Gouty Arthritis; Causes, Symptoms, Diagnosis, Treatment

Gouty Arthritis








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Gouty Arthritis is a form of acute arthritis that causes severe pain and swelling in the joints. It most commonly affects the big toe, but may also affect the heel, ankle, hand, wrist, or elbow. It affects the spine often enough to be a factor in back pain. Gout usually comes on suddenly, goes away after 5-10 days, and can keep recurring. Gout is different from other forms of arthritis because it occurs when there are high levels of uric acid circulating in the blood, which can cause urate crystals to settle in the tissues of the joints.
Gout is the most common crystal arthropathy and the leading cause of inflammatory arthritis. It is associated with functional impairment and, for many, a diminished health-related quality of life. Numerous studies have demonstrated the impact of gout and its associated conditions on patient morbidity and mortality. Unfortunately, gout remains under-diagnosed and under-treated in the general community. Despite major advances in treatment strategies, as many as 90% of patients with gout are poorly controlled or improperly managed and their hyperuricemia and recurrent flares continue. The introduction of novel urate-lowering therapies, new imaging modalities, and a deeper understanding of the pathogenesis of gout raise the possibility of better gout care and improved patient outcomes. Here, we spotlight recent advances in the diagnosis and management of gout and discuss novel therapeutics in gout treatment.
gout

Types of Gouty Arthritis

  • Asymptomatic hyperuricemia – Gout undergoes 4 stages during its course starting with asymptomatic hyperuricemia. In this stage, patients have no symptoms or signs and are usually accidentally discovered when measuring SUA (serum level greater than 7 mg/dL). However, some patients with hyperuricemia may develop an acute gouty attack.
  • Acute gouty attack – The acute gouty attack is usually monoarthritic that peaks within hours too severely inflamed joint with cardinal signs of inflammation including redness, hotness, tenderness, swelling, and loss of function. In large joints such as knees and ankles, skin signs are infrequent, but swelling and pain can be intense.
  • Intercritical period – When the acute attack settles down within hours to days following the introduction of colchicine or NSAIDs, patients enter into a remission phase. This period is characterized by the absence of symptoms. It may be interrupted suddenly by newer attacks if proper treatment for hyperuricemia has not been introduced. This quiescent stage can be prolonged after the first attack. Without proper treatment, however, attacks become more frequent and more severe .
  • Chronic tophaceous gout – The untreated disease progresses into the destruction of joints with the formation of palpable tophi. A tophus is a mass formed of large amounts of accumulated crystals. It happens in chronic untreated gout. It can be present around the joints in the ears, the subcutaneous tissue or the skin. It is a manifestation of chronicity and uncontrolled disease. Macroscopically, tophi contain a white chalky material. Tophi may lead to joint destruction and deformity. Bony erosions may also occur as growing tophi extend to the bone. Differentiation of tophi from other nodules such as rheumatoid nodules, osteoarthritic Heberden’s and Bouchard’s nodules, lipomas or is essential for further management. This can be easily done by taking a simple needle biopsy that will show MSU crystals characteristic of gout .

According to the  Severity 

Gout is divided into 4 stages ():

  • Asymptomatic deposits in tissues
  • Acute gout –  This is defined as rapidly-developing inflammation, usually of only one joint, with painful overheating and swelling. Uric acid crystals trigger the inflammation reaction in joints or tissues around joints.
  • Intercritical periods – These are clinically inactive disease phases between 2 flares. During these periods, gout patients also have hyperuricemia, which can lead to increased deposition of urate crystals in tissues. Intercritical periods become shorter as the disease progresses.
  • Chronic gout – This is characterized by long-term joint inflammation, which leads to joint pain at rest and/or on movement.

Causes of Gouty Arthritis

Although experts do not fully understand why some people get gout and others do not, many causes and risk factors of gout are well established.

  • Diet – The risk of gout is increased by the frequent consumption of foods high in purines, including meats, seafood, certain vegetables and beans, and foods containing fructose.
  • Alcohol use – Drinking alcohol decreases the body’s ability to flush out uric acid. Additionally, beer is made with brewer’s yeast, which is high in purines.
  • Gender – Men are more likely to have gout. Women are less likely to get gout, however, their risk of developing gout increases after menopause.
  • Age –  Many people have their first episode of gout between the ages of 30 and 50, and the risk of gout continues to increase with age. It is estimated that nearly 12% of men aged 70 to 79 have had gout while less than 3% of men under the age of 50 have had it.
  • Excess weight – People who are overweight have a greater risk of developing gout.
  • Race –  African American men are nearly twice as likely to report having had gout as Caucasian men, according to a study cited by the Centers for Disease Control and Prevention.
  • Family history – Genetics plays a role, making some people’s bodies more prone to accumulating uric acid and developing the uric acid crystals that lead to gout. More research needs to be done to understand why some people have several risk factors and never get gout while other people have few or no risk factors and do get out.

mechanism of gout

Certain medications. Taking certain medications can increase the risk of gout. Some of these medications include:

  • Diuretics sometimes called “water pills”) used to treat high blood pressure
  • Aspirin
  • Cyclosporine, an immunosuppressant sometimes prescribed to people who have rheumatoid arthritis or psoriasis, or who have had an organ transplant
  • Levodopa often used to treat Parkinson’s disease
  • Medicines that may cause gout include the following
  • Niacin (a B-complex vitamin)
  • Some drugs used to treat cancer
  • Pyrazinamide and ethambutol, which are used to treat tuberculosis
  • Chronic renal failure – A person who has chronic renal failure no longer has fully functioning kidneys. When the kidneys’ ability to flush out uric acid is compromised, gout may develop.
  • Lead exposure – People who are exposed to lead in the environment have a higher incidence of gout. Though much less common today, gout caused by lead exposure was common years ago when people unwittingly drank from leaded crystal glassware.
  • A trigger event, such as injury, surgery, or medical therapy – Specific events can trigger a change in body chemistry and bring on a gout flare-up. Such events include, but are not limited to, infection, trauma, surgery, psoriasis, and the initiation of chemotherapy. Stopping or starting allopurinol, which is used to treat gout, can also bring on gout symptoms
  • Interestingly – many people who experience an episode of gout may not ever have symptoms again, or at least not for several years. People who do experience gout symptoms repeatedly may notice that episodes get longer and more severe. Gout and its precursor, hyperuricemia, should be addressed to prevent joint damage in the long term.
  • Many forms of arthritis occur gradually –  and in the early stages a person may experience only occasional mild pain. In contrast, gout strikes quickly, severely, and without warning. In fact, gout pain can be so severe that some people assume a more serious medical problem is at play, which can delay an accurate diagnosis.gout -over-view

Symptoms of Gouty Arthritis

  • Pain – The most notable symptom of gout is extreme pain at the affected joint. Gout sufferers have compared the pain to being constantly stabbed with tiny, hot knives. Typically, it is uncomfortable if not impossible for a person to put weight on an affected foot or knee.
  • Rapid onset – Acute gout can develop suddenly and without warning, taking only a few hours to become severely painful. (Though not usually the case, it is possible for gout symptoms to appear more gradually)
  • Symptoms interrupt sleep – It is not uncommon to hear a gout sufferer recount how a gout flare-up struck in the middle of the night, waking the person from a sound sleep. The affected joint, often a big toe, causes so much pain that the person cannot tolerate even a bed sheet resting on it. The reason gout episodes often strike at night is that body temperature drops slightly during sleep, and this drop in temperature catalyzes the formation of uric acid crystals in the joint. This factor also helps explain why gout often affects joints in the feet and fingers – these extremities tend to maintain a lower temperature than the rest of the body.
  • Only one joint is affected – In about 90% of gout cases, only one joint is affected.9About 50% of gout cases involve the big toe, although other joints in the foot are also commonly affected, including the ankle, instep, and heel. Other joints susceptible to gout include the fingertips, wrist, knee, and elbow.
  • Short duration – Left untreated, an episode of gout can last from 3 to 10 days, or even a few weeks, during which time the pain tapers off. Usually, a person’s first episode of gout lasts just a few days but successive episodes may last longer.
  • Swelling – The affected joint swells as the uric acid crystals create irritation and inflammation.
  • Redness – The skin at and around the joint will appear red.
  • Warmth – The skin at and around the joint will be warm to the touch.
  • Stiffness – Swelling, and pain may significantly reduce the joint’s range of motion.
  • Fever – The person may get a fever as the immune system reacts to the uric acid crystals.
  • Tophi – In some cases, the collection of uric acid crystals create small white chunks called tophi that can be visible through the skin. Tophi (sing. tophus) usually only occur in people who have suffered from chronic gout for several years. This is referred to as chronic tophaceous gout and is the most disabling form of gout. Although gout symptoms normally resolve within several days or weeks, gout should not be left untreated. Over time gout can become chronic, tophi may develop, and permanent joint damage can occur.
  • Wrist Pain  – People who experience gout-related wrist pain typically have polyarticular gout, meaning their gout affects more than one joint. Gout pain appearing only in the wrist is rare but possible.7 When a person has gout in a joint that is not known for its susceptibility to gouts, such as the wrist or ankle, an accurate gout diagnosis can be elusive. If the joint is swollen, the physician may aspirate it with a needle and send the joint fluid to a lab for diagnostic analysis.
  • Sacroiliac joint pain – Gout is commonly associated with the big toe joint (metatarsophalangeal joint), but only about half of cases occur there. The remaining cases affect other areas, such as knees, fingertips, and—less often—sacroiliac joints, which are located on either side of the pelvis between the sacrum and the ilium. Gout in a sacroiliac joint can cause low back pain or hip pain.

Gouty Arthritis

Diagnosis of Gouty Arthritis

The goals with testing are to identify gout, to distinguish it from other conditions, such as other types of arthritis that may have similar symptoms, and to investigate the cause of increased uric acid concentrations in the blood.

Laboratory tests

  • Synovial fluid analysis – used to detect the needle-like crystals derived from uric acid or other crystals that may be present; to look for signs of joint infection.
  • Uric acid – to detect elevated levels in the blood; if a diagnosis of gout is made, uric acid testing may be performed regularly to monitor levels.
  • Basic metabolic panel (BMP) – this group of tests may be used to evaluate and monitor kidney function.
  • Complete blood count (CBC) – to determine if there is an abnormal increase in the number of white blood cells (leukocytosis) and to help differentiate between septic arthritis and gout.
  • Sometimes other tests, such as an RF (rheumatoid factor) or an ANA (anti-nuclear antibody), may be ordered to rule out other causes of arthritis symptoms. A blood culture and/or synovial fluid culture may be ordered if septic arthritis is suspected.
  • Increased uric acid, often410 µmol/L–US: 7.0 mg/ml, a level found in a significant minority of men (90% of gout occurs in men).
  • X-rays of joints –  will reveal joint damage if you have long-standing and poorly controlled gout. However, x-rays are rarely helpful in confirming the diagnosis because they’re usually normal in the early years of having gout. Ultrasound of joints can be used to detect earlier signs of gout and can be useful where the diagnosis is uncertain.
  • Synovial fluid examinations involve taking fluid samples from a joint through a needle and examining them under a microscope for urate crystals. This test can confirm the diagnosis but isn’t always practical – it can be difficult and sometimes uncomfortable to draw fluid from a small joint such as the big toe. However, it may be possible to identify a few crystals in a sample taken from your knee, even if you’ve not yet had an attack of gout there. A fine needle inserted into a tophus under your skin can also be used to identify urate crystals.
  • Ultrasound – Musculoskeletal ultrasound can detect urate crystals in a joint or in a tophus. This technique is more widely used in Europe than in the United States.
  • Dual-energy CT scan – This type of imaging can detect the presence of urate crystals in a joint, even when it is not acutely inflamed. This test is not used routinely in clinical practice due to the expense and is not widely available.
  • Conventional Radiography (CR) – It is the most widely used method in clinical practice, however, in the early stages of the disease, it is not very helpful . Radiographic changes may be missed for a minimum of 10 years after the first gouty attack . During the early stages of gout, radiographic images are usually normal or may show asymmetric soft tissue swelling near the affected joints, but subtle early lesions such as small erosions and tophi are difficult to detect .

In chronic tophaceous gout, the main radiographic features are:

  • Tophi which are articular or periarticular soft tissue dense nodules 
  • MSU deposits in the cartilaginous part
  • Joint space narrowing in advanced disease 
  • Bone erosions are characteristic. They are well-circumscribed intraarticular or juxta-articular lesions with overhanging margins . They result from the growth of tophi into the bone, hence they are usually seen near tophi .
  • Periarticular osteopenia is usually absent and proliferating bone can be seen mostly as irregular spicules 
  • Calcified MSU deposits can penetrate in the bone; in severe cases, they should not be confused with bone infarcts or enchondromas. Radiography has low sensitivity (31%), however, its specificity is high (93%) .
  • CR is widely available, inexpensive, quick, and acceptable to patients. The radiation hazard is small . The CR Sharp-van de Hejde scoring system for gout (SvdH-G), has been adapted from its RA counterpart and modified. The gout version includes scoring for bone erosions as well as joint space narrowing with the distal interphalangeal joints (DIPjs) added .
  • Ultrasound (US) – Recently, progress in US technology (machines, transducers, techniques), encouraged its use by rheumatologists for the diagnosis and management of gout. In their excellent review, Nestrova and Foder , listed the main indications for using the US in crystal-induced arthritis. These include detection of joint effusion and synovitis, differentiating between active and inactive synovitis, studying cartilage, describing bone contour for erosions and osteophytes, evaluation of tendons, evaluation of crystal deposition, execution of US-guided procedures (diagnostic and/or therapeutic), monitoring disease evolution as well as being helpful for the differential diagnosis with other arthritides [Rx]

In gout, US features can be either nonspecific or specific. Nonspecific features include

  • Synovial fluid – Synovial fluid varies from being totally anechoic to containing aggregates of variable echogenicity. Aggregates of MSU microcrystals can be detected as hyperechoic spots or bright stippled foci. They tend to float in the joint space sometimes giving a snow-storm appearance when applying gentle pressure on the skin surface .
  • Synovial proliferation and hypervascularization – The Doppler mode can differentiate active from inactive synovial tissue by assessing its vascularity. This is essential for diagnosis and in monitoring the disease and its response to therapy .
  • Bone erosions – These are defined in gout as “intra- and/or extra-articular discontinuity of the bone surface (visible in two perpendicular planes) . They are more likely found in patients who experience frequent attacks, or who have long disease duration, and tophi . US has a threefold sensitivity than CR in detecting erosions < 2 mm (P < 0.001) . There is, however, standardized US scoring system for erosions in gout .
  • Articular cartilage “double contour Sign” (DCS) – DCS is very specific for gout. It is defined as an abnormal hyperechoic band over the superficial margin of the articular hyaline cartilage, independent of the angle of insonation and which may be either irregular or regular, continuous or intermittent and can be distinguished from the cartilage interface sign . DCS is reported in acute flare-up in clinically uninvolved joints, and in patients with asymptomatic hyperuricemia . False-positive results have also been reported . Three and Schlesinger demonstrated that DCS can disappear when SUA levels were lowered to 6 mg/dl for 7 months or more .

MSU deposits (Tophi and Aggregates)

  • A tophus is a circumscribed, inhomogeneous, hyperechoic, and/or hypoechoic aggregation (that may or may not generate posterior acoustic shadow), which may be surrounded by a small anechoic rim. Aggregates are heterogeneous hyperechoic foci that maintain their high degree of reflectivity even when the gain setting is minimized or the insonation angle is changed and which occasionally may generate the posterior acoustic shadow.
  • Tophi have been also described by the US as “wet sugar clumps” with an oval or irregular shape .
  • Intra-articular and intrabursal tophi have been defined as heterogeneous hyperechoic (relative to subdermal fat) aggregates with poorly defined margins with or without areas with acoustic shadowing within the synovial recesses or bursae, respectively .

Doppler US can distinguish between active/hot tophi and inactive/cold ones based on their doppler signal . Tophi can directly be measured by the US using special calipers. There is good sensitivity to change associated with ULT . US is feasible as it can be performed in the clinic and there are no radiation hazards involved. The time required for scanning, however, may be significant and training costs may be considerable .

  • Conventional CT (CCT) – CT is characterized by excellent resolution and high contrast, hence it is the best technique for the assessment and characterization of crystal arthropathies . CCT is not helpful in the diagnosis of acute gout as it can’t detect inflammation, synovitis, tenosynovitis, and osteitis. This handicap is, however, more than counterbalanced by its role in chronic gout. It is able to detect erosions better than Magnetic Resonance Imaging (MRI) or CR . These are described as well defined, punched out lytic bone lesions, with sclerotic overhanging edges . The specificity of CCT for the assessment of tophi exceeds that of US or MRI . CT of tophi has been confirmed microscopically by identifying MSU crystals . Its measurement of tophi has also been compared to physical exam using Vernier calipers . Tophi, soft tissue, intra-articular as well as intra-osseous ones appear as soft tissue masses with well-described attenuation, making it easier to distinguish them from other soft tissue lesions . CCT can help to monitor disease burden and response to therapy but has the disadvantage of radiation exposure 
  • Dual-Energy CT (DECT) – The introduction of this new imaging technique opened a new horizon. It allows the differentiation of deposits based on their different X-ray spectra. It applies the concept that the attenuation of tissues depends on their density, atomic number as well as the photon beam energy . Like CCT, it can detect damage but does not help in inflammation. It is superior to all other available imaging technologies in its ability to identify all urate deposition in the area imaged   DECT can offer a quick, non-invasive method to visualize MSU crystals, soft tissue changes, and early erosions at high-resolution, even before CR. This, particularly, helps in the differential diagnosis from pigmented villonodular synovitis, psoriasis, and septic arthritis which can share clinical features with gout . DECT is highly accurate in detecting MSU crystals in joints, tendons, ligaments, and soft tissues and can be used to identify subclinical gout with high specificity . It, however, misses crystal deposition on the surface of cartilage, a feature US can detect as the DCS . There are many causes of false negatives; lower density of tophi due to lower crystal concentrations, the small size of tophi or crystals (less than 2 mm.) or technical parameters . On the other hand, false-positive results were described around nail beds, in the skin, in regions of metal artifacts and in severe OA . DECT is not widely available, which limits its application for clinical and research purposes. Its costs are equivalent or higher than CCT and it entails radiation exposure .
  • MRI – MRI features of arthritis are those of nonspecific inflammation, synovial thickening, effusion, erosion, and bone marrow edema. Tophi show homogenous T1 signal intensity (low to intermediate) and heterogeneous T2 signal intensity (variable low to intermediate), depending on the degree of its hydration and classification . MRI role is limited because of expense and limited availability. It is, however, useful for the evaluation of gout at unusual sites. The literature abounds with case reports in the axial skeleton or presentation as spondyloarthritis , carpal tunnel syndrome , crown dens syndrome , paraspinal abscess , or intra-abdominal mass . The diagnosis in these reports was made by MRI, which was occasionally combined with other modalities.
  • Nuclear scintigraphy – Nuclear Scintigraphy is rarely used for evaluation. Positive results are often found incidentally when a study is performed for other indications.
  • Positron emission tomography (PET) – Case reports of (PET/CT) in gout showed articular and periarticular FDG (18 F-fluoro-2-deoxy-D-glucose) uptake. Soft tissue FDG uptake identifying tophi has also been reported. This can be helpful when gout presents at unusual locations .
Diagnosis criteria for gout*
CriterionCharacteristicsPoints
Pattern of involvementAnkle/foot
MTP-1
1
2
Symptoms:
– Erythema of joint
– Affected joint very sensitive to touch
– Movement very limited
1/3 symptoms
2/3 symptoms
All 3 symptoms
1
2
3
Criteria for typical episode:
– Pain develops within 24 hours
– Resolves after ≤14 days
– Complaint-free intervals
1 typical episode
Multiple typical episodes
1
2
Evidence of tophusPresent4
Laboratory tests:
– Serum uric acid (preferably without treatment, 4 weeks before/after an episode or highest value during the episode)
– Joint fluid analysis following puncture (if performed)
<4 mg/dl
6 to 8 mg/dL
8 to <10 mg/dl
≥10 mg/dL
No urate crystals
–4
2
3
4
–2
Imaging:
– Urate deposits on ultrasound or DECT
– Erosions characteristic of gout on conventional X-ray
Present
Present
4
4

According to Neogi et al. [

*If the swelling score is 8 or more out of a maximum of 23 points, arthritis can be classified as gout with a sensitivity of 92% and a specificity of 89%. Evidence of uric acid crystals on puncture is a sufficient criterion.

DECT: Dual-energy computed tomography; MTP-1: Metatarsophalangeal joint I

 

  • Gouty Arthritis

Treatment of Gouty Arthritis

Gouty Arthritis

The immediate goals for treating a gout flare-up are to reduce intense pain, swelling, warmth, and redness. With proper treatment, gout pain and other symptoms can be under control within 24 hours and completely gone within a matter of days.

  • Ice – A soft cool compress applied to the affected joint can help relieve discomfort.
  • Avoid pressure – Avoid contact with anything. Anything that touches the affected joint may cause a sharp increase in pain.
  • Rest – It is usually painful to use the affected joint, and resting it will help alleviate pain, swelling, and other symptoms.
  • Elevation – Elevate the affected limb to help reduce swelling. If the foot is affected, sit down with the foot resting on a footstool or lie down with the foot propped up on a pillow.
  • Patient education – As already emphasized above, patient education is key to gout management success, as shown by a preliminary study that explored the effect of a predominantly nurse-delivered education program. Following this program, 98 of 103 included patients who had their uricemia at a target after one year of allopurinol treatment, in sharp contrast with what is usually observed . Information should be given on the pathophysiology of the disease, its relationship with uricemia, its curable nature, uricemia targets to be reached, the life-long nature of the urate-lowering treatment, the importance to treat flares early, the mechanisms of ULD-induced flares and ways to prevent them. Patient education takes time and must frequently be repeated, but it is a mandatory tool to achieve success in long-term gout management.
  • Over-the-counter medication – Over-the-counter anti-inflammatory medications, such as ibuprofen and naproxen, can relieve pain, particularly if pills are taken as soon as the patient perceives the gout attack coming on. A doctor should be consulted regarding the adequate dosage. Aspirin should be avoided, since it can impair the kidneys’ ability to filter out uric acid, making gout symptoms worse.
  • Prescription pain relievers – When over-the-counter pain relievers are not sufficient, prescription painkillers such as codeine, hydrocodone, and oxycodone may be prescribed for short-term relief of acute pain.
  • Colchicine – A prescription drug called colchicine is very effective at stopping an acute gout attack. Evidence shows that gout pain, swelling, and inflammation decrease when colchicine is taken within the first 12 to 24 hours of an attack, along with a second, smaller dose an hour or two later. When taken within 12 h after flare onset, 1.8 mg (1.2 mg then 0.6 mg one hour later) of colchicine has been shown to be as effective as the traditional higher doses . In clinical practice, this drug appears as much less efficient when given long after the flare onset. The EULAR and American College of Rheumatology (ACR) have restricted the use of colchicine to patients presenting within 12 and 24 h of flare onset respectively. Colchicine should be taken only as directed. Many people taking colchicine to experience gastrointestinal side effects, such as vomiting or diarrhea.
  • Corticosteroid injections – A doctor may inject the inflamed joint with steroids to relieve the pain. This treatment is particularly useful for people with sensitivities to certain medications. Repeated corticosteroid injections, however, can have side effects. Up until recently, colchicine was the treatment of choice for acute gout. However, due to recent safety concerns, colchicine is now only recommended if NSAIDs or corticosteroids are inappropriate. High dose colchicine therapy is no longer recommended because of its toxicity.
  • NSAIDs – NSAIDs (non-steroidal anti-inflammatory drugs) – These are generally the medicines of choice for most patients who do not have underlying health problems. Aspirin should be avoided as it can alter urate levels and worsen the attack. NSAIDs or COXIBs are used at the maximum authorized dose, with proton inhibitors when indicated. Their efficacy is largely accepted, even though no placebo-controlled trial has been performed. Early prescription allows reducing administered doses.
  • Steroids – Oral prednisone, at a daily dose of 30 mg/d for 7 days has been shown to be effective  and is recommended by the ACR and EULAR panels as potential first-line therapy in the management of gout flares . However, steroids can worsen hypertension and diabetes  and are, in our view, best indicated in patients contraindicated for NSAIDs or colchicine (i.e. CKD patients). Co-prescription of a small dose (0.5–1 mg/d) of colchicine, when not contraindicated, may avoid rare inflammation relapses after steroid cessation. Open studies also suggest that ACTH can relieve gouty inflammation .
  • Intra-articular steroid injections – appear as very efficient and are recommended by both the ACR and the EULAR in the management of mono or pauciarticular flares, despite the lack of randomized clinical trials (RCT).
  • IL-1 blockers – Open studies of the IL-1 receptor antagonist anakinra  support its off-label use in patients resistant or contraindicated to NSAIDs, colchicine, and steroids. Canakinumab, a long-lasting antibody to IL-1 beta, has been approved by the European Medical Agency, following 2 RCT trials against intramuscular triamcinolone acetonide . The EULAR recommends considering IL-1 blockers for the management of gout flares in patients with frequent flares contraindicated to NSAIDs, colchicine, and steroids (oral or injectable). Current infection is a contraindication .
Treatment options for chronic gout
Substance/groupProposed therapyAdverse drug effectsMajor contraindicationsRecommendation gradeComments
Xanthine oxidase inhibitor: allopurinolInitially 50 to 100 mg/day; increase to max. 800 mg/dayDiarrhea, nausea, vomiting, increased liver enzymes, skin reactions (2%), hypersensitivity syndrome (0.1%) [Known hypersensitivity to allopurinol(A) Cochrane review: target serum uric acid levels achieved more frequently with allopurinol than with placebo [Adjust dose in cases of known renal failure (table) Monitor liver and kidney enzyme levels
Xanthine oxidase inhibitor: febuxostatInitially 80 mg/day, increase to 120 mg/day if necessaryLiver dysfunction, diarrhea, nausea, headache, skin rashIschemic heart disease <12 months or decompensated heart failure [(A) Cochrane review: lowers uric acid levels more effectively than allopurinol [If allopurinol not toler‧ated, in cases of renal failure, or if target uric acid level not achieved despite increased allopurinol dose (A)
Uricosuric agent: probenecidProbenecid can be combined with allopurinol if allopurinol alone is insufficiently effective [Irritation of gastrointestinal tract, skin reactions, anorexiaUrolithiasis, advanced renal failure (creatinine clearance <50 ml/min), or increased uric acid production (e.g. during chemotherapy)[(B) There are no placebo-controlled trials of uricosuric agents. RCT [: probenecid less effective than allopurinolTake with sufficient fluids to prevent kidney stone formation
Selective inhibitor of URAT1 transporter: leisureAuthorized in combination with xanthine oxidase inhibitor for treatment-refractory cases since February 2016 [A headache, influenza-like symptoms increased creatinine levels, gastroesophageal refluxSevere renal failure, tumor lysis syndrome, Lesch–Nyhan syndrome(B) RCT: lowers uric acid levels more effectively in combination with allopurinol [Further studies required on cardiovascular safety according to the European Medicines Agency (EMA) [. Therefore not currently recommended by these authors for patients with cardiovascular events <12 months (c).
Uricosuric agent: benzbromaroneNot recommended by these authors due to liver toxicity [ (C)
Uricase: pegloticaseTaken off the market in July 2016 [Uric acid levels reduced due to the breakdown of uric acid into allantoin, which is eliminated in the urine. Adverse drug effects: infusion issues, anaphylaxis, antibody formation.

RCT: Randomized controlled trial

Medicines to reduce uric acid

Long-term management of gout focuses on lowering urate levels, aiming for levels under 0.36 mmol/L, or better still, under 0.30 mmol/L. These medicines can prevent attacks of gouty arthritis and prevent MSU crystals from being deposited in the tissues. Medicines that lower urate levels should not be started during an acute attack of gout; instead they should be started a few weeks after the attack has resolved.

  • Allopurinol – Allopurinol is an effective uric-acid lowering therapy, but it has a number of side effects and interactions with other medicines. Dermatological side effects of allopurinol range from a mild morbilliform eruption (measles-like rash, which resolves when the drug is discontinued) to Stevens-Johnson syndrome / toxic epidermal necrolysis and drug hypersensitivity syndrome. Drug hypersensitivity syndrome is rare but potentially very severe. It usually occurs within the first 6 weeks of therapy but some cases have been reported up to 12 weeks after starting allopurinol.
  • Febuxostat – Febuxostat is a new medication for gout that may be used to reduce urate levels in patients with poor kidney function or intolerant of allopurinol. Phase III clinical trials have reported febuxostat to be more effective than allopurinol at a dose of 300mg.
  • Probenecid – Probenecid is an alternative uric acid lowering medicine with fewer significant side effects than allopurinol. It is important to drink plenty of fluids while on probenecid, to flush out the uric acid and prevent crystals from forming within the kidneys or urinary tract. The starting dose of probenecid is usually 250 mg twice daily but it may need to be increased to up to 1 g twice daily.
  • Benzbromarone – Benzbromarone is a new medication for gout that may be used to reduce urate levels where allopurinol and/or probenecid are contraindicated, not tolerated, or are ineffective. A liver function must be monitored on benzbromarone, as it is reported to cause hepatic toxicity. ACR considers febuxostat as a first-line ULD , whereas for EULAR, the drug is indicated in patients intolerant or refractory to allopurinol. Dose titration is recommended to reduce ULD-induced flares, even though there is no evidence that this improves febuxostat tolerance .
  • Uricosurics – Uricosurics lower uricemia by increasing uric acid output in the urine. Therefore they expose the patients to the risk of uric acid stone, which is worse at the onset of treatment. When uricemia has decreased, urticaria and the risk become lower, as urticaria also decreases. They should not be administered as a monotherapy in patients with a history of uric acid stone or hyperuricosuria and should be taken with abundant water intake; the urinary pH should also be checked and kept above 6 to decrease the concentration of uric acid in the urine, which governs the risk of lithiasis. Except for lesinurad, uricosurics can be used alone; they are now most often used in combination with xanthine oxidase inhibitors when these fail to obtain the uricemia targets.
  • Probenecid – has been the first commercialized ULD  and was at first a very popular drug. When allopurinol became available, probenecid was much less used because it had to be given in divided doses and required high fluid intakes and adjustment of the urine pH. In addition, probenecid, which was first developed to decrease the renal excretion of penicillin, could interfere with the excretion of other organic acid drugs and gastrointestinal or cutaneous intolerance were fairly common. It has been recently confirmed to be a decent ULD, including those patients with moderate kidney involvement and remains one of the therapeutic options in patients intolerant or refractory to allopurinol . The initial dose is 250 mg twice daily, which can be weekly increased up to 1 g twice daily. Larger doses expose to major central nervous system toxicity.
  • Sulfinpyrazone – is not universally available. This uricosuric drug is usually given twice daily at the total daily doses of 200–400 mg, progressively attained. Side effects include gastrointestinal intolerance, skin rashes, platelet aggregation impairment, and rare bone marrow toxicity.
  • Benzbromarone –  is a powerful uricosuric drug, which is used once a day at a dose of 100–200 mg/d. . Following reports of severe liver toxicity, the drug has been retrieved from Europe, where it can still be prescribed on a named patient basis, but is still largely used in Asia. The uricosuric property is largely retained in renal failure patients .
  • Lesinurad – is a selective URAT1 inhibitor that has been recently approved at the dose of 200 mg/d in the USA and Europe, as an add-on therapy to xanthine oxidase inhibitors when these failed to lower uricemia down to the suitable target  . Serum creatinine elevations have been observed, which although most often transient, require renal function monitoring.
  • Fenofibrate –  atorvastatin and losartan are non-licensed uricosurics which can be used to treat gout comorbidities or in association with xanthine oxidase inhibitors .
  • Urate oxidases – Rasburicase is a short-life IV uricase, which is approved for the management of tumor lysis syndrome. Its non-licensed use has been reported in a tophaceous gout . Pegloticase is a PEGylated uricase that has been approved, in the USA and Europe, for the management of severe gout, refractory to oral ULDs and is commercially available in the USA. The drug is administered by IV infusions of 8 mg every 2 weeks and has been shown to be very effective . Antibodies develop at high titers in about half of the patients, leading to loss of uricemia response and to an increased risk of serious infusion reactions. It is therefore recommended to measure uricemia in the 24 h preceding every planned reinfusion and to stop the drug if uricemia is not decreased. No other ULD should be prescribed concomitantly to keep this warning signal.
  • Canakinumab –Canakinumab, a monoclonal antibody, neutralizes IL-1β to suppress inflammation. Canakinumab is a US Food and Drug Administration (FDA)-approved for cryopyrin-associated periodic fever syndromes, Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and systemic idiopathic juvenile arthritis. Phase 3 trials of canakinumab by Schlesinger et al. demonstrated its efficacy in acute gout and for prophylaxis during a-lowering therapy (ULT) . The FDA declined to approve canakinumab for acute gout therapy, citing concerns about the use of a long-acting immunosuppressant for an ostensibly short-term condition. In contrast, the European Medicines Agency approved canakinumab for the same indication.
  • Anakinra –Anakinra is a recombinant human IL-1β receptor antagonist that is FDA-approved for rheumatoid arthritis and neonatal-onset multisystem inflammatory disease. To date, randomized controlled trials assessing anakinra’s efficacy in the management of gout are lacking , but case series and uncontrolled trials support its efficacy . In practice, anakinra has been the preferred off-label anti-IL-1β strategy among experienced gerontologists, based on its relatively short half-life and lower cost compared with canakinumab.
  • Pegloticase – Pegloticase is a recombinant, pegylated uricase that degrades uric acid . Approved by the FDA in 2010, pegloticase is indicated for the treatment of hyperuricemia in adults with chronic or tophaceous gout refractory to conventional ULT. Pegloticase is administered intravenously every 2 weeks. Studies confirm the ability of pegloticase to rapidly and dramatically lower sUA and to promote the often-dramatic resolution of tophi .
  • Lesinurad Lesinurad is a selective, highly potent uric acid reabsorption inhibitor. Lesinurad reduces sUA by inhibiting both the USA-anion exchanger transporter 1 (URAT1) and the organic anion transporter 4 (OAT4), which are involved in the reabsorption of sUA across the renal proximal tubule . In contrast to the older uricosuric probenecid, lesinurad is more potent and remains effective even in moderate renal insufficiency.
  • Arhalofenate Arhalofenate is a pipeline drug with a dual mechanism of action. Patients initiating ULT are routinely prescribed concurrent anti-inflammatory prophylaxis to reduce the risk of gout attacks precipitated by the sUA-lowering process itself. Historically, all gout medications have been either anti-inflammatory or sUA-lowering. In contrast, halogenate, a peroxisome proliferator-activated receptor-gamma (PPAR-γ) partial agonist, demonstrates dual ULT and anti-inflammatory effects. Specifically, halogenate inhibits expression of IL-1β while inhibiting renal reabsorption of uric acid at the URAT1, OAT4, and OAT10 transporters .
  • Allgemeinmedizin recommends that uric acid levels should be maintained below 6.5 mg [. The EULAR advises uric acid levels of less than 6 mg/dL, and even as low as <5 mg/dL in patients with severe gout (B). Lifelong therapy is recommended. A prospective cohort study has shown that withdrawal can be attempted after uric acid levels have successfully been maintained at a low level for more than 5 years [ (B).
  • Complementary and Alternative Therapies  – A combination of therapies can be very effective at reducing both the length and frequency of attacks. When choosing complementary and alternative therapies (CAM) for gout treatment, it is best to work with a knowledgeable provider. Herbs and supplements that may be beneficial for some people, maybe harmful to others. If you are pregnant or thinking about becoming pregnant, do not use any CAM therapies unless directed to do so by your physician.

Nutrition and Supplements

These nutritional tips may help reduce symptoms:

  • Eliminate potential food allergens, including dairy, wheat (gluten), corn, preservatives, and food additives. Your health care provider may test for food sensitivities.
  • Eat antioxidant-rich foods, including fruits (such as blueberries, cherries, and tomatoes), and vegetables (such as squash and bell peppers). Some nutrition-minded doctors promote a low fructose diet to treat gout. Another theory states that one-half pound of cherries per day (fresh or frozen) for 2 weeks lowers uric acid and prevents attacks. Cherry juice (8 to 16 oz. per day) is also helpful.
  • Eat more high fiber foods, including oats, root vegetables (such as potatoes and yams), and psyllium seed.
  • Avoid refined foods, such as white bread, pasta, and sugar.
  • Eat fewer red meats and more lean meats, cold-water fish, tofu (soy, if no allergy) or beans for protein.
  • Cut down on foods containing oxalates, such as spinach, rhubarb, beets, nuts, chocolate, black tea, wheat bran, strawberries, and beans.
  • Include foods rich in magnesium and low in calcium, such as barley, bran, corn, rye, oats, soy, brown rice, avocado, banana, and potato.
  • Restrict purines in your diet. Foods with high purine content include beef, goose, organ meats, sweetbreads, mussels, anchovies, herring, mackerel, and yeast. Foods with a moderate amount of purines include meats, poultry, fish, and shellfish not listed above. Spinach, asparagus, beans, lentils, mushrooms, and dried peas also contain moderate amounts of purines.
  • Use healthy cooking oils, such as olive oil or coconut oil.
  • Reduce or eliminate trans fatty acids, found in commercially baked goods, such as cookies, crackers, cakes, French fries, onion rings, donuts, processed foods, and margarine.
  • Avoid alcohol and tobacco.
  • Drink 6 to 8 glasses of filtered water daily to help flush uric acid from the body. Dehydration often triggers a gout attack.
  • Exercise at least 30 minutes daily, 5 days a week.
  • Avoid sugar-sweetened soft drinks. Diet soft drinks have not been associated with the risk of gout.
  • Preliminary studies suggest moderate coffee consumption may help alleviate symptoms.

You may address nutritional deficiencies with the following supplements:

  • A daily multivitamin, containing the antioxidant vitamins A, C, E, the B-complex vitamins, and trace minerals, such as magnesium, calcium, zinc, and selenium.
  • Omega-3 fatty acids, such as fish oil, to help reduce inflammation and promote general health. Cold-water fish, such as salmon or halibut, are good sources. Talk to your provider before taking omega-3 supplements if you are taking blood-thinning medications, such as aspirin or warfarin (Coumadin).
  • Inositol hexophosphonate (IP-6). Check with your alternative health care provider for proper dosing.

Caution – May increase the blood-thinning effects of anti-clotting medications, such as warfarin and others. IP-6 may lower iron and calcium in the body.

  • N-acetyl cysteine, for antioxidant effects.
  • Vitamin C, as an antioxidant. In one study, higher vitamin C intake was independently associated with a lower risk of gout.
  • Acidophilus (Lactobacillus acidophilus). When needed to maintain gastrointestinal and immune health. Some acidophilus products may need refrigeration. Although acidophilus is good for the immune system, people with severely compromised immune systems should check with their physicians before starting a probiotic supplement. Check the labels carefully.
  • Methylsulfonylmethane (MSM), to help reduce inflammation.

Avoid taking extra niacin and vitamin A. Both may play a role in gout.


Herbs

Herbs are generally a safe way to strengthen and tone the body’s systems. As with any therapy, you should work with your provider before starting any treatment. You may use herbs as dried extracts (capsules, powders, or teas), glycerites (glycerine extracts), or tinctures (alcohol extracts). Unless otherwise indicated, make teas with 1 tsp. herb per cup of hot water. Steep covered 5 to 10 minutes for leaf or flowers, and 10 to 20 minutes for roots. Drink 2 to 4 cups per day. You may use tinctures alone, or in combination, as noted.

  • Cranberry (Vaccinium macrocarpon). For kidney health. You may also take 8 to 16 ounces of unsweetened cranberry juice daily.
  • Green tea (Camellia Sinensis). For antioxidant and immune effects. Use caffeine-free products. You may also prepare teas from the leaf of this herb.
  • Devil’s claw (Harpagophytum procumbens). For pain and inflammation. Devil’s claw may increase the blood-thinning effect of certain medications, such as aspirin and warfarin (Coumadin). Devil’s claw should never be used during pregnancy, or while breastfeeding. It can potentially affect blood sugar levels, as well as blood pressure, and can interact with many medications.
  • Cat’s claw (Uncaria tomentosa) standardized extract. For inflammation, immune, and antibacterial/antifungal activity. Cat’s claw may worsen certain conditions, such as leukemia or some autoimmune disorders. Cat’s claw may also interact with many different medications. Talk to your doctor.
  • Bromelain (Ananas comosus). For pain and inflammation. Bromelain can increase the blood-thinning effect of certain medications, such as aspirin and warfarin (Coumadin).
  • Turmeric (Curcuma longa). For inflammation. Tumeric may increase the blood-thinning effect of certain medications, such as aspirin and warfarin (Coumadin).

Homeopathy

Although few studies have examined the effectiveness of specific homeopathic therapies, professional homeopaths may consider the following remedies for the treatment of gout symptoms (such as pain and inflammation) based on their knowledge and experience. Before prescribing a remedy, homeopaths take into account your constitutional type, includes your physical, emotional, and psychological makeup. An experienced homeopath assesses all of these factors when determining the most appropriate treatment for you individually.

Some of the most common remedies used for gout are listed below. A common dose is 3 to 5 pellets of a 12X – 30C remedy every 1 to 4 hours until your symptoms improve.

  • Aconite – For the sudden onset of burning pain, anxiety, restlessness, and attacks that come after a shock or injury. Also, take if your joints are swollen and painful.
  • Belladonna – For intense pain that may be throbbing, if motion worsens pain and pressure improves it, or if the joint is very hot.
  • Berberis vulgaris  For spasms of pain in joints or twinges made worse by walking. There may be back pain and a tendency to develop kidney stones.
  • Bryonia –For pain that worsens with motion, or if the pain is better with pressure and with heat.
  • Colchicum –For pains made worse by motion and weather changes, especially if there is any nausea associated with the attacks.
  • Ledum -When joints become mottled, purple, and swollen, or if the pain is much better with cold applications and is worse when overheated.
  • Rhus Toxicodendron – For stiff, swollen joints that are hot and painful, or if the pain is worse with cold applications and better with heat.


References

Gouty Arthritis


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