Gout: causes, symptoms, stages, diagnosis, treatment, prognosis

Gout is a systemic disease in which monosodium urate crystals are deposited in various tissues and in individuals with hyperuricemia, inflammation develops due to environmental and/or genetic factors.

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Epidemiology

According to expert estimates, at least 1-3% of the adult population suffers from gout. The incidence of gout in different populations ranges from 5 to 50 per 1000 men and 1.9 per 1000 women. The number of new cases per year is 1-3 per 1000 for men and 0.2 per 1000 for women, the ratio of men to women is 7:1. The peak incidence is noted at 40-50 years for men. 60 years and older - for women.

Causes gout

Persistent hyperuricemia (elevated serum uric acid) is an obligatory risk factor for gout. Previously, hyperuricemia was defined as uric acid levels above 420 μmol/L, based on the serum urate supersaturation point, at which monosodium urate crystals begin to form. The European League Against Rheumatism recommends defining hyperuricemia as uric acid levels above 60 μmol/L (6 mg/dL), based on studies demonstrating a 4-fold increase in the risk of gout in men and a 17-fold increase in women when serum uric acid levels exceed this level.

Causes of hyperuricemia: obesity, arterial hypertension, medication intake, genetic defects leading to hyperproduction of urates, other concomitant diseases, alcohol consumption.

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Pathogenesis

The strong intensity of pain in gout is explained by the local synthesis of an extremely wide range of mediators involved in the sensitization of pain nociceptors, which include prostaglandins, bradykinin, and substance P. Let us recall that substance P is released from unmyelinated nerve fibers and leads to vasodilation, extravasation of plasma proteins, and the release of prostaglandins and cytokines.

The deposition of urate crystals in joints and periarticular tissues is the main mechanism of development of acute and chronic gouty arthritis. The interaction of urate crystals with various joint cells (monocytes, macrophages, synoviocytes of types A and B, neutrophils, osteoblasts) leads to the synthesis of a wide range of proinflammatory cytokines (IL-1, IL-6, FIO a), chemokines (IL-8, monocyte chemoattractant protein 1, etc.), metabolites of arachidonic acid, superoxide oxygen radicals, proteinases. In turn, these mediators, as well as kinins, complement components and histamine induce joint inflammation, clinically defined as gouty arthritis, as well as systemic reactions characteristic of exacerbation of gout. The pathophysiological significance of other inflammation mediators, in particular nitric oxide (NO), is discussed. It is shown that uranium crystals do not have the ability to directly stimulate the synthesis of nitric oxide by J774 macrophage cells and bone marrow macrophages. However, they induce the expression of messenger RNA and protein of inducible nitric oxide synthetase and the synthesis of nitric oxide itself by these cells prestimulated with interferon. This process is associated with the phosphorylation of ERK 1/2 and nuclear translocation of NF-kB in response to stimulation with interferon. It is noteworthy that urate crystals induce the synthesis of nitrogen monoxide (as well as matrix metalloproteinase and chondrocytes), and this effect is not secondary, associated with the induction of the synthesis of "proinflammatory" cytokines, such as IL-1ß. The implementation of this process involves p38 mitogen-activated protein kinase, the blocking of which cancels the effect of urate crystals.

Among the numerous cells involved in the development of gouty inflammation, a special role is given to neutrophils, the pronounced infiltration of which into the blue anal tissue is considered a characteristic sign of gouty arthritis.

It has been established that activation of neutrophils by urate crystals leads to the release of a wide range of proinflammatory mediators: leukotrienes, IL-1, IL-8, lysosomal enzymes of superoxide oxygen radicals, which play an important role in tissue damage. In addition, activation of neutrophils in gouty arthritis is accompanied by activation of phospholipases A2 and D, mobilization of intracellular calcium, formation of inositol-1,4,5-triphosphate and increased phosphorylation of protein kinase. The interaction between urate crystals and human neutrophils is carried out through Fcy receptors IIIB (CD16) and CD11b/CD18.

The role of activated complement components in the recruitment of neutrophils to the gouty inflammation zone is being intensively studied. Early studies have shown an increase in complement concentration in synovial tissue in patients with gouty arthritis. Activated complement components (Clq, Clr, Cls) are found on the surface of urate crystals present in plasma. Urate crystals have the ability to activate the complement system via the classical and alternative pathways, resulting in the formation of anaphylatoxins (C3a and C5a), which have the ability to modulate the migration of leukocytes to the joint inflammation zone. The membrane attack complex (C5a-C9) plays a special role in the recruitment of neutrophils to the joint cavity in response to urate crystals.

Endothelin-1, an endothelial peptide, one of whose many effects is the regulation of neutrophil migration, may also have a certain significance. There is evidence that the introduction of endothelin receptor antagonists to laboratory animals suppresses the entry of neutrophils into the peritoneal cavity induced by the intraperitoneal introduction of urate crystals.

The interaction between leukocytes and vascular endothelial cells is a key stage in the development of inflammation, including gout. It was found that the supernatant of the culture of monocytes stimulated by urate crystals contains factors (proinflammatory cytokines IL-1 and TNF-a) that induce the expression of E-selectin, ICAM-1 and VCAM-1 in the culture of umbilical vein endothelial cells, and blocking TNF-a inhibits the expression of E-selectin and the "recruitment" of neutrophils into the joint cavity in guinea pigs with arthritis induced by urate crystals.

Important mediators that ensure the "recruitment" of leukocytes to the zone of microcrystalline inflammation include chemokines. In a model of arthritis induced by urate crystals in rabbits, it was found that inflammation is inhibited by the introduction of antibodies to IL-8. Other studies have shown that in mice with a deficiency of IL-8 receptors, there is no neutrophil recruitment to the inflammation zone after the introduction of urate crystals.

To decipher the molecular mechanisms underlying gouty inflammation, signaling molecules involved in the implementation of the neutrophil response to urate crystals are actively studied. It has been established that tyrosine kinases Syk, Lyn and Hck are involved in the activation of neutrophils by urate crystals. In addition, several tyrosine-phosphorylated substrates have been identified: p38 extracellular signaling kinase 1/2, paxillin, Cb1 and SAM68. Recall that tyrosine kinase Syk is involved in the regulation of phagocytosis and activation of neutrophils in response to urate crystals. Syk-SH2 suppresses the synthesis of leukotrienes and the activation of mitogen-activated protein kinase/phospholipase.

A characteristic feature of acute gouty arthritis is its self-limiting nature. The decrease in the proinflammatory potential of urate crystals may be associated with their ability to bind apolipoproteins B and E on their surface. It is known that apolipoprotein E, synthesized by macrophages, is present in excess in the synovial fluid of patients with gouty arthritis, and urate crystals coated with apolipoprotein B lose the ability to induce neutrophil degranulation. It is assumed that this is due to the ability of apolipoprotein B to displace "proinflammatory" IgG from the surface of urate crystals, which leads to a loss of the ability to cause neutrophil activation.

Another potential mechanism is associated with the activation of the hypothalamic-pituitary-adrenal axis, manifested in the synthesis of melanocortins (adrenocorticotropic hormone, melanocyte-stimulating hormone), which, in turn, exhibit powerful anti-inflammatory activity.

There is evidence that urate crystals induce the synthesis of not only proinflammatory but also a number of antiinflammatory mediators. These include receptor antagonists of IL-1 and IL-10, which have the ability to suppress inflammation induced by urate crystals, as well as transforming growth factor b. Particular attention has been drawn to transforming growth factor b, which is found in the synovial fluid of patients with gouty arthritis and has the ability to suppress microcrystalline inflammation in laboratory animals.

Another unique mechanism that determines the peculiar course of gouty arthritis is that urate crystals have the ability to quickly and selectively induce the expression of peroxisome proliferator-activated receptor y (PPAR-y). PPARs are members of the nuclear hormone receptor superfamily that act as ligand-dependent transcription factors. It was long believed that PPAR-y are expressed mainly in adipose tissue cells (adinocytes) and participate in the regulation of lipid and glucose metabolism. However, it has now been established that PPARs are expressed in many cells, including monocytes and macrophages. According to modern concepts, the fundamental significance of PPARs lies in the negative regulation of the inflammatory response.

Thus, the development of gouty inflammation is based on a complex interaction of different cell types, leading to an imbalance between the synthesis of proinflammatory and anti-inflammatory mediators.

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Symptoms gout

Acute gouty arthritis is characterized by a sudden, rapid increase in intense pain, usually in one joint, hyperemia of the skin, swelling and dysfunction of the affected joint. The attack often develops at night or in the early morning hours. At the onset of the disease, the duration of the attack varies from 1 to 10 days and proceeds with complete, sometimes spontaneous recovery and the absence of any symptoms between attacks. Provoking factors are often identified: trauma, dietary errors, alcohol intake, surgical procedures, taking diuretics. The first gouty attack in most patients is manifested by damage to the first metatarsophalangeal joint of the foot. High specificity of this symptom has been shown by a number of studies, however, damage to the first metatarsophalangeal joint can also occur in other arthritis.

In the absence of antihyperuricemic therapy, more than half of patients experience a recurrent attack within the first year. Subsequently, attacks become more frequent, the duration of the asymptomatic period becomes shorter, and arthritis becomes protracted. Despite the anti-inflammatory therapy, new joints are involved in the pathological process, and the lesions become oligo- and polyarticular in nature.

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Chronic tophaceous gout

The formation of monosodium urate crystal deposits in the form of tophi is a characteristic sign of the disease, observed in gout in almost all organs and tissues. The development of visible tophi, often subcutaneous or intradermal, in the area of the fingers and toes, knee joints, on the elbows and auricles is characteristic of the chronic stage of gout. Sometimes ulceration of the skin over the tophi is noted with spontaneous release of the contents in the form of a pasty white mass.

Tophi can form in almost any part of the body and internal organs, including intraosseous (the “puncher” symptom).

Pephrolithiasis in gout is also classified as one of the tophaceous forms, since the components of the stones are urates.

Tophi may also appear at the earliest stage of gout, depending on the severity of hyperuricemia and the rate of crystal formation. This is often observed in chronic renal failure: in elderly women taking diuretics; in some forms of juvenile gout, myeloproliferative diseases and post-transplant (cyclosporine) gout. Usually, the presence of tophi in any location is combined with chronic gouty arthritis, in which there is no asymptomatic period, and the joint damage is oligo- or polyarticular.

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Stages

The following are distinguished:

• Acute gouty arthritis.
• Interictal period of the disease.
• Chronic tophaceous gout.

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Diagnostics gout

To establish the diagnosis of gout, the criteria developed by SL Wallace are used.

Classification criteria for acute gouty arthritis

• Detection of characteristic monosodium urate crystals in the synovial fluid.
• The presence of tophi, the content of sodium monourate crystals in which is confirmed chemically or by polarization microscopy.
• Presence of six of the 12 signs listed below:
  • more than one acute arthritis in the anamnesis;
  • maximum joint inflammation on the first day of illness;
  • monoarthritis;
  • hyperemia of the skin over the affected joint;
  • swelling and pain in the first metatarsophalangeal joint;
  • unilateral lesion of the first metatarsophalangeal joint;
  • unilateral damage to the joints of the foot;
  • suspected tophi;
  • hyperuricemia;
  • asymmetric joint swelling;
  • subcortical cysts without erosions (on radiography);
  • negative results in synovial fluid culture.

For adequate diagnosis of gout, widespread use of polarization microscopy is necessary. A diagnosis of gout based on clinical signs may be correct, but not final, unless the presence of monosodium urate crystals is confirmed. An accurate diagnosis of gout, both during an exacerbation and in the interictal period of the disease, can only be made after detection of monosodium urate crystals in the synovial fluid or in the contents of a tophus using polarization microscopy. Routine search for crystals is recommended in any synovial fluid obtained from an inflamed joint in patients with no definite diagnosis.

In the absence of a polarizing microscope, typical clinical manifestations of gout (intermittent inflammation of the first metatarsophalangeal joint and an acute attack with rapid development of severe pain, erythema and inflammation, reaching a maximum within 6-12 hours) allow early suspicion of gout and are highly sensitive and specific.

Laboratory diagnostics of gout

Serum uric acid levels should be measured before and to monitor antihyperuricemic therapy. Although hyperuricemia is a proven risk factor for gout, serum uric acid levels do not rule out or confirm gout. Many people with hyperuricemia do not develop gout. During an acute gout attack, serum uric acid levels are not useful for diagnosing hyperuricemia, as they may reach normal levels in almost half of patients during this period due to increased renal excretion of uric acid.

To identify concomitant pathology, it is recommended to conduct a biochemical study of blood serum with determination of the lipid spectrum, liver enzymes, creatinine, urea, and a study of glucose in blood plasma.

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Synovial fluid examination

Polarization microscopy of synovial fluid and other tissues (e.g. tophi) allows detection of monosodium urate crystals (3-30 µm, characteristic needle-like shape and optical properties - negative double refraction of the beam).

X-ray of affected joints in gout

The "puncher" symptom is a radiolucent intraosseous tophus (a typical but late sign). In elderly patients with gout and concomitant osteoarthrosis, there may be difficulties in differential diagnosis of cysts.

The "punch" symptom is useful for diagnosing tophaceous forms and determining the degree of tophaceous bone tissue damage.

Differential diagnosis

Differential diagnostics are carried out with:

• septic arthritis (due to the high risk of complications and mortality in case of suspected septic arthritis, Gram staining and synovial fluid culture studies must be performed for any nosological classification of arthritis, including in case of identification of sodium monourate crystals; if the septic nature of arthritis is confirmed, the patient is transferred to the purulent surgery department);
• pyrophosphate arthropathy;
• reactive arthritis:
• rheumatoid arthritis;
• osteoarthritis (often combined with gout);
• psoriatic arthritis.

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Treatment gout

Treatment of gout has several goals:

• Fast and safe relief of acute gouty arthritis.
• Prevention of arthritis relapses and development of complications associated with hyperuricemia.
• Prevention and treatment of concomitant diseases and complications of drug therapy.

Indications for hospitalization

• Prolonged attack of gouty arthritis, ineffectiveness of NSAIDs
• Selection of antihyperuricemic therapy.

Non-drug treatment of gout

Optimal treatment of gout involves a combination of non-pharmacological and pharmacological approaches. It is necessary to consider:

• specific risk factors (uric acid levels, number of previous attacks, X-ray results);
• stage of the disease (acute/intermittent arthritis, interictal period, chronic tophaceous gout);
• general risk factors (age, gender, obesity, alcohol abuse, taking drugs that increase uric acid levels, drug interactions, concomitant diseases).

Patient education includes:

• information about the need to change your lifestyle (quitting smoking and drinking alcohol, losing weight if you are obese, diet):
• information on the nature of clinical manifestations in acute gouty arthritis and the consequences of uncontrolled hyperuricemia:
• training in rapid relief of acute gouty arthritis (constantly carrying an effective NSAID, avoiding analgesics);
• warning about possible side effects of drug therapy.

Drug treatment of gout

Treatment tactics for acute gouty arthritis and complications associated with hyperuricemia vary.

To relieve an acute attack of gout, NSAIDs, colchicine, and glucocorticoids (locally and systemically) are prescribed.

Treatment of gout should be started as early as possible, preferably within 24 hours of the onset of arthritis.

NSAIDs

First-line drugs in the absence of contraindications. Nimesulide (100 mg 2 times a day), diclofenac (25-50 mg 4 times a day), and indomethacin (25-50 mg 4 times a day) are used in full therapeutic doses. No differences in the effectiveness of NSAIDs have been established when prescribed in the first 48 hours of arthritis. In the case of prolonged or chronic gouty arthritis, delayed treatment, or ineffectiveness of previously prescribed NSAIDs, the granulated form of nimesulide has advantages in terms of both the speed of onset of effect and safety.

Colchicine

High doses of colchicine cause side effects (diarrhea, nausea), which is why it is rarely used at present. Colchicine should not be prescribed to patients with severe renal, gastrointestinal and cardiovascular diseases due to the increased risk of severe side effects. A potential indication for colchicine is contraindications to NSAIDs. Low doses (0.5-1.5 mg/day) may be used at the beginning of antihyperuricemic therapy to prevent arthritis exacerbations. Combination therapy with colchicine and NSAIDs has no advantages over monotherapy.

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Glucocorticoids

They are used in the presence of contraindications to the administration of NSAIDs and colchicine, in chronic arthritis in case of ineffectiveness of NSAIDs. In case of damage to one or two joints (if septic arthritis is excluded), intra-articular administration of triamcinolone acetamide (40 mg in large joints, 5-20 mg in small ones) or methylprednisolone acetate (40-80 mg in large joints, 20-40 mg in small ones) or betamethasone (1.5-6 g) is used. In case of polyarticular joint damage and chronic arthritis, systemic administration of glucocorticoids is recommended:

• prednisolone (40-60 mg orally on the first day, followed by a reduction of 5 mg each subsequent day);
• triamcinolone acetonide (60 mg intramuscularly) or methylprednisolone (50-500 mg intravenously); if necessary, repeat the administration after 24 hours.

Antihyperuricemic treatment of gout

Effectively prevents relapses of gouty arthritis and the development of complications associated with uncontrolled hyperuricemia. Therapy is indicated for patients with repeated attacks, chronic arthritis and tophaceous forms. Not used for asymptomatic hyperuricemia, with the exception of patients with hyperuricemia against the background of chemotherapy for low-quality neoplasms.

Antihyperuricemic therapy should not be started during an acute attack of arthritis; it is necessary to initially relieve inflammation in the joints as much as possible. If an attack of arthritis develops while taking antihyperuricemic drugs, treatment should be continued with additional prescription of adequate anti-inflammatory therapy.

The target uric acid level during antihyperuricemic therapy is below 36 mmol/L (6 mg/dL).

The effectiveness of antihyperuricemic therapy is determined by the normalization of uric acid levels in the blood serum, a decrease in the frequency of gout attacks, the resorption of tophi, and the absence of progression of urolithiasis.

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Allopurinol

Absolute indications for the use of allopurinol:

• frequent attacks of acute gouty arthritis (four or more attacks per year);
• clinical and radiological signs of chronic gouty arthritis;
• formation of tophi in soft tissues and subchondral bone;
• combination of gout with renal failure;
• nephrolithiasis;
• an increase in uric acid levels of more than 0.78 mmol/L (13 mg/dL) in men and more than 600 mmol/L (10 mg/dL) in women;
• Conducting cytotoxic therapy or radiotherapy for lymphoproliferative tumors to prevent urate crisis.

To prevent acute arthritis attacks and severe adverse reactions, allopurinol therapy is started with a small dose (50-100 mg/day) with a gradual increase of 50-100 mg every 2-4 weeks until the target uric acid level is achieved (<0.36 mmol/l).

When selecting the dose of allopurinol, the glomerular filtration rate should be taken into account. At a glomerular filtration rate of < 30 ml/min, low doses are usually prescribed due to the slow excretion and, accordingly, the existing possibility of accumulation of the drug. Treatment with allopurinol is associated with the development of side effects, sometimes severe (5%), so it should be carried out under strict control.

Uricosuric drugs (eg, sulfinmirazon) can be prescribed to patients with normal glomerular filtration rate (as an alternative to allopurinol). However, these drugs are contraindicated in nephrolithiasis. Benzbromarone can be prescribed in moderate renal failure, monitoring of liver enzymes, since it has moderate hepatotoxicity.

During treatment with these drugs, it is recommended to drink at least 2 liters of water per day.

Diuretics are prescribed to patients with gout only for vital indications (chronic heart failure, pulmonary edema, etc.). In other cases, diuretics should be discontinued. In patients with gout who are forced to take them, allopurinol therapy is carried out according to the standard scheme.

Fenofibrate and losartan have a moderate uricosuric effect; the use of these drugs is advantageous in patients with gout with concomitant dyslipidemia and arterial hypertension.

Patients with gout and nephrolithiasis are recommended to take courses of citrate-hydrocarbonate-potassium-sodium mixture (blemaren), especially at the beginning of antihyperuricemic therapy with uricosuric drugs to reduce urine acidity and the risk of stone formation.

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Further management

Determination of uric acid levels:

• at the beginning of treatment every 2-4 weeks;
• subsequently - every 6 months.

Biochemical studies during antihyperuricemic therapy:

• at the beginning - every 3 weeks:
• subsequently - every 6 months.

Evaluation of therapy effectiveness:

• reduction of uric acid concentrations;
• reduction in the need for NSAIDs, colchicine and glucocorticoids;
• reduction in the frequency of gout attacks leading to loss of ability to work.

Diet for gout

A low-calorie, low-carbohydrate diet with the inclusion of polyunsaturated fatty acids is recommended (leads to a decrease in uric acid levels); exclusion of ethanol-containing drinks, especially beer (dry natural wine has a lower ability to increase uric acid).

In patients with gout, it is necessary to identify concomitant diseases and cardiovascular risk factors (hyperlipidemia, arterial hypertension, hyperglycemia, obesity and smoking).

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Prevention

Antihyperuricemic therapy (allopurinol) for prophylactic purposes is carried out only in patients receiving chemotherapy for malignant neoplasms.

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Forecast

The prognosis for gouty arthritis is favorable, but urolithiasis develops in 20-50% of cases. The cause of death in patients with gout is renal failure.