of hyaline cartilage that covers and protects the ends of each bone. Cartilage is not static. It undergoes turnover. This degradation and formation is controlled by chrondrocytes. Reduces friction in joint and distributes forces.
It is composed of -Chondrocytes
-collagen -proteoglycans -proteins -water.
Has a property of resiliency

Cartilage may wear down, and it had no blood supply in an adult. Body changes with age. Joint inflammation can result. Caused by an increase in synovial fluid-overproduction. Vascular phases of inflammation takes place in synovium called Rheumatoid arthritis.

Involves immune system components, plasma factors and other molecular mediators. Exudative inflammation predominates followed by degeneration (liposomal products causes this)
Can get extensive formation of granulation tissue that my become fibrous- little movement

2 categories
1) Non-inflammatory joint disease
Reduced or absent synovial membrane inflammation
Lack of systemic signs and symptoms
Near normal synovial fluid.

2) Inflammatory joint disease

Most prevalent Non.Inflammatory disease is Degeneration Joint disease (osteoarthritis)

# 1 form of arthritis
Degeneration and loss of articulating cartilage in synovial joints. Prevalence with increase age and weight. Subdivided into
1) Primary (idiopathic)
Not associated with known risk factors,most common, aging is most common factor

2) Secondary- associated with risk factors, joint stress and trauma

Pathophysiology of DJD
articulating cartilage loss, and it becomes a yellowish gray. Has more water and less proteoglycans. Early---> cartilage loses its glistening appearance
then surface areas start to flake off. Decrease in synthesis and increase in breakdown of collagen. Eventually bone is left unprotected.
Bone becomes hard and dense (scierotic). Cysts may develope in bone due to synovial fluid leaking in.
Osteophyte-bone spurs- can grow out of margins of joint and break off irritating the synovium.
The cartilage is lost through enzymatic breakdown. Cytokines (IL) which produce and release proteases that are destructive thus chondrocytes less able to produce new collagen and proteoglycans. Loss of proteoglycans are the hallmark of osteoarthritic process.
Summary-1-erosin of articulation cartilage
2- sclerosis of bone underneath cartilage
3- formation of bone spurs (osteophytes)

Pain in 1 more more joints relieve by rest, appear in 5 + 6 decades of life. Changes to cartilage but asymptomatic. Stiffness or enlargement. No systemic symptoms because synovial fluid is free of inflammation. Diagnosis is based on exclusion-see cystic bone changes.

Commonly termed arthritis and characterized by inflammatory damage or destruction of synovial membrane, articulation cartilage and by systemic signs of inflammation

2nd most common form or arthritis. It is a chronic systemic autoimmune disease. The most common manifestation is joint involvement. Most likely Rheumatoid arthritis is a heterogeneous group of disorders in which inflammation of multiple joints is a major manifestation

Have fibrinoid necrosis of collagen. It is characterized by joint deformities and disabilities. Occurs more freq in women. Onset may be insidious (slow) or may be acute (fast). RA occasionally goes into remission spontaneously or in response to treatment.

No single agent responsible. Combination of genetics and environment. Diff stimuli is responsible for triggering the condition in individuals with specific immunological susceptibility. HLA- system-determines how your immune system works.
In RA it appears that an immune response is initiated by an antigen.
Some possible sources are
1) Esptein-barr virus
2)Parvovirus infection
3) Bacteria and mycoplasms

Due to some aberrant immune response to an unidentified anitgen
---> activate helper T cells, release cytokines. Eventually get antibody formed to react with fragment of normal antibodies. These transformed autoantibodies (IgG, and IgM and some IgA) are termed Rheumatoid factors-form immune complexes (abnormal-work against body).
These Rheumatoid factors bind and form complexes in the blood and synovial membrane (type III injury). Have a continual production of antigenic material that chronically stimulate the immune response. Anti-collagen antibodies also have been demonstrated in synovial fluid of patients with R.A.

2 aspects of synovial inflammation
1) Synovial fluid- bathes articulate cartilage- comprised of PMN's that phagocytize immune complexes and release many mediators. (RF is in constant supply)
2) Synovial membrane- perivascular infiltration with mononuclear and a striking accumulation of new blood vessels (angiogenesis)- becomes engorged. Eventually transforms into a granulation tissue (pannus) that covers articulating cartilage . This tissue is rich in inflammatory cells that secrete enzymes and various mediators of inflammation to destroy bone and cartilage. This leads to joint instability and muscle atrophy (muscle wasting due to loss of mobility)

-monocytes/macrophages and fibroblasts release proteases and chemotactic factors that eat at the bone
-Hypoxia from diminished blood flow (loss of functional synovial membrane-vascularity decreased as granulation tissue and fibrous develop (pannus). This causes acidosis, which stimulates release of hydrolytic enzymes-more damage
-heparin release from mast cells may also play role in bone resorption (eating away)

Leads to proliferative synovitis- serves as a chemotactic force.
The PMN's lead to aggregation degranulation and superoxide anion generation
Numerous inflammatory pathways activated- Hageman factor, Kinins complement.

Environment & genetics---> immune response---> transformation of antibody to RF---> two things happening 1)Inflammatory response to immune complex--->PMN, monocytes,complement, lympocytes congregate---> Phagocytosis of immune complex--->release of lysosomal enzymes and PG---> additional lymphocytes and plasma cell attract causes positive feedback and 2) angiogenesis in synovium which increases synovial cell proliferation---> pannus-invasion develops into granulation tissue on synovial membrae- causes cartilage and bone destruction

Systemic disease- fatigue, anorexia, fever.
Symmetrical polyarthritis- if in left wrist will be in right ( not like osteoarthritis which could occur in just one joint)
Deformity can result- joints may become ankylosed-fusion on bone-loss of mobility. Can also have muscular atrophy

Has a lot of extra-articular disease
such as rheumatoid nodules-granulomas- contains many RH factors in middle. Tissue is inflammation and can become fibrotic---> could lead to organ failure/scarring.

-Check immune complexes
- RF factor helpful test-although not always positive-ppl get older it increases
- Anemia- altered bone formation
-Elevated ESR
- Synovial fluid viscosity-lower since there are more leukocytes, decrease in hyaluronic acid
- Radiological features-narrower joint
- need 4/7 diagnostic criteria for > 6 weeks.

R.A.- Joint involvment is symmetic
O- symmetric or asymmetric
R.A.- Morning stiffness>30 min
O- <30 min
R.A.- Osteophyte is absent
O- Present
R.A.- Pannus?--- present
O- absent
R.A.- RF?----positive
O- negative
R.A.- subcutaneous nodules? freq present
O- absent
R.A.- Swelling- diffuse, symmetric
O- Irregular, knobby
R.A.- typical presentation- malaise, fatigue, musculoskeletal pain
O- deep aching, pain in joint
R.A.- systemic manifestations? Yes
O- usually not

3rd most freq in U.S.--> higher in men.
-Associated with hyperuricemia-eventual uric acid deposits.
Source of uric acid?
-Food containing purines, synthesis of purine nucleotides and breakdown of nucleic acids.
This uric acid is eliminated by kidneys and GI.

1)Primary- due to the overproduction of uric acid (95%)inherent defect in purine metabolism and some enzymes defects.(mostly men)
2) Secondary process (5%) develop as consequence of an acquired or associated disorder or the use of drugs. (both men and women).

Sometime classified as metabolic (making too much) or renal (not excreting it)-this is the cause of hyperuricemia

1) Patients that lack enzyme HGPRT- x-linked recessive (men) Overproduction of uric acid
2) Increased activity of PRPP synthestase (x-linked) Overproduction of purine pathway hence increase of uric acid
3) Deficiency in Glucose-6- Phosphatase (autosomal recessive disorder) decreased uric acid clearance. Overproduction and under secretion - fasting could cause a gout attack because when you fast it uses up the glucose 6-phosphatase

-Decrease uric acid clearance (contributes in 75-85% of patients with gout).
- Increase in uric acid in plasma and body fluids. men>7 mg%, women > 6mg%- can see 9 to 10 mg% in gout.

Normal- men 5 +/- 1 % and women 4 +/- 1 mg%

Only 5% with hyperuricemia develop gout. Supersaturation result in uric acid precipitation out---> caused by lower pH, lower temp of synovial fluid.

Crystallization and deposition or uric acid crystals. These crystals activate Hageman factor. PMN's causes a more severe problem because they cause a lowering of the pH when they use energy for phagocytosis.

1) Asymptomactic Hyperuricemia- no symptoms- levels 9-10 mg%
2) Acute gouty arthritis- crystals form. Seen in single joint usually and occurs at night (big toe)- attack lasts for several hrs to weeks and is self-limiting. May be brought on to trauma, drugs and or alcohol.
3) Intracritical gout- no symptoms . can be long or short period. If untreated, attacks increase in freq and severity
4) Chronic Tophaceous Gout- Chronic soreness and aching of affected joints, eventually leads to grotesque deformities. More systemic affects. Have the formation of granulomas called tophi. Deposit of urate crystals surrounded by granuloma (macrophages and giant cells)

You may never get to the 4th stage

Get urate or uric acid nephropathy- a result of deposition of the urate salt crystals in renal interstitium and collecting tubules and results in inflammation (Hypertension is common). This may result in acute renal failure and death. Renal stones are much more prevalent.

- 75% patients are overweight
-Hematological disorders
- Lead poisoning
- Starvation
- Hypertension
-Diabetes
-Drugs that block uric acid excretions: diuretics, nicotinic acid, levodopa.
-Strong correlation of alcohol use- decreases renal excretion of urate, increases catabolism of purine nucleotides, "moonshine" causes tubular damage, beer contains large quantities of guanosine-catabolized to uric acid.
- A diet high in purines- organ meats-liver, brain, sardines.

Patients must fulfill one of the following 3 criteria.
1) Presence of monosodium urate crystals in leukocytes (neutrophils) found in the synovial fluid obtained from inflamed joints
2) Demonstration of urate crystals in biopsy or aspirate of tophi
3) Use combination of the following
- presence of hyperuricemia
- response of synovitis following colchicine administration
- history of monoarticulate arthritis followed by time with no symtoms

-Lifetime commitment to therapy is usually required.
- Drugs for acute attack (pain) are diff. from those drugs used to normalize serum uric acid.
-Education is important b/c compliance is low