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

Gout is a systemic disease in which crystals of monourate sodium are deposited in various tissues and inflammation due to external and / or genetic factors develops in persons with hyperuricemia.

[1], [2]

Epidemiology

According to expert estimates, at least 1-3% of the adult population suffers from gout. The incidence of gout in various populations ranges from 5 to 50 per 1,000 men and 1 to 9 to 1,000 women. The number of new cases per year is 1-3 per 1000 for men and 0.2 for 1000 for women, the ratio of men and women is 7: 1. The peak incidence is noted in 40-50 years in men. 60 years and older - in women.

Causes of the gout

Persistent hyperuricemia (elevated serum uric acid level) is an obligate risk factor for gout. Previously hyperuricemia was considered a uric acid level above 420 μmol / l, based on the serum super saturation point of urate, at which sodium monoaurate crystals begin to form. The European League for the control of rheumatism recommends that the level of uric acid above 60 μmol / L (6 mg / dL) be considered hyperuricemic, based on the results of studies showing a 4-fold increase in the risk of gout in men and a 17-fold increase in women above this level serum uric acid.

Causes of hyperuricemia: obesity, hypertension, medication, genetic defects that lead to hyperproduction of urates, other concomitant diseases, alcohol intake.

[3], [4], [5], [6]

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 large nociceptors, which include prostaglandins, bradykinin, and also substance P. Recall that substance P is released from unmyelinated nerve fibers and leads to vasodilation, extravasation of plasma proteins , the release of prostaglandins and cytokines.

The deposition of urate crystals in the 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 pro-inflammatory 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 the prolonged exacerbation of gout. The pathophysiological significance of other mediators of inflammation, in particular nitrogen monoxide (N0), is also discussed. It is shown that uranium crystals do not have the ability to directly stimulate the synthesis of nitrogen monoxide by macrophage J774 cells and bone marrow macrophages. However, they induce the expression of the information RNA and the protein of inducible synthetase of nitrogen monoxide and the synthesis of the most nitrogen monoxide by these cells, pre-stimulated with interferon. This process is associated with the phosphorylation of ERK 1/2 and the nuclear dislocation of NF-κB 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, due to the induction of the synthesis of "pro-inflammatory" cytokines, for example IL-1ß.P38 mitogen-activated protein kinase, which cancels blocking effect of urate crystals.

Among the numerous cells involved in the development of gouty inflammation, a special role is attached to neutrophils, a pronounced infiltration by which blue anal tissue is seen as 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 and 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 enhancement of protein kinase phosphorylation. The interaction between urate crystals and human neutrophils is via Fcy receptors IIIB (CD16) and CD11b / CD18.

The role of the activated complement components in the "recruiting" of neutrophils in the zone of gouty inflammation is intensively studied. In early studies, an increase in complement concentration in synovial tissue was found in patients with gouty arthritis. The activated complement components (Clq, Clr, Cls) show on the surface of urate crystals present in the plasma. Urat crystals have the ability to activate the complement system in the classical and alternative ways, resulting in the formation of anaphylatoxins (C3a and C5a), which have the ability to modulate the migration of leukocytes to the joint inflammatory zone. In the "recruiting" of neutrophils in the joint cavity in response to urate crystals, the membrane-attacking complex (C5a-C9) plays a special role.

Endothelin-1, an endothelial peptide, can also have a definite value, one of the numerous effects of which is the regulation of neutrophil migration. There are data that the introduction of endothelial receptor antagonists to laboratory animals suppresses the entry of neutrophils into the peritoneal cavity, induced by intraperitoneal administration of urate crystals.

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

Important chemokines providing "recruiting" of leukocytes to the zone of microcrystalline inflammation include chemokines. On the model of arthritis, induced by urate crystals in rabbits, it was found that inflammation is inhibited by the administration of antibodies to IL-8. In other studies, it has been shown that in mice deficient in IL-8 receptors, no neutrophils enter the inflammation zone after administration of urate crystals.

To decipher the molecular mechanisms underlying gouty inflammation, signaling molecules that participate in the realization of the neutrophil response to urate crystals are actively studied. It was established that tyrosine kinases Syk, Lyn and Hck are involved in the activation of neutrophils in urate crystals. In addition, several tyrosine-phosphorylated substrates have been identified: p38 extracellular signal kinase 1/2, paxilin, 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 inhibits 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 pro-inflammatory potential of urate crystals may be due to 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 synovial fluid in patients with gouty arthritis, and urate crystals coated with apolipoprotein B lose ability to induce degranulation of neutrophils. It is assumed that this is due to the ability of apolipoprotein B to displace the "pro-inflammatory" IgG from the surface of urate crystals, which leads to a loss of ability to induce neutrophil activation.

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

There is evidence that urate crystals induce the synthesis of not only pro-inflammatory, but also a number of anti-inflammatory mediators. These include the receptor antagonists IL-1 and IL-10, which have the ability to undercut the inflammation induced by urate crystals, as well as the transforming growth factor b. Particular attention is drawn to the transforming growth factor b, which is found in synovial fluid in 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 rapidly and selectively induce the expression of activated peroxisome proliferator-activated receptor receptors (PPAR-y). PPAR are members of the nuclear hormone receptor superfamily, which act as ligand-dependent transcription factors. For a long time it was thought that PPRA-y is expressed mainly in fatty tissue cells (adinocytes) and is involved in the regulation of lipid and glucose metabolism. However, it has now been found that PPAR is expressed in very many cells, including monocytes and macrophages. According to modern ideas, the fundamental significance of PPAR is the negative regulation of the inflammatory response.

Thus, the basis for the development of gouty inflammation is the complex interaction of different types of cells, leading to a disbalance between the synthesis of proinflammatory and anti-inflammatory mediators.

[7], [8], [9], [10], [11], [12], [13], [14], [15],

Symptoms of the gout

Acute gouty arthritis characterizes a sudden, rapid increase in intense pain, usually in one joint, flushing of the skin, swelling and impaired function of the affected joint. Attack often develop "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 a complete, sometimes spontaneous, recovery and no symptoms between seizures. Often revealed provoking factors: trauma, inaccuracies in the diet, alcohol intake, surgical procedures, taking diuretics. The first gouty attack in most patients is manifested by the lesion of the first metatarsophalangeal foot joint. High specificity of this feature is shown by a number of studies, nevertheless, the lesion of the first metatarsophalangeal joint can occur in other arthritis.

In the absence of antihyperurichemic therapy, more than half of the large, repeated attack develops within the first year. In the future, there are more attacks, a decrease in the duration of the asymptomatic period, a prolonged course of arthritis. Despite the ongoing anti-inflammatory therapy, new joints are involved in the pathological process, lesions acquire oligo- and polyarticular character.

[16]

Chronic tofusnaya gout

The formation of deposits of sodium monoaurate crystals in the form of tofus is a characteristic symptom of the disease observed with gout almost in all organs and tissues. The development of visible tofus, more often subcutaneous or intradermal, in the region of the fingers and toes, knee joints, on the elbows and the auricles is characteristic of the chronic stage of gout. Occasionally, skin ulceration occurs over tofusos with spontaneous release of the contents in the form of a paste-like white mass.

Tofusy can be formed practically in any parts of the body and internal organs, including intraosseous (symptom "piercer").

Paphrolithiasis with gout is also referred to as one of the tofus forms, as the components of the stones are urate.

Tofusi can appear in the earliest stage of gout disease, which depends on the severity of hyperuricemia and the rate of crystal formation. This is often observed in chronic renal failure: in elderly women taking diuretics; with some forms of juvenile gout, myeloproliferative diseases and posttransplantation (cyclosporin) gout. Usually the presence of tofus of any localization is combined with chronic gouty arthritis, in which there is no asymptomatic period, and joint damage is oligo- or polyarticular.

[17], [18]

Stages

Allocate:

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

[19], [20]

Diagnostics of the gout

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

Classification criteria for acute gouty arthritis

• Detection of characteristic crystals of sodium monourate in the joint fluid.
• The presence of tofus, the content of sodium monoaurate crystals in which is confirmed by chemical or polarization microscopy.
• The presence of six of the following 12 signs:
  • more than one and the same acute arthritis in the anamnesis;
  • maximum inflammation of the joint on the first day of illness;
  • monoarthritis;
  • hyperemia of the skin above the affected joint;
  • swelling and pain in the first metatarsophalangeal joint;
  • one-sided lesion of the first metatarsophalangeal joint;
  • one-sided lesion of the joints of the foot;
  • suspicion of tofusi;
  • hyperuricemia;
  • asymmetric edema of the joints;
  • subcortical cysts without erosion (with radiography);
  • negative results when sowing synovial fluid.

For the adequate diagnosis of gout, a wide application of polarization microscopy is necessary. The diagnosis of gout, based on clinical signs, may be true, but not definitive, if the presence of sodium monoaurate crystals is not confirmed. An accurate diagnosis of gout both during an exacerbation and during the interictal period of the disease can be made only after the detection of sodium monoaurate crystals in the synovial fluid or in the contents of tofus by means of 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 acute attack with rapid development of severe pain, erythema and inflammation, reaching a maximum within 6-12 hours) allow early suspected gout and are highly sensitive and specific.

Laboratory Diagnosis of Gout

Determination of serum uric acid level should be done before the initiation of antihyperurichemic therapy and for its control. Despite the fact that hyperuricemia is a proven risk factor for gout, serum uric acid does not serve as an indicator excluding or confirming gout. So, many people with hyperuricemia do not develop gout. In the period of acute gouty attack, the determination of serum uric acid level for the diagnosis of hyperuricemia is not informative, since almost half of patients during this period can reach normal levels because of increased excretion of uric acid by the kidneys.

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

[21], [22]

Investigation of synovial fluid

Polarization microscopy of synovial fluid and other tissues (for example, tofusov) makes it possible to detect crystals of sodium monourate (3-30 μm, a characteristic needle-like shape and optical properties-negative double refraction of the beam).

Radiography of affected joints with gout

The symptom of the "piercer" is an X-ray negative intraosseous tofus (a typical sign, but a late one). In elderly patients with gout and concomitant osteoarthritis, difficulties in performing differential diagnosis of cysts are possible.

The symptom "piercer" is useful for the diagnosis of tofus forms and the determination of the degree of tofusnogo lesions of bone tissue.

Differential diagnosis

Differential diagnosis is carried out with:

• septic arthritis (due to the high risk of complications and mortality in case of suspected septic arthritis, Gram staining and examination of the synovial fluid culture should be performed with any nosological affiliation of arthritis, including in the case of sodium monoaurate crystals, with confirmation of the septic character of the patient's arthritis in the department of purulent surgery);
• pyrophosphate arthropathy;
• reactive arthritis:
• rheumatoid arthritis;
• osteoarthritis (often combined with gout);
• psoriatic arthritis.

[23], [24], [25], [26], [27],

Treatment of the gout

Treatment of gout has several purposes:

• Rapid and safe relief of acute gouty arthritis.
• Prevention of recurrence of arthritis 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, inefficiency of NSAIDs
• Selection of antihyperuricemic therapy.

Non-medicamentous treatment of gout

Optimal treatment of gout includes a combination of non-pharmacological and pharmacological approaches. Should be considered:

• specific risk factors (uric acid level, number of previous attacks, radiographic findings);
• stage of the disease (acute / intermittent arthritis, interictal period, chronic tofusnaya gout);
• general risk factors (age, sex, obesity, alcohol abuse, taking drugs that increase the level of wet acid, drug interactions, concomitant diseases).

Patient education includes:

• information on the need to change the way of life (refusal to smoke and alcohol, weight loss for obesity, diet):
• information on the nature of clinical manifestations in acute gouty arthritis and the consequences of uncontrolled hyperuricemia:
• training rapid coping of acute gouty arthritis (constant wearing with an effective NSAID, refusal of analgesics);
• warning of possible side effects of drug therapy.

Medication for gout

The tactics of treating acute gouty arthritis and complications associated with hyperuricemia are different.

For relief of an acute attack gout is prescribed NSAIDs, colchicine, glucocorticoids (locally and systemically).

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

NSAIDs

Preparations of the first line in the absence of contraindications. Applied in full therapeutic doses nimesulide (100 mg 2 times a day), diclofenac (25-50 mg 4 times a day), indomethacin (25-50 mg 4 times a day). Differences in efficacy between NSAIDs in the case of their appointment in the first 48 hours of arthritis have not been established. In the case of protracted or chronic gouty arthritis, delay in treatment, ineffectiveness of previously prescribed NSAIDs, the granular form of nimesulide is advantageous both in the speed of onset of the effect and in safety.

Colchicine

High doses of colchicine lead to side effects (diarrhea, nausea), which is why it is rarely used at present. Colchicine should not be given to patients with severe kidney, gastrointestinal and cardiovascular damage due to an increased risk of serious side effects. Potential indication for the appointment of colchicine - a contraindication to the appointment of NSAIDs. It is possible to use low doses (0.5 1.5 mg / day) at the onset of antihyperuricherapy to prevent exacerbations of arthritis. Combination therapy with colchicine and NSAIDs does not have advantages over monotherapy.

[28], [29], [30], [31]

Glucocorticoids

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

• prednisolone (40-60 mg orally and the first day, followed by a decrease in the vine at 5 mg every subsequent day);
• triamcinolone acetonide (60 mg intramuscularly) or methylprednisolone (50-500 mg intravenously); if necessary, repeat after 24 hours.

Antihyperurichemic treatment of gout

Effectively prevents the recurrence of gouty arthritis and the development of complications associated with uncontrolled hyperuricemia. Therapy is indicated to patients with repeated attacks, chronic arthritis and tofusnymi forms. It is not used for asymptomatic hyperuricemia, except for patients with hyperuricemia against chemotherapy of alo quality neoplasms.

It is impossible to initiate antithyperichemic therapy during an acute attack of arthritis, it is first necessary to minimize inflammatory phenomena and joints as much as possible. If the attack of arthritis has developed against the background of taking antihyperuricemic drugs, treatment should be continued with the additional appointment of adequate anti-inflammatory therapy.

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

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

[32], [33], [34], [35], [36], [37]

Allopurinol

Absolute indications for the appointment of allopurinol:

• frequent attacks of acute gouty arthritis (four attacks or more per year);
• clinical and radiological signs of chronic gouty arthritis;
• the formation of tofus in soft tissues and subchondral bone;
• combination of gout with renal insufficiency;
• 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;
• carrying out cytotoxic therapy or X-ray therapy but for lymphoproliferative tumors to prevent urate crises.

For the prevention of acute attacks of arthritis and severe adverse reactions, therapy with allopurinol begins 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 (<0.36 mmol / l ).

When selecting a dose of allopurinol, the rate of glomerular filtration should be taken into account. At a glomerular filtration rate <30 ml / min, low doses are usually given in connection with delayed excretion and, accordingly, the available 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 (for example, sulfinirasone) 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 with moderate renal failure, control of liver enzymes, since it has moderate hepatotoxicity.

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

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

Moderate uricosuric effect of fenofibrate and losartan; the use of these drugs has advantages in patients with gout with concomitant dyslipidemia and hypertension.

Patients with gout and nephrolithiasis are advised to prescribe citrate-hydrogen carbonate-potassium-sodium mixture (blemarin) courses, especially with the initiation of antihyperurichemic therapy with uricosuric drugs to reduce acidity of urine and the risk of stone formation.

[38], [39], [40], [41], [42],

Further management

Determination of uric acid level:

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

Biochemical studies on the background of antihyperuricherapy:

• in the beginning - every 3 weeks:
• in the subsequent - every 6 months.

Evaluation of the effectiveness of therapy:

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

Diet for gout

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

Patients with gout should be diagnosed with concomitant diseases and cardiovascular risk factors (hyperlipidemia, hypertension, hyperglycemia, obesity and smoking).

[43], [44], [45], [46]

Prevention

Antihyperurichemic therapy (allopurinol) for preventive purposes is performed only in patients receiving chemotherapy for malignant neoplasms.

[47], [48], [49], [50],

Forecast

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