B105 Degenererative and inflammatory joint disease

Question 1

What are the (primary) degenerative and inflammatory joint diseases

Answer 1

Osteoarthritis

Gout

Pseudogout

Infetious arthritis

Question 2

Osteoarthritis, pathogenesis, types,

Answer 2

Aka, Degenerative Joint disease. Its name is a misnomer, and inflammation is not a major component.

Almost inevitable joint disease of aging, causes significant disability in people over 65 years.

Key feature is degeneration of the articular cartilage

Pathogenesis is primarily from chondrocytes responding to chronic mechanical and biologic stress and causing breakdown of the cartilage matrix.

Women’s knees and hands are more affected

Men’s hips are more affected

Types:

• Primary osteoarthritis. Of aging, no specific cause.
• Secondary osteoarthritis. Occurs in young people and caused by prior trauma, joint deformity, ochonochrosis of alkaptonuria, hemochromatosis, and marked obesity.

Question 3

Osteoarthritis, morphology and progression

Answer 3

First, Chondromalacia occurs, with cracking and fibrillation of the cartilage matrix. Some areas of cartilage are totally lost and bone is exposed. Friction on the bone smoothens it, a process called bone eburnation giving it a polished ivory appearance.

Small fractures occur, creating cysts filled with joint fluid and potentially loose bone bits in the joint, called joint mice.

Osteophytes, outgrowths of bone develop at the articular margins.

Synovial pannus occurs particularly at the periphery of the joint (where mechanical damage is the least), from proliferation and thickening of the synovium.

Pannus is an abnormal layer of fibrovascular tissue or granulation tissue. Pannus is composed of aggressive macrophage- and fibroblast-like mesenchymal cells, extracellular matrix, and vasculature.

Question 4

Osteoarthritis, presentation, symptoms, progression

Answer 4

Presents in elderly, or in patients with specific predisposing conditions: onchronosis, hemosiderosis, morbid obesity, trauma, or deformity

Symptoms:

• pain
• stiffness
• crepitus
• limited movement
• nerve compression, pain, muscle spasms and/or atrophy from the bony eburnations or pannus.
• Heberden’s nodes, seen in the distal interphalangeal joints are characteristic in women, and differ form the RA nodes that are typically in proximal interphalangeal joints.
• Also distinct from RA, there is no fusion of the joints.

There is unfortunately no treatment, and it is a slow progressing pathology of age.

Question 5

Gout, causes of congenital hyperuricemia

Answer 5

Congenital:

HPRT deficiency, Lesh Nyan syndrome, Hpoxanthine-guanine phosphoribosyl transferase.

• No purine salvage so there is excessive breakdown
• Excessive PRPP stimulates constant purine synthesis.
• hyperuricemia
• Mental retardation and self mutilation
• X linked, affects males. females can be affected but are just prone to hyperuricemia and spared the other symptoms (heterozygous)

Von Gierke’s disease

• G6Phosphatase
• Liver can’t perform glycogenolysis
• Liver can’t release glucose from gluconeogenesis (trapped in cells by phosphorylation)
• Causes trapping of phosphate, and buildup of AMP and ADP.
• AMP and ADP get degraded, causing hyperuricemia.

Fructose intolerance,

• aldolase B deficiency
• normally exogenous fructose is taken up by the liver and phosphorylated to F-1-P and cleaved by aldolase B.
• Deficiency causes phosphate trapping as aldolase A is much slower at cleaving this.
• F-1-P also inhibits:
• glycogen phosphorylase
• aldolase A
• F1-6-bisphosphatase
• Essentially F-1-P buildup halts gluconeogenesis glycogenolysis, inducing hypoglycemia.
• Phosphate trapping causes buildup of AMP, generating hyperuricemia.

Question 6

Causes of acquired hyperuricemia

Answer 6

Idiopathic, primary gout is the most common due to unknown cause of hyperuricemia.

Myeloproliferative disorders

Leukemia

Renal insufficiency and decreased excretion

Tumor lysis syndrome

Cytotoxic drugs - Thiazide

Obesity - unclear mechanism

Alcoholism - alcohol induces lactic acid in the kidneys, competes with uric acid (both weak acids) for excretion, causing uric acid buildup.

Diuretics - also weak acids and compete for uric acid exretion.

Question 7

Symptoms of hyperuricemia, gout.

Answer 7

Acute arthritis:

• Urate crystal deposition and neutrophil infiltration.
• Crystals show negative, yellow-blue birefringence.
• in both the synovium and synovial fluid.
• Synovium is edematous and congested.
• ‘Exquisite’ severe pain

Chronic tophaceous arthritis:

• repetitive bouts of urate deposition and inflammation.
• heavy deposits of urate crystals visible in the synovium.
• hyperplastic, fibrotic synovium
• pannus formation
• destruction of underlying cartilage
• bone erosions
• fibrosis
• ankylosis and fusion of bones
• joint immobility

Tophus formation:

• diagnostic, pathognomonic for gout.
• chalky white urate stones surrounded by inflmmatory cells and giant cells.
• most often in the joint cartilage of fingers and toes, but also sometimes in tendons.

Renal nephropathy:

• medullary tophi,
• intratubular precipitations and tubular obstruction, necrosis
• free uric acid crystals
• renal calculi.
• urinary obstruction
• pyelonephritis

Causes acut inflammation, swelling, and severe pain.

Prediliction to affect the metatarsophalangeal joint of the first toe.

Question 8

What is the molecular/signaling pathogenesis of gout inflammation

Answer 8

Hyperuricemia

Precipitation and deposition into synovium

Urate crystals can directly activate complement

C3a C5a stimulate inflammatory cell chemotaxis

The crystals are phagocytosed by macrophages and recognized by the intracellular
sensor called the inflammasome, which is activated and stimulates the production of the cytokine IL-1.

IL-1 strong pro-inflammatory signal.

inflammatory mediators and cytokines released

damage

Question 9

What is pseudogout?

What is its pathogenesis and progression?

Answer 9

Psuedogout = Chondrocalcinosis = calcium pyrophosphate crystal deposition disease

The cause is unclear, but is initiated by: calcium pyrophosphate crystals depositng into mensici of the knees, intervertebral discs, and synovial cartilage. It is likely related to impaired degradation or increased local overproduction of pyrophosphate. There is a rare familial, hereditary variant caused by mutated pyrophosphate transmembrane transporter, causing severe osteoarthritis very early in children.

These deposits are silent until they grow large enough, causing rupture of the cartilage inducing an inflammatory reaction.

The subsequent pathology is very similar to gout.

Occurs in people over 50 years, and is as high as 30-60% prevalence in patients over 85 years.

No gender or race associations.

There is no treatment, and therapy is supportive.

Question 10

Types of infecitous arthritis?

Infectious agents causing them?

Answer 10

Suppurative arthritis: bacterial

• Haemophilus influenzae in children younger than 2 years.
• S. aureus in older children and adults
• Gonococcus in sexually active women most often, especially with MAC complement deficiencies.
• Salmonella in sickle cell patients

Lyme arthritis: Bacterial spirochete Borrelia burdorferi

• Develops in 60-80% of lymes patients, in the late stage, stage 3 of the disease. often occuring along with encephalitis that can be mild or deadly.
• Migratory, remitting-relapsing polyarthritis of the large joints.
• Chronic, papillary synovitis
• Synoviocyte hyperplasia
• Fibrin deposition
• mononuclear cell infiltration
• onion-skin thickening of the arterial walls.
• Can resemble RA in severe cases.
• 10% of patients develop chronic arthritis with pannus formation and ankylosis.

Question 11

What are the sources of infecitous arthritis?

ie, how does the pathogen spread to the joint

Answer 11

Typically by hematogenous spread.

Less commonly, by spread from osteomyelitis, or by direct innoculation from trauma.