In recent years, the incidence of hyperuricemia and gout in China has been increasing year by year, and it has been reported in the literature that the incidence of hyperuricemia in some areas of China has reached 13.39% in 2003, which is comparable to 2%-18% in Europe and America, while the incidence of gout has also increased from 0.34% in 1998 to 1.33% in 2003, and gout has gradually become a common and frequent disease that seriously threatens people’s health. It is worth noting that hyperuricemia and gout are often combined with hypertension, diabetes mellitus, hyperlipidemia, obesity, and various cardiovascular diseases, which aggravate the damage to the kidney, cardiovascular and cerebrovascular organs. Therefore, it is necessary to pay attention to the clinical characteristics of hyperuricemia and gout, early diagnosis and systematic standardized treatment. However, for a long time, hyperuricemia and gout have not attracted enough attention from physicians in rheumatology, endocrinology, cardiovascular and other related disciplines, which often leads to misdiagnosis, underdiagnosis or non-standardized treatment.
1. The latest epidemiological trend of hyperuricemia and gout.
Gout is a group of syndromes caused by disorders of purine metabolism and/or impaired uric acid excretion resulting in elevated blood uric acid and deposition of urate from supersaturated extracellular fluid in tissues or organs, including asymptomatic hyperuricemia, gouty arthritis, gout stone formation, and gouty nephropathy (including chronic hyperuricemia nephropathy, acute hyperuricemia nephropathy, and uric acid kidney stones).
1.1 The incidence of gout is significantly higher in postmenopausal women.
Previously, it was believed that the majority of gout patients were men, but the current study found that the ratio of men to women was 3.6:1, and the prevalence of women increased significantly with age. 2005 epidemiological study by Mikuls et al. showed that the prevalence of gout in elderly patients over 75 years of age was 7% in men and 4% in women, while gout in women of childbearing age was rare.
1.2 Blood uric acid concentration is closely related to the occurrence of gout.
Campion et al. studied the correlation between the degree of elevated blood uric acid and the incidence of gout in patients within 5 years, showing that the incidence of gout was 30.5% when blood uric acid was ≥595.0 μmol/L (10 mg/dl), while the incidence of gout was only 0.5% when blood uric acid was <416.5 μmol/L (7 mg/dl). The incidence of gout was only 0.6%. The degree of hyperuricemia was also closely related to the age of gout attack, and the average age of gout attack was 55 years when blood uric acid was <416.5μmol/L, while the average age of attack was 39 years when blood uric acid was ≥535.5μmol/L (9mg/dl).
1.3 It is essential to recognize the characteristics of atypical gout.
Acute gouty arthritis is 90% monoarthritic, and 50% of the first symptoms are first metatarsophalangeal arthritis. However, many recent studies have found that there is now a significantly higher incidence of acute gouty arthritis in atypical sites, including other parts of the lower extremities or small joints of the upper extremities, while older women may even develop polyarthritis. In patients with hyperuricemia who are left untreated, 12% can develop gouty stones after 5 years, while the percentage of gouty stones after 20 years is 55%. In contrast, in patients with osteoarthritis, the time to develop gouty stones was significantly shorter in the presence of Heberden’s nodes. This result suggests that patients with osteoarthritis combined with hyperuricemia should be more concerned about the risk of developing gouty arthritis in the short term.
2. Two issues in the pathogenesis of gout that should be of concern.
2.1 Factors associated with acute exacerbation of gouty arthritis.
Acute attacks of gouty arthritis are closely related to hyperuricemia. Many studies have confirmed that the degree of elevated blood uric acid and the duration of hyperuricemia are positively associated with acute attacks of gouty arthritis; however, acute gouty arthritis does not occur in all patients with hyperuricemia. The factors contributing to the development of acute gouty arthritis in patients with hyperuricemia are not fully understood and are one of the hot topics in the field of gout research. The following describes the mechanisms associated with acute gouty arthritis attacks. Early in the acute attack of gout, polymorphonuclear leukocytes enter the synovial fluid, and inflammatory cytokines stimulate proliferation of the synovial lining layer and infiltration of neutrophils, mononuclear macrophages, and lymphocytes. These inflammatory responses are promoted by monosodium urate crystals. The process may also play a key role in mast cells, which originally contain pro-inflammatory substances, including histamine, cytokines, and enzymes, all of which may contribute to the downstream inflammatory response. The same immunity that is present plays a key role in the early inflammatory response to an acute attack of gout. Monosodium urate crystals activate both the classical and alternative pathways of complement, causing the production of chemotactic C5a, and the formation of the membrane attack complex C5b-C9. In addition, uncoated monosodium urate crystals activate macrophages, synovial lining cells, and neutrophils via Toll-like receptor (TLR) 2 and TLR4 signaling.TLR is located on the cell membrane, and activation of TLR2 and TLR4 not only induces crystal phagocytosis, but also plays a role in pro-inflammatory expression of cytokines, including nuclear factor kB, plays a key role. The intracellular neutrophil alkaline phosphatase (NALP3 or ca-lopyrin) inflammasome also plays a major role in the acute inflammatory response induced by monosodium urate crystals.NALP3 is predominantly expressed in leukocytes, and when NALP3 is activated, the bridging protein apoptosis-associated speckle-like protein (ASC, containing a caspase recruitment domain) connects it to caspase-1 leading to cytokine (IL)-1β and IL-18 production.
Many neutrophil surface receptors are currently thought to be involved in mediating the response to monosodium urate crystals, and these include CR3 (CD11b/CD18) and FcγRIII (CD16), which bind to crystal-linked iC3b and IgG, respectively. As neutrophils interact with monosodium urate crystals, a large number of mediators are synthesized and released, and these mediators (e.g. superoxide, hydrogen peroxide and monomorphic oxygen) trigger vasodilation, erythema and pain associated with acute gouty attacks.
2.2 Causes of spontaneous remission of acute gouty arthritis.
Acute gouty attacks are usually self-limiting and resolve within 7-10 d even without anti-inflammatory therapy. Causes of this phenomenon include: monosodium urate crystals with protein encapsulation during the inflammatory response may significantly attenuate the leukocyte response. Melanocortins, such as adrenocorticotropic hormone (ACTH) and melanocyte stimulating hormone, may play a role in the remission of acute attacks. In addition, spontaneous remission of acute attacks may involve the induction of the transcription factor peroxisome proliferator-activated receptor γ (PPAR-γ), which plays an important negative regulatory role in the inflammatory response. PPAR-γ can be detected on monocytes after exposure to monosodium urate crystals, and it inhibits IL-1β, tumor necrosis factor (TNF) α production, and cellular infiltration. After exposure to monosodium urate crystals, undifferentiated peripheral blood monocytes secreted pro-inflammatory cytokines (IL-1β, TNF-α and IL-6), induced endothelial cell activation and prompted neutrophil adhesion to endothelial cells. However, monocytes lose the ability to release pro-inflammatory cytokines when they differentiate into mature macrophages. This loss of the ability to release pro-inflammatory cytokines is accompanied by an increase in the ability to release transforming bovine growth factor (TGF) β1. High levels of TGF I beta1 are present in the synovial fluid of patients with acute gout, and TGF I beta1 is a key soluble factor in the process of inhibition of monosodium urate crystal-induced inflammatory responses by differentiated macrophages.
3. The pathogenetic features of gout are of concern.
3.1 Asymptomatic hyperuricemia.
Asymptomatic hyperuricemia is defined as elevated serum urate levels, but no gout has yet occurred (manifested as arthritis or uric acid kidney stones). Most people with hyperuricemia can remain asymptomatic for life, but the tendency to shift to acute gout increases with increasing serum urate levels. The risk of developing uric acid kidney stones increases with increased serum urate concentration and urinary uric acid excretion. Numerous studies have shown a close association between hyperuricemia and cardiovascular disease, with the literature reporting that 75% to 80% of patients with gout have combined hypertriglyceridemia, while more than 80% of patients with hypertriglyceridemia have combined hyperuricemia. In hypertension, 22% to 38% of untreated hypertensive patients were combined with hyperuricemia, and when patients were treated with diuretics and combined. The percentage rises to 67% when kidney disease is present. Hyperuricemia may be a potential risk predictor for hypertension in young men, and 1/4 to 1/2 of typical gout patients have comorbid hypertension, but the presence of hypertension is not associated with the duration of gout. In addition, many literatures support that hyperuricemia is an independent risk factor for the development of coronary artery disease.
3.2 Acute gouty arthritis.
The first episode of acute gouty arthritis usually occurs between 40 and 60 years of age in male patients and after 60 years of age in females. the onset of acute gouty arthritis before the age of 25 years may be related to a specific enzyme deficiency leading to a significant increase in purine production, hereditary renal disease or cyclosporine use. 85-90% of patients have their first episode as a single joint involvement, most commonly in the the first metatarsophalangeal joint. Recent studies have shown a significant increase in the number of patients with other joints of the lower extremities or single joints of the upper extremities, while the first episode of polyarticular involvement accounts for about 3% to 14% of patients, especially in elderly women. The joints commonly involved in acute gouty arthritis are, in order, the dorsalis pedis, ankle, heel, knee, wrist, fingers, and elbow. 90% of patients experience an acute attack of first metatarsophalangeal arthritis during the course of the disease. In most patients, the first attack occurs abruptly, often at night after falling asleep. Within a few hours, the affected joint becomes red, swollen, warm, and extremely painful. Occasionally, lymphangitis may occur. Systemic signs of inflammation include leukocytosis, fever, and increased erythrocyte sedimentation rate. Early onset x-rays usually show only soft tissue swelling.
The course of untreated acute gout varies widely. Mild attacks may resolve within hours or last only 1 to 2 d and do not reach the intensity of a typical attack. Severe attacks may last for several days or weeks. After remission, the patient’s symptoms disappear and he or she enters the gout interval.
There are many triggers for acute gouty arthritis attacks, and contributing factors include trauma, alcohol consumption, surgery, dietary overdose, bleeding, allogeneic protein therapy, infection, and use of radiographic contrast agents. Diuretic therapy is a very important trigger for the development of gouty arthritis in the elderly. Diuretics, intravenous heparin and the use of cyclosporine can trigger gout attacks by increasing serum urate levels. It is also important to note that uric acid-lowering drugs can trigger acute gout attacks by rapidly lowering serum urate levels. In fact, the stronger the uric acid-lowering effect, the greater the likelihood of triggering an acute gout attack.
3.3 Intermittent gout.
The intermittent period is the period between two gout attacks. Although some patients never have a second gout attack again, most patients have a second attack within 6 months to 2 years. The frequency of gout attacks in untreated patients usually increases with time. Subsequent attacks are rarely sudden and can be polyarthritic, with symptoms that can be more severe, last longer, and resolve more slowly, but can still resolve completely.
3.4 Chronic gouty arthritis.
Patients with recurrent attacks will eventually enter a chronic polyarthritic phase, characterized by an intermittent phase without pain and often with gouty stone formation. This stage is easily confused with other types of arthritis or other diseases.
Studies of patients without systematic treatment have found that the time interval from the first gout attack to the development of chronic symptoms or visible gout stones varies widely. It generally ranged from 3 to 42 years, with a mean of 11.6 years. Gout stones occurred in 12% of patients not given uric acid-lowering interventions after 5 years, compared with 55% after 20 years. Gout stones may appear earlier in patients with comorbid osteoarthritis, in women with renal insufficiency, in patients with heart failure treated with diuretics, and in organ transplant patients treated with cyclosporine. Other risk factors for the development of gout stones include young age of onset, alcohol abuse, high blood uric acid levels, and ineffective drug therapy.
Gout stones can be deposited in many different areas of the body, such as the ear, fingers and toes, knees or ankles, often in an irregular, asymmetrical distribution, or along the ulnar side of the forearm, forming a cystic swelling of the hawk’s bursa or depositing in the Achilles tendon to form a pyknotic swelling. The progression of gouty stone deposits is very insidious. Although the gouty stone itself is relatively painless, acute inflammation can occur around it. Eventually, there is extensive joint destruction and subcutaneous giant gouty stones can lead to joint deformity and dysfunction in patients.
3.5 Kidney disease.
In addition to gouty arthritis, proteinuria, usually mild and intermittent, is present in 20% to 40% of patients with gout. Hyperuricemia itself may be a cause of chronic kidney disease only when urate concentrations are chronically elevated, exceeding 773.5 μmol/L (13 mg/dl) in men or 595.0 μmol/L in women. The prevalence of kidney stones in patients with primary gout is 10% to 25%, higher than in the general population. The likelihood of kidney stones in patients with gout increases with the increase in serum urate concentration and uric acid excretion. more than 50% of kidney stone patients have serum urate higher than 773.5 μmol/L or 24h uric acid excretion rate more than 1100 mg.
4. Diagnosis and differentiation of gouty arthritis.
4.1 Acute gouty arthritis.
Acute gouty arthritis is the main clinical manifestation of gout, and is often the first symptom. The diagnosis can be confirmed by the detection of sodium urate (MSU) crystals in synovial fluid or gout stones. Many countries still use the classification criteria recommended by the American College of Rheumatology (ACR), which considers the presence of typical urate crystals in synovial fluid or gout stones confirmed by chemical methods or polarized light microscopy to confirm the diagnosis of acute gouty arthritis. The clinical features of acute gouty arthritis are characterized by sudden onset of acute monoarthritis, with pain and redness in the first metatarsophalangeal joint being the most representative. Hyperuricemia and suspected gout stones are important diagnostic criteria, but not required. In addition, it should be differentiated from infective septic arthritis, traumatic arthritis, reactive arthritis, and pseudogout. The application of this criterion also has some limitations, such as not all patients with hyperuricemia have inflammation of the first metatarsophalangeal joint caused by gout; some patients with gout have normal serum urate concentrations during acute attacks; some non-gouty diseases can also manifest as acute mono- or oligoarticular inflammation, such as pseudogout, hydroxyapatite calcific tendonitis, reactive arthritis, peripheral joint involvement in ankylosing spondylitis, infectious In 2006, the European League Against Rheumatism (EULAR) summarized the characteristics, detection means and risk factors of gouty arthritis based on a large amount of evidence-based medical evidence, which is of great significance for the diagnosis of gout. The consensus emphasizes that confirmation of urate crystals in the patient’s synovial fluid or gout stone aspirate confirms the diagnosis of gout, and routine search for urate crystals in the synovial fluid of any inflammatory arthritis that cannot be diagnosed is recommended. Although radiography is useful for differential diagnosis and can show the typical features of chronic gout, it is not helpful in confirming the diagnosis of early or acute gout. In terms of clinical manifestations, it is believed that an acute attack of gouty arthritis, characterized by rapid onset of severe pain, swelling and pressure, peaking at 6-12 h, and especially redness of the skin surface, is highly suggestive of crystal inflammation, although it is not specific for the diagnosis of gout. In addition, gout and sepsis can coexist, so Gram stain and synovial fluid culture should be performed when septic arthritis is suspected, even if the presence of urate crystals is confirmed. The consensus re-emphasizes that hyperuricemia is the most important risk factor for gout, but emphasizes that high or low blood uric acid does not confirm or exclude gout, as most patients with hyperuricemia do not develop gout, and blood uric acid levels can be normal during acute attacks of gout. The consensus also emphasizes the need to assess risk factors for gout and related complications including metabolic syndrome (obesity, hyperlipidemia, hyperglycemia, hypertension).
4.2 Intermittent gout.
This period is a state of remission between repeated acute attacks, usually without significant joint symptoms, and therefore the diagnosis of intermittent gout relies on a history of previous recurrent attacks of acute gouty arthritis and hyperuricemia. Some joints with a longer history and frequent attacks may show mild imaging changes. The diagnosis can be confirmed by finding MSU crystals in the synovial fluid of previously involved joints at this stage.
4.3 Chronic stage gout.
Subcutaneous gout stones are common and are the hallmark of the chronic phase. The diagnosis can be confirmed by repeated acute attacks for many years and persistent unrelieved symptoms such as swelling and pain in the affected joints, combined with x-ray examination of bone and joint and the discovery of MSU crystals in gout stone aspirates. This stage should be differentiated from rheumatoid arthritis, psoriatic arthritis and bone tumors.
4.4 Renal lesions.
Chronic uric acid nephropathy may have increased nocturia, reduced urine specific gravity and osmolality, mild red and white cell urine and tubular, mild proteinuria, and even renal insufficiency. Uric acid urinary tract stones to. Renal colic and hematuria as the main clinical manifestations, this period should be distinguished from secondary gout caused by kidney disease.
5, should pay attention to the standardized treatment of gout.
When to give therapeutic intervention for hyperuricemia and gout and how it should be treated are getting more and more attention. Treatment is divided into lifestyle changes, diet control, treatment of acute gouty arthritis, strict timing of application of uric acid-lowering drugs and management of complications. After the diagnosis of acute gouty arthritis, anti-inflammatory and pain-relieving treatment should be given immediately, including non-steroidal anti-inflammatory drugs (NSAIDs), colchicine and glucocorticoids, and cold compresses and avoidance of activities for the affected joints. Diet and lifestyle changes are an important part of the prevention and treatment of hyperuricemia and gout. It is important to strictly grasp the timing of application of uric acid-lowering drugs. A large number of studies have concluded that uric acid-lowering drugs should be given to patients with gout stones, combined renal insufficiency, the presence of uric acid stones, recurrent gout attacks and patients who must continue to use diuretics. For patients without comorbidities, if the arthritis flares up again within 1 year, uric acid-lowering drugs can be given. Uric acid-lowering drugs are usually started after 1-2 weeks of acute inflammation control, and blood uric acid should be maintained at ≤360 μmol/L (6.1 mg/dl). With the improvement of people’s living standard and the extension of life expectancy, hyperuricemia and gout have become more and more the main diseases that seriously threaten human health, and the occurrence of these diseases has a tendency to be younger, in addition, hyperuricemia and gout are often combined with hypertension, hyperlipidemia or diabetes, and there is a lot of evidence that hyperuricemia has become an independent risk factor for cardiovascular and cerebrovascular diseases.
Therefore, it is important to improve the understanding and diagnosis and treatment of hyperuricemia and gout. Only systematic, standardized, and individualized diagnosis and treatment of hyperuricemia and gout and their comorbidities can minimize the multiple harms caused by this disease.