Gout is the arthritic syndrome due to the deposition of monosodium urate crystals. The attacks tend to come in discrete episodes, with normal joints in the intervening period, until late stages of the disease. Gout attacks often are monoarticular, but polyarticular episodes can occur.
Primary gout is not associated with an identifiable cause, other than perhaps a family history. Secondary gout refers to the presence of a recognized cause or precipitating factor, such as lymphoma (especially following chemotherapy), the excessive use of alcohol, or the use of diuretics (see Pathogenesis below).
Gout develops as a result of the build-up of purines in the body, either by decreased excretion (about 90% of cases of primary gout) or by increased production (about 10% of primary gout). When the concentration of urate exceeds its solubility, crystals precipitate, and the crystals are phlogistic. The crystals lead to activation of the classical and alternative pathways of complement, the influx of neutrophils into the joint, and the release of numerous inflammatory cytokines. In those patients who are over-producers of uric acid, their 24-hour urinary uric acid will likely be elevated, and they will be at risk of urate kidney stones as well as gouty attacks.
Gout is associated with atherosclerosis, hypertension and renal insufficiency, but there remains debate as to whether the association is independent. That is, debate exists as to whether patients with renal disease, for example, have elevated serum uric acid levels due purely to their decreased glomerular filtration rate or whether the hyperuricemia itself can damage the kidney (and whether uric acid is a risk factor for hypertension and coronary artery disease). In rats, data suggest that hyperuricemia has a direct effect on renal blood vessels.
Until the age of menopause, women lag far behind men in the incidence of gout. After menopause, the numbers become closer to equal, but still favor men.
Any factors that raise nucleoprotein production will increase its breakdown -- ultimately, by the action of xanthine oxidase -- into uric acid. Factors that decrease the secretion, or increase the reabsorption, of uric acid will likewise increase the risk of gout.
Secondary factors that may contribute to the elevation of serum urate and the development of gout include:
III. Clinical Presentation
From a diagnostic and therapeutic point of view, gout is most efficiently seen in three distinct stages: acute gout, inter-critical (between attacks) gout, and chronic tophaceous gout.
A. Acute gout
In about 70% of acute gout attacks, a single joint becomes suddenly inflamed, often with excruciating pain, erythema, swelling and exquisite tenderness. The attack may be accompanied by chills and a low fever. If untreated, the attack generally peaks within 24 hours and may linger for weeks, especially if the patient continues to use the affected joint actively. Those who get one attack of gout will generally get further attacks, usually within 2 years; 62% have a second attack within a year - and 90% within 10 years. However, 10% never experience an attack again.
The first metatarso-phalangeal (MTP) joint is the single most likely joint to be affected by gout, but many other joints can be involved. The mid-foot, ankle and knee are, respectively, the next most common locations, and the olecranon bursa may also be involved. Gout attacks in Heberden's nodes, especially in elderly women, have been frequently described. Gout is sufficiently rare enough in the shoulders and hips as to suggest that a different cause may be present, even in patients with known gouty arthritis.
Other diseases can also affect the first metatarso-phalangeal joint, such as pseudogout and Reiter's syndrome, (see Differential Diagnosis below), so involvement of this joint does not provide a definitive diagnosis of gout.
B. Inter-critical gout
Patients seen between gouty attacks generally appear normal - with no symptoms and with unremarkable joint examinations. The exception to this is in patients with long-standing gout who develop chronic tophaceous gout. The greatest controversies in the treatment of gout concern patients in the inter-critical phase.
C. Chronic Tophaceous Gout
After multiple gouty attacks, some permanent changes may occur in the joint, including joint damage and large collections of uric acid, or tophi.
Multiple tophi in the hands of a patient with long-standing gout.
Tophi can drain the white uric acid crystals to the surface, which presents an infection risk.
Gout tophi draining to the surface of the skin over a distal inter-phalangeal joint of the finger.
Patients with tophi are often over-producers of uric acid and therefore have elevated 24-hour urinary uric acid and are at risk of kidney stones.
IV. Laboratory Findings
The great majority of patients with gout have hyperuricemia. However, this is not always true, and some patients drop their serum urate levels in the setting of an acute attack.
Since gout is a life-long disease, often requiring life-long therapy, the importance of a definitive diagnosis cannot be over-emphasized. When a patient first presents with possible gout, it is almost always optimal to drain synovial fluid to examine for crystals. The needle-shaped urate crystals, seen as strongly negatively birefringent under polarized light microscopy, confirm the diagnosis. In some cases, the definitive diagnosis is even easier, such as when the patient has a tophus on the ear, where a scrape of the skin will provide material for crystal analysis, or when a tophus is about to break through to the skin - and a 27- or 30-gauge needle can be used to puncture the skin and obtain material for crystal analysis. It has been well-documented that urate crystals can even be found in asymptomatic metatarso-phalangeal joints. It is more difficult to aspirate a joint with minimal fluid, but often the diagnosis of gout can be made from only the tiny drop of serosanguinous fluid at the tip of an aspirating needle.
The 24-hour urinary urate determination can help when the prescriber is unsure whether to consider using probenecid as a uricosuric agent in a particular patient. When a patient is identified as a high urate excretor (i.e., an over-producer rather than an under-excretor), this is a significant push toward using avoiding the use of probenecid. Patients who excrete more than 800 mg of urate per 24h are considered over-excretors. When the decision is made to treat a patient with a xanthine oxidase inhibitor, such as allopurinol or febuxostat, then 24 hour uric acid determination may not be necessary, since decreasing the production of uric acid is effective therapy for both the overproducer and the underexcretor.
X-rays are often normal early in gout, but in later stages (e.g. chronic tophaceous gout) the x-rays can help distinguish gout from other conditions.
X-ray changes in chronic tophaceous gout. White arrow = erosion with overhanging edge.
X-rays in gout differ from those in rheumatoid arthritis in that there is no periarticular osteopenia. Erosions are seen in gout, but without surrounding decreased bone density.
V. Differential Diagnosis
Without crystal identification, great caution needs to be taken before making a diagnosis of gout, in view of the chronic treatment implications. The two "major criteria" for the diagnosis of gout are the documentation of urate crystals in either a joint or in a tophus.
Since certain clinical situations preclude crystal identification (e.g. patient refusal of arthrocentesis), "minor criteria" for gout diagnosis have been set up. To make the presumptive diagnosis of gout, six of the following 12 criteria should be present (note the importance of the history of a single joint with rapid and marked inflammation):
In addition, it's important to differentiate gout from pseudogout. Ideally, the differentiation is made by identifying the calcium pyrophosphate crystals under polarizing microscopy. When this is not possible, some clues to strongly consider pseudogout are:
1. calcifications seen in typical locations for pseudogout, e.g. the knee menisci, the triangular cartilage of the wrist, or surrounding the humeral head;
2. acute arthritis that seems like gout but is in a joint not usually involved by gout, such as the wrists, shoulders or elbows. (Gout is common in the olecranon bursa but rare in the elbow joint itself; osteoarthritis of the knees is much more prominent in the patello-femoral joint than in the medial or lateral compartment.)
VI. Initial Treatment
A number of different treatments are available for the management of acute gout. The options for managing chronic gout are more limited (see Long-Term Management Issues). A way to help patients think about the different approaches to gout treatment has been suggested by Dr. Robert L. Wortmann (see reference "1" below).
Other factors in management of acute gout
VII. Long-term Management Issues
B. Medications for Inter-Critical Gout
Because of their relative safety, uricosuric drugs are good choices for patients with recurrent gouty attacks despite colchicine prophylaxis in those who have a creatinine clearance greater than 80 mL/m. (These medications are not effective in the setting of renal insufficiency). Uricosurics prevent reabsorption of uric acid by the kidney, and therefore their major risk is kidney stone. Thus, once a patient is placed on a uricosuric agent, it is reasonable to follow up on the 24-hour urinary uric acid to be sure that the amount has not risen above ~600 mg/24h. If it does, then the gout risk may be lowered while increasing the risk of kidney stone. Patients on uricosurics also need to be sure to take sufficient water to maintain a strong urine flow.
A new uricosuric agent, presently known only as RDEA 594, is currently under investigation. This agent can be used once a day, rather than the twice-daily probenecid, and has other features that might make it easier to use than probenecid.
Allopurinol has, rarely, caused a severe allergic reaction, the so-called “allopurinol hypersensitivity syndrome,” with leukopenia, fever, very severe skin rash, and a significant mortality. It remains unclear whether this is a dose-related phenomenon, although one uncontrolled case report described all 11 cases with this syndrome as having renal insufficiency, raising the question of allopurinol accumulation. Febuxostat may avoid this issue of accumulation in patients with mild to moderate renal insufficiency. Recent studies, so far presented only in abstract form, have reached different conclusions as to whether renal insufficiency is a risk factor for allopurinol hypersensitivity.
General considerations in the management of chronic gout require taking each patient on an individual basis.
Considerations regarding long-term treatment of gout include:
When choosing to use no prophylaxis, versus colchicine, a uricosuric or xanthine oxidase inhibitor, one must note whether the patient is likely to comply with treatment. Allopurinol, for example, carries some long-term risk of liver toxicity, and may not be ideal in a patient who cannot be counted on to have lab tests on a 6-12 month basis. The variability of gout severity and joint damage makes it important to assess these issues in each patients. Concurrent illnesses, such as alcoholism, renal insufficiency and colitis, would all have an impact on the choice of chronic medication for gout.
C. Management of Chronic Tophaceous Gout
D. Management of Patients with Gout and Kidney Stones
E. Management of hypertension, obesity, hyperlipidemia, and coronary disease in patients with gout
Gout as a clue to the above conditions is important in that they should be sought in any patient with gout. It appears to be quite clear that hyperuricemia is an independent risk factor for coronary artery disease. It has not been proven as yet that lowering uric acid improves outcome in patients with coronary artery disease, so at this time it cannot be justified to treat asymptomatic hyperuricemia on the basis of cardiac prevention or treatment. It should be noted that patients with gout quite often have many cardiac risk factors, and they should be closely monitored and managed in terms of risk factor reduction.
Response to treatment is generally quite good, and most patients with gout can be managed with allopurinol (or probenecid) or febuxostat.
IX. Future Possible Alternatives for Gout Management
For treatment of acute gout, there is some early case report evidence that the IL-1 receptor antagonist anakinra is helpful for acute gout in patients where other therapies are ineffective or contra-indicated. Two longer-acting IL1 blockers are under study [canakinumab (Ilaris®) and rilonacept (Arcalyst®)], both for acute treatment of gout and for prophylaxis against gout attacks early in the course of uric acid lowering therapy.
X. When to Seek Referral to a Specialist
Most patients with gout can be managed by their primary care physicians. Cases where a rheumatologist may be helpful include:
XI. Annotated References
A. Wortmann RL. Effective management of gout: an analogy. Am J Med. 1998 Dec;105(6):513-4. A review article that includes the "match" analogy to help patients understand the management of the various stages of gout.
B. Schneiter J. Gout Hater's Cookbook: Recipes Lower in Purines and Lower in Fat. (Reachment Publications; 2000) In addition to comprehensive lists of foods lower, relatively high, and highest in purines, this book offers nearly 100 low-purine recipes.
C. Schneiter J. Gout Hater's Cookbook II: The Low Purine Diet Cookbook. (Reachment Publications: 2001) More recipes from the same author. This book is useful for your patients, who often find the recommendations about low purine diets confusing and difficult to follow even when well understood.
D. Wallace SL, Singer JZ. Review: Systemic toxicity associated with the intravenous administration of colchicine - Guidelines for use. J Rheumatol 1987;15:495-9. This is an important article on potentially lethal complications of intravenous colchicine; it emphasizes the importance of renal insufficiency as a risk factor for complications.
E. Singer JZ, Wallace SL. The allopurinol hypersensitivity syndrome: Unnecessary morbidity and mortality. Arthritis Rheum 1986;29:82-6. This article stresses the importance of renal insufficiency as a risk factor in allopurinol hypersensitivity, and the importance of reducing allopurinol dose in patients with renal insufficiency and of making sure that only patients who meet appropriate criteria get treated with allopurinol.
F. Moriwaki Y, Yamamoto T, Takahashi S, et al. Spot urine uric acid to creatinine ratio used in the estimation of uric acid excretion in primary gout. J Rheum 2001;28:1306-10. This article is part of an ongoing discussion among rheumatologists as to whether spot urinary urate/creatinine ratio can replace 24-hour urinary urate determination.
G. Fam AG, Dunne SM, Iazzetta J, et al. Efficacy and safety of desensitization to allopurinol following cutaneous reactions. Arthritis Rheum 2001;44:231. This article reviews a regimen of oral desensitization to allopurinol, which has had significant success with low risk.
H. Sundy JS et al: Reduction of Plasma Urate Levels Following Treatment With Multiple Doses of Pegloticase (Polyethylene Glycol–Conjugated Uricase) in Patients With Treatment-Failure Gout: Results of a Phase II Randomized Study. Arthritis Rheum 58:9, 2882-2891, 2008. This article showed the effectiveness of pegloticase in rapidly lowering uric acid level.
I. Baraf, HSB et al: Reduction of tophus size with pegloticase (PGL) in treatment failure gout (TFG): Results from Gout-1 and Gout-2, European League Against Rheumatism Abstract OP-0047, June 2009. Abstract from European League Against Rheumatism Meeting 2009. Tophi were shown to be rapidly decreased in size.
K. So A et al: A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Research & Therapy 9(2):R28, 2007. IL-1 receptor blocker was shown effective in acute gout.
L. Terkeltaub R et al: The interleukin 1 inhibitor rilonacept in treatment of chronic gouty arthritis: results of a placebo-controlled, monosequence crossover, non-randomised, single-blind pilot study. Annals of Rheumatic Disease 68:1613-1617, 2009. IL-1 receptor inhibition was shown to be effective in acute gout, with a longer-acting blocker.
M. So A at al: Canakinumab (ACZ885) Vs. Triamcinolone Acetonide for Treatment of Acute Flares and Prevention of Recurrent Flares in Gouty Arthritis Patients Refractory to or Contraindicated to NSAIDs and/or Colchicine. American College of Rheumatology Abstract LB4, October 2009. Abstract from American College of Rheumatology Meeting, Oct. 2009. An extended-release blocker of IL-1 was effective in both treating flares and preventing the flares induced by urate lowering agents.
N. Yeh N et al: RDEA594, a potential uric acid lowering agent through inhibition of uric acid reuptake, shows better pharmocokinetics than its prodrug, RDEA806, poster #28, American College of Rheumatology Meeting, October 2008. Abstract from American College of Rheumatology Meeting 2008. A uricosuric is under study which may be easier to use and more effective than probenecid.
O. Fitz-patrick D et al: Abstract 150: Effects of a Purine Nucleoside Phosphorylase Inhibitor, BCX4208, on the Serum Uric Acid Concentrations in Patients with Gout. Abstract from the American College of Rheumatology Meeting November 2010. Another blocker of uric acid production is under study.