Joint inflammation begins with a trigger that activate the immune system response in the synovial tissue.

Synoviocytes Type A

• Responsible for clearing debris & pathogens in the joint space through phagocytosis.

Synoviocytes Type B

• Overproduction of hyaluronic acid leading to joint swelling, however the fluid becomes diluted & mixed with inflammatory exudates.

ii. Angiogenesis

• Type B secrete vascular endothelial growth factor (VEGF) promote new blood vessel in synovial membrane & increase vascular permeability.

iii. Hyperplasia of synovial lining

• Proliferating Type B form pannus, a thickened synovial membrane which contribute to enlargement of the joint capsule.

• It migrate into the synovial fluid & release :

- Reactive oxygen species

(ROS)

- Proteolytic enzymes (matrix

metalloproteinase)

ii. Macrophages

• Activated macrophage produce cytokines & enzymes that lead to tissue destruction.

iii. Lymphocytes

• In autoimmune arthritis, Th1 & Th17 release IFN-γ to active macrophages & IL-17 to enhance neutrophil recruitment & tissue destruction.

Inflammatory cytokines stimulate chondrocytes, leading to

• Increased production of matrix degrading enzymes that breakdown proteoglycans & collagen in cartilage.

• Loss of cartilage resilience & structure, impairing joint function.

  
  

ii. Bone erosion

• Osteoclast activation by RANKL (receptor activator nuclear factor-κB ligand), lead to resorption of bone (bone erosion & deformities).

• Prostaglandin (E2) is a mediator of pain in inflammation which it sensitize the nociceptors in the joint which it cause pain & swelling.

  
  

ii. Bradykinin & histamine

PGE2 also enhance bradykinin & histamine, leading to :

• Vasodilation of blood vessels at the site of inflammation, increase blood flow lead to redness (erythema) in inflamed tissue.

• Increase vascular permeability which it allow plasma protein & immune cell to leak to tissue contributing to edema & swelling.

• The pannus invades and destroys cartilage & bone leading to joint deformaties.

  
  

ii. Fibrosis

• Fibrosis replaces the healthy synovial tissue causing joint stiffness & loss of mobility.

  
  

iii. Ankylosis

• In severe cases, inflammatory and fibrotic changes which it characterized by the replacement of normal joint structures with fibrous connective tissue

• Release of pro-inflammatory cytokines (TNF-α, IL-1, IL-6) and eicosanoids (prostaglandins, leukotrienes).

• Recruitment of immune cells to the joint.

Secondary Causes: Dietary Intake, Alcohol Consumption, Metabolic Disorders, Kidney Dysfunction, Medications, Lead Poisoning, Hypertension, Postmenopausal State & Heart Failure

Pharmacological Treatment: Xanthine Oxidase Inhibitors, Uricosuric Agents, Uricase Enzyme Therapy & Anti-Inflammatory Agents

-Reduction of PG formation

-Inhibition of crystal phagocytosis by macrophages

Toxicity

NSAIDs -> renal damage (indomethacin -> bone marrow suppression)

2. Anti-gout agent -> colchicine

Inhibition of microtubule assembly in leukocyte -> Reduce production of leukotriene B4 -> Decrease free radical formation

At low doses, these agents may compete with uric acid for secretion by the tubule and occasionally can elevate serum uric acid con.

1. Probenecid

2. Sulfinpyrazone

Toxicity

May precipitate acute gout attacks during early phase of action -> administer with colchicine or indomethacin

Allopurinol -> Oxypurinol (Alloxanthine) -> Inhibition of xanthine oxidase

*Alloxanthine

Irreversible suicide inhibitor of XO Inhibits other enzymes involved in purine-metabolism as well

2. Febuxostat

-Non-purine selective inhibitor

-Highly specific

Toxicity & drug interactions

-GIT upset, rash, and rarely, peripheral nephritis, vasculitis, or bone marrow dysfunction

-Inhibits metabolism of mercaptopurine & azathioprine

• Metatarsal bones: The long bones that connect the mid and rear foot to the toes.

• Proximal phalanges: The toe bones.

• The dorsalis pedis artery supplies the dorsal aspect of the metatarsals and the tarsal bones.

• The posterior tibial artery enters the sole of the foot through the tarsal tunnel and divides into the medial and lateral plantar arteries.

Excess uric acid in the blood leads to the precipitation of urate crystals in joints.

2. Crystal Deposition:

The urate crystals trigger inflammation by activating the complement system and recruiting immune cells like monocytes and neutrophils.

3. Monocyte Activation:

Monocytes phagocytose (ingest) the urate crystals and release inflammatory cytokines such as:

IL-1 (Interleukin-1).

TNF (Tumor Necrosis Factor).

IL-6 (Interleukin-6).

4. Neutrophil Chemotaxis:

The complement system and cytokines attract neutrophils to the site of inflammation.

5. Neutrophil Activation and Phagocytosis:

Neutrophils attempt to phagocytose urate crystals. This process often fails, leading to neutrophil lysis (cell destruction) and release of:

Lysosomal enzymes.

Leukotriene B4 (LTB4), prostaglandins, and free radicals—all of which amplify inflammation.

6. Cartilage and Synovium Damage:

Inflammatory mediators (cytokines, proteases) damage the cartilage and synovium, leading to joint pain and swelling.

7. Tissue Injury and Inflammation:

The accumulation of inflammatory cells, enzymes, and mediators results in:

8. Tissue injury.

Acute inflammation, clinically presenting as red, swollen, and painful joints.

Secondary gout caused by increase urid acid due to known disease such as renal insufficiency, metabolic & hematological disorders .

Purine Recycling: The HPRT enzyme converts hypoxanthine and guanine back into usable forms.  

Uric Acid Buildup: In individuals with HPRT deficiency, these purines are not recycled efficiently, leading to increased uric acid production.

• Purine Breakdown: Nucleic acids, including DNA and RNA, are composed of nucleotides, which contain purine bases (adenine and guanine).  
  

• Uric Acid Production: When nucleic acids are broken down, the purine bases are converted into uric acid, a waste product that is normally filtered out by the kidneys.  
  

Increased Nucleic Acid Turnover and Gout:

When nucleic acid turnover is increased, more purines are released, leading to an increase in uric acid production. If the kidneys are unable to effectively eliminate this excess uric acid, it can build up in the blood, leading to hyperuricemia. This can eventually lead to the formation of uric acid crystals in the joints, causing the painful symptoms of gout.  Purine Breakdown: Nucleic acids, including DNA and RNA, are composed of nucleotides, which contain purine bases (adenine and guanine).