Clinical Features and Natural Course

Introduction

The natural course of classic gout passes through three stages (Figure 3-1):

• Asymptomatic hyperuricemia
• Acute/intermittent gout
• Advanced gout (or what used to be called chronic tophaceous gout).

The rate of progression from asymptomatic hyperuricemia to advanced gout varies considerably from person to person and is dependent on numerous endogenous and exogenous factors, the most important of which is serum urate concentration (Who Gets Gout?).

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Asymptomatic Hyperuricemia

Hyperuricemia is defined in both men and women as a state in which the serum urate level exceeds 6.8 mg/dL; above this concentration in vitro, urate ions are insoluble in physiologic fluids at normal pH and temperature. The term “asymptomatic hyperuricemia” is the state in which serum urate concentration is above the solubility level, but no symptoms or signs of gout or kidney stones have occurred. Men generally attain their adult level of serum urate shortly after puberty. Women, on the other hand, maintain a relatively low concentration of serum urate throughout most of their adult lives and only at the time of menopause do they reach their adult maximum concentration due to loss of the uricosuric effect of estrogen. Since the clinical symptoms of gout are a consequence of the accumulated level of urate over time, the difference between the time of attaining maximum adult serum urate levels between men and women is the reason for a male predominance of this disease. In the postmenopause period, the incidence of gout in women gradually approaches that in elderly men.

During the period of asymptomatic hyperuricemia, MSU crystals can develop intra-articularly and be deposited over the articular cartilage as well as in the synovial lining. Small aggregates of these crystals (referred to as “microtophi”) can be seen microscopically and contribute to the total body urate burden (Figure 3-1). This urate burden will continue to grow in the presence of hyperuricemia and is ultimately responsible for the progression of clinical symptoms through the various stages of gout. The microtophi remain stable as long as the synovial fluid and extracellular fluid bathing them maintain a constant urate concentration, pH and temperature. This period of asymptomatic hyperuricemia can extend for several decades in most men with primary hyperuricemia. It can also be as short as 1 to 2 years in patients being treated with cyclosporine or those who have inborn errors of purine metabolism resulting in uric acid overproduction.

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Acute Intermittent Gout

This is the stage that most people think of when they envision a patient with gout. In men, the initial attack usually occurs between the fourth and sixth decades of life, although onset of gout in older people is increasingly common (Who Gets Gout?). In women, the age at onset is older and varies with several factors, the most important of which is the age at menopause. The classic description of the initial gout attack is outlined in Table 3-1. The pain is usually explosive with escalation from no pain to maximum intensity over an 8- to 12-hour period. The initial attack usually occurs in a single joint and most often in a joint of the lower extremity.

In more than 50% of cases, the presentation will include involvement of the first metatarsophalangeal (MTP) joint, also known as podagra (Figure 3-2). Other commonly involved joints with mono- and oligoarthritis include the hands, wrists, midfoot, ankles and knees. The pain of acute gout is usually listed as an 8 to 10 on a 10-point scale and often described as excruciating; most patients will be unable to bear weight on the afflicted joints. Systemic symptoms, such as low-grade fever, chills and malaise, frequently accompany gout. The intensity of the inflammation also involves the overlying skin, with erythema frequently extending beyond the area of the joint, sometimes resembling a bacterial cellulitis. An acute stress reaction with an elevated peripheral white blood cell (WBC) count and elevated acute-phase reactants are typical. The severe phase of the initial attack usually lasts 3 to 4 days, with gradual lessening of the pain over the next 3 to 4 days, with the total attack lasting approximately 1 week to 10 days if untreated, with desquamation of the skin overlying the affected joint classic as the attack resolves.

The self-resolving nature of these painful attacks is characteristic of gout and is an important historic feature when making the diagnosis of gout clinically.

Recurrence rates after the initial attack of gout are relatively high. A 2019 study from Olmsted Couty, Minnesota, examined gout flare recurrence rates in two cohorts: one consisting of patients diagnosed in 1989-1992, and the other of patients diagnosed in 2009-2010. The study reported the following cumulative gout flare recurrence rates:

• 1 year: 30% (1989-1992 cohort) and 37% (2009-2010 cohort)
• 2 years: 45% (1989-1992 cohort) and 51% (2009-2010 cohort)
• 3 years: 56% (1989-1992 cohort) and 54% (2009-2010 cohort)
• 4 years: 58% (1989-1992 cohort) and 57% (2009-2010 cohort)
• 5 years: 62% (1989-1992 cohort) and 60% (2009-2010 cohort).

Untreated, up to 75% of patients will develop tophaceous gout within 20 years of initial attack. Tophus and clinical gout development are more rapid in the elderly and in cyclosporine-treated major organ transplant–associated gout.

The period of acute/intermittent gout will typically last for a decade or more, with acute flares being interspersed with periods of no joint symptoms. The mean duration between the initial attacks of gout are approximately 11 months, but as more and more attacks occur, this interval between the acute attacks (inter-critical period) decreases and the duration of the flare itself will increase from a week up to 10-14 days in the latter stages of acute intermittent gout. If urate-lowering therapy (ULT) is not introduced during this period, there will be gradual accumulation of urate crystals in and around the joints and bursae (e.g., olecranon and first MTP joint bursae) and sometimes in the subcutaneous tissues. Although not palpable or visible, tophi are present during this stage and have been documented by computed tomography (CT), ultrasound and magnetic resonance imaging (MRI) studies (Figure 3-3 and Figure 3-4).

Areas of bone destruction caused by the presence of periarticular tophi can also begin at this stage. Toward the end of this middle stage of clinical gout, joints in the upper extremity as well as bursae and tendons can become clinically involved, but high resolution ultrasound shows subclinical Achilles tendon involvement and patellar enthesopathy, as well as tophi, even in a fraction of subjects with asymptomatic hyperuricemia. It is also common for several joints to be involved during an acute flare during the latter stages of acute intermittent gout (Figure 3-5).

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Advanced Gout

Eventually, untreated patients with acute intermittent gout will progress to advanced gout in which the pain-free intercritical periods have disappeared and the patient develops a chronic arthritis due to tophaceous disease and chronic proliferative synovial inflammation, in which the joints are persistently stiff, swollen and painful (Table 3-2). Acute flares will continue during this time period of chronic pain. In this stage of gout, involvement of joints in the upper extremity often becomes a prominent clinical feature (Figure 3-6). The clinically evident tophi may or may not be detected by physical exam during the first few years of this stage, but with time will occur in most patients. The development of tophi is a function of the duration and severity of hyperuricemia. Gouty tophi can be found almost anywhere over the body. Although uric acid deposits are most apparent in the fingers, wrists, helix and antihelix of the ears, knees and bursae around the patella, olecranon bursae and a pressure point such as the ulnar aspect of the forearm and the Achilles tendon (Figure 3-7), advanced imaging and autopsy studies have revealed that deposits also occur in the spine, heart and vasculature, kidneys, and many other tissues (see the Systemic Urate Deposition sub-section below). In older patients with nodal osteoarthritis of the hands, tophi have a propensity for forming in Heberden’s and Bouchard’s nodes (Figure 3-8). This is especially true in elderly women who develop gout.

Gout at this stage can be confused with rheumatoid arthritis(RA), in light of bilateral and diffuse involvement of small and large joints and especially if the tophi are mistaken for rheumatoid nodules. A loss of function occurs and quality of life (QOL) is greatly impacted during this stage. Patients with advanced gout have a similar level of disability as patients with advanced RA.

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Nonclassic Presentations of Gouty Arthritis

Early-Onset Gout

While we generally think of gout affecting men in their 40s and 50s, about 5% of patients with gout had symptom onset before age 25. This subgroup of gout patients generally has a genetic component to their disease and a more accelerated clinical course requiring more aggressive antihyperuricemic therapies. A uric acid overproduction state should be ruled out in this subset. Nephrolithiasis is also much more common in this group of gout patients. Patients with gout diagnosed at an age of less than 40 years, have a much higher rate of CVD risk factors.

Gout in Women

Ninety percent of women who develop gout do so postmenopausally. Those who have gouty symptoms before menopause usually have hypertension and chronic kidney disease (CKD), and many are using thiazide or loop diuretics. A history of other family members having gout is also much more prominent in women with gout.

Gout and Major Organ Transplant

Hyperuricemia is present in about 75% of heart transplant recipients who take cyclosporine (Difficult Gout and Hyperuricemia). In kidney and liver transplant recipients on cyclosporine, the incidence of gout is approximately 50%. In general, the patients with organ transplant–related gout have a greatly accelerated course from asymptomatic hyperuricemia to advanced and tophaceous disease. The stage of asymptomatic hyperuricemia may last several years instead of the several decades seen in classic gout. Similarly, the period of acute intermittent gout may last for only several years before progressing into advanced destructive arthritis. Early involvement of the hips (and other joints typically spared in early gout) is common in major transplant-associated gout, and polyarticular gout flares are common. Gout flares often break through maintenance low-dose prednisone (up to 7.5-15 mg/day) in major organ transplant-associated gout.

Acute Polyarticular Gout

In older individuals, acute polyarticular flares of gout may be the initial clinical presentation of the disease (Difficult Gout and Hyperuricemia). Acute polyarticular gout often presents with fever and peripheral blood leukocytosis (which can reach the 20,000/mm³ range) and thereby may mimic sepsis. In part because joints affected by gout are more prone to infection, inpatient admission and blood and joint cultures are often required in work-up and management of acute polyarticular gout.

Axial Skeletal Gout

Gout is usually thought of as being a peripheral arthritis with a predilection for the coolest of joints. However, numerous case reports have been published over the past few decades documenting vertebral and sacroiliac involvement. Many of these reports describe spinal cord impingement caused by a tophus in the spinal canal or an acutely painful back problem mimicking an epidural abscess. These symptoms usually occur in patients with long-standing tophaceous gout but occasionally they may be the presenting symptom of gout. Since the advent of dual-energy computed tomography (DECT) scanning, we now appreciate that uric acid deposition in the spine is not a rare finding in gout patients and may occur in as many as 15% (Figure 3-9). It is still not clear how much of the chronic back pain experienced by gout patients may be related to such deposits.

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Systemic Urate Deposition

Historically, MSU crystal deposition was thought to occur primarily in articular and periarticular locations, with extra-articular deposits thought to be rare and not clinically relevant. However, recent advances in imaging technology and utilization (e.g., the increased use of DECT in gout evaluation), have revealed that MSU crystal deposits can be found in many tissues. In a 2020 review, Khanna and colleagues have collated 290 reports of extra-articular MSU deposition from imaging, surgical, histopathological, autopsy and other studies. These studies reported MSU deposits in a wide range of anatomic locations, including the spine (113 reports), skin (48 reports), ocular and periocular tissues (36 reports), kidneys (25 reports), cardiac and vascular tissues (21 reports), larynx (11 reports) and other organs and tissues (bowel, breast, pancreas, nose, lungs, prostate, liver, penis, pelvis and nailbed; <10 reports each). Extra-articular MSU deposits may increase both local and systemic inflammation, and could represent a mechanistic link with common gout comorbidities, including hypertension, CKD, heart failure and atherosclerotic cardiovascular disease.

Clinical Presentations of Renal Disease With Gout and Hyperuricemia

The most common clinical renal manifestation linked with gout is urolithiasis with uric acid calculi forming in acid urine (Table 3-3, Figure 3-10). Calcium oxalate stones also can occur. Chronic MSU crystal deposition in the physiologic pH of the renal interstitium (“gouty nephropathy”) occurs in many with advanced gout (Figure 3-11), where it can be detected on detailed histopathologic exam (typically at autopsy). However, chronic gouty nephropathy as a clinical entity causing marked renal function impairment is now much less common than it was in the first part of the 20th century before advent of effective management of both hyperuricemia and hypertension. Tumor Lysis Syndrome (TLS) is a dreaded complication of acute uric acid overproduction via marked cell death (Table 3-4). In TLS, marked uric acid crystallization in the renal collecting system is followed by obstruction-induced renal impairment. Attention to risk factors for TLS is essential, and TLS can be effectively prevented by prophylactic ULT with a xanthine oxidase inhibitor or FDA-approved recombinant uricase (rasburicase) therapy. Supportive care for TLS includes fluids and urine alkalization.

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Take-Away Messages

• The characteristic presentation of acute gout is excruciatingly painful intermittent flares with associated inflammatory symptoms and signs, and lab abnormalities linked to inflammation.
• The majority of patients with gout will have further flares within the first few years following the first flare.
• Over time, the clinical course of gout is progressive, with development of tophi at various joints and urate deposition in other organ systems.
• Early, effective intervention with ULT halts the clinical and systemic progression of gout and reverses tophus deposition in the body.
• Gouty tophi can be found almost anywhere over the body. They are most commonly apparent in the fingers, wrists, helix and antihelix of the ears, knees and bursae around the patella, olecranon bursae and pressure points, such as the ulnar aspect of the forearm and the Achilles tendon. However, advanced imaging and autopsy studies have revealed that tophaceous urate crystal deposits also occur in non-articular tissues, including the spine, heart and vasculature, kidneys and many others.
• In older patients with nodal osteoarthritis of the hands, tophi have a propensity for forming in Heberden’s and Bouchard’s nodes. This is especially true in elderly women who develop gout.
• Acute gout can present as polyarthritis, often accompanied by substantial leukocytosis and fever, and this presentation is more common in the elderly and those with advanced disease, such as in major organ transplant.
• Chronic gouty arthritis can look like RA and be comparably debilitating, and tophi and rheumatoid nodules can resemble each other.
• While we generally think of gout affecting men in their 40s and 50s, about 5% of patients with gout have symptom onset before age 25. This subgroup of gout patients generally has a genetic component to their disease and a more accelerated clinical course requiring more aggressive antihyperuricemic therapies; uric acid overproduction state should be ruled out. Nephrolithiasis is also much more common in this group of gout patients, as are CVD risk factors in patients with gout <40 years of age.
• Ninety percent of women who develop gout do so postmenopausally. Those who have gouty symptoms before menopause usually have hypertension and CKD and many are using thiazide diuretics. A history of other family members having gout is also much more prominent in women with gout.