Biochemical Basis and Pathogenesis
The disease is rooted in impaired purine base metabolism. Normally, purines undergo a chain of biochemical transformations through intermediate stages (hypoxanthine, then xanthine) until they convert into the final metabolite — uric acid. In gout, the concentration of this substance in blood plasma increases pathologically, a condition known as hyperuricemia.
Elevated uric acid levels occur via two main mechanisms:
- Decreased renal excretion. This is the leading factor, accounting for 90% of all clinical cases. The kidneys fail to excrete the metabolite from the body.
- Overproduction. Metabolic disruptions leading to uric acid overproduction are observed in only 10% of cases.
Mechanism of Acute Attack Development
The inflammatory response in gout develops through a strict logical sequence where physicochemical processes trigger an immune response:
- Crystallization. Uric acid has poor solubility. At high concentrations, it precipitates in tissues (predominantly in joints), forming salts called urate crystals.
- Cellular activation. Urate crystals interact with toll-like receptors on the membranes of monocytes and synoviocytes.
- Phagocytosis. Immune cells engulf the crystals. Inside the cell, the enzyme caspase-1 is activated via inflammasomes.
- Cytokine cascade. Caspase-1 cleaves the inactive precursor pro-IL-1β into active interleukin-1β (IL-1β). This exact cytokine is the key trigger of inflammation.
- Clinical result. Acute gouty arthritis develops.
> Pharmacological nuance: Based on the understanding of this mechanism, the drug anakinra (a selective IL-1β receptor blocker) is currently being investigated for the effective relief of acute attacks.
Pharmacotherapy Strategy
Gout treatment is strictly divided into two directions depending on the stage of the disease. Drugs used for acute attack relief are not suitable for prophylaxis, and vice versa.
A. Relief of the Acute Attack The main goal at this stage is to relieve pain and suppress inflammation.
- Nonsteroidal anti-inflammatory drugs (NSAIDs). Administered systemically.
- Colchicine. A specific agent used to interrupt gouty inflammation.
- Glucocorticoids (GCs). Intra-articular administration is possible in severe cases.
Important exception: Acetylsalicylic acid (ASA) is categorically not recommended. It impairs the renal excretion of uric acid, increasing its plasma concentration and worsening the patient's condition.
B. Prophylaxis of Attacks (Urate-Lowering Therapy) The goal of chronic treatment is the systemic reduction of plasma uric acid levels to prevent the formation of new crystals. Two groups of drugs are distinguished:
- Uric acid synthesis inhibitors (urate-lowering drugs). They inhibit the formation of the metabolite. Representatives: allopurinol, febuxostat.
- Uricosuric agents. They enhance the excretion of uric acid from the body. Representatives: sulfinpyrazone, benzbromarone.