When to use ULTs in gout

When to use ULTs in gout: Dr Vineeta Shobha

M3 India Newsdesk Feb 16, 2022

The golden axiom has always been- to 'treat the patient and not the lab value.' Hyperuricemia in itself is not a disease. Uric acid has significant physiological implications as a natural antioxidant. However, it is important to acknowledge it as a harbinger of several illnesses only in association with symptoms, which requires appropriate lifestyle measures, close monitoring, and medications when warranted.

Medical Historians notoriously wax lyrical about the enduring yet glamorous intrigue called gout. However, it is easily misdiagnosed despite being the most prevalent arthritis in the modern era. Descriptions of an acute attack likened to “walking on my eyeballs” or “so exquisitely painful as to not endure the weight of the clothes” are well known, yet it evoked a kind of snobbish respectability among the elite sufferers of this “monarch among maladies”.

Gout is among the oldest recognised diseases, first identified by the Egyptians in 2640 BC as podagra. Galen, the famous physician of the Greco-Roman world was the first to describe Monosodium urate (MSU) crystallisation as tophi.

Presentation of gout

Serum uric acid (SUA) is routinely requested as part of screening blood tests for musculoskeletal complaints. But as the saying goes, “There are no right answers to wrong questions”. The usefulness of a clinical test lies entirely in its proper interpretation taking into account key factors such as pretest probability and clinical context.

The first presentation of gout is typically monoarticular and intensely inflammatory, occurring in the lower extremities. Indiscriminate testing for uric acid levels in patients with inflammatory polyarthritis, especially, seronegative patients, frequently results in erroneous diagnosis and treatment.

Serum uric acid range and tests

Uric acid exists majorly as urate, the salt of uric acid (SUA). The normal reference interval of SUA in human blood is 1.5 to 6.0 mg/dL in women and 2.5 to 7.0 mg/dL in men. The SUA levels are influenced by age, ethnicity, and sex.

Following puberty, values rise to adult levels with women typically I mg/dl less than men. This lower level in women apparently reflects estrogen-related enhancement of renal urate clearance and disappears at menopause. Many additional factors, including exercise, diet, drugs, and state of hydration, may result in transient fluctuations of uric acid levels.

The chemical definition of hyperuricemia is 6.8 mg/dl (416 mmol/l), based on its chemical properties, determined by the solubility limit of urate in body fluids resulting in its deposition in tissues. Hyperuricemia can be caused by excessive purine intake, endogenous overproduction (rare), or mainly by renal (70%) and digestive (30%) underexcretion.

Common drugs leading to hyperuricemia include:

Antitubercular drugs (ethambutol and pyrazinamide)
Aspirin (low dose)
Cytotoxic chemotherapy
Diuretics
Immunosuppressant agents (cyclosporine and tacrolimus)
Fructose
Lactate infusion
Nicotinic acid
Testosterone
Xylitol

Uric acid synthesis and physiologic functions: Is it good or bad for our body?

Uric acid is the end product of exogenous purines, synthesized mainly in the liver, intestines, vascular endothelium and other tissues such as muscles, kidneys. In addition, live and dying cells degrade their nucleic acids, adenine and guanine into uric acid. Humans cannot oxidise uric acid to the more soluble compound allantoin due to the lack of uricase enzyme.

The kidneys eliminate approximately two-thirds, while the gastrointestinal tract eliminates one-third of the uric acid load. URAT-1 is considered to be a key urate transporter at the proximal renal tubule; diuretics such as furosemide or thiazides enhance its activity and increase UA reabsorption; conversely, old and new uricosurics inhibit this transporter.

Recently, the deficiency of the ABCG2 transporter, present both in the renal epithelial cell apical membrane and in the gut, was found to affect SUA levels through the reduction of gut urate excretion. Over half the antioxidant capacity of the blood, plasma comes from uric acid.

Uric acid is a potent scavenger of reactive oxygen species and peroxynitrite. High levels of uric acid are readily detected in the cytosol of normal human cells, especially in the liver, vascular endothelial cells, and human nasal secretions. Uric acid is the principal antioxidant molecule in plasma and is of paramount importance in the induction of type 2 immune responses.

These properties may explain its protective potential in neurological and infectious diseases, such as schistosomiasis. It plays a pivotal protective role against blood-borne pathogens, neurological and certain autoimmune diseases. Uric acid may exert fundamental roles in tissue healing via initiating the inflammatory process necessary for tissue repair, scavenging oxygen free radicals, and mobilising progenitor endothelial cells.

Gout in India

The incidence of gout in India is not clear. The prevalence is 0.12% as per the International League of Nations Against Rheumatism, Community Oriented Program for Control of Rheumatic Diseases (ILAR COPCORD) study in Bhigwan village of India.

A study from Vellore revealed that 15.8% of the affected patients are <30 years of age; the urban Indian population is more involved than the rural population and the first attack of gout occurs a decade earlier due to the increased prevalence of metabolic syndrome in the in the younger population.

In a similar study, it was found that females had a later onset, longer duration and higher uric acid levels when compared to males. Polyarticular gout was more frequent in the elderly and females, with a greater association with tophi, renal calculi, renal dysfunction and ischaemic heart disease. Hypertension, diabetes and obesity were more frequent in oligoarticular gout.

Utility and fallacies of SUA testing in gout

In gout, serum and synovial fluid (SF) urate levels are significantly higher than other types of inflammatory arthritis. Around one-third of patients with gouty arthritis will have normal uric acid levels during the acute attack, but urate crystals can be demonstrated in the synovial fluid of these patients.

Thus, hyperuricemia is not a requirement for the diagnosis of gout and its presence in a patient with arthritis does not necessarily establish the diagnosis. Indiscriminate testing for uric acid levels in patients with inflammatory polyarthritis, especially, seronegative patients, frequently results in erroneous diagnosis and treatment.

Other diagnostic tools in gout

The diagnosis of gout can be confirmed if the joint or tophus aspirate shows needle-shaped negatively birefringent MSU crystals under compensated polarised light microscopy.
Radiography in acute initial attacks is typically not useful, may show only soft tissue swelling of the affected joint. The classically described radiographic findings of gout are appreciated only in long-standing gout. These include asymmetric inflammatory erosive arthritis with sharply punched out oval or round defects situated in the marginal area of joints often with overhanging margins often accompanied by soft tissue nodules and retention of normal joint space.
On ultrasonography (US), MSU crystals may appear within the synovial fluid as a ‘snow storm appearance’ or deposit on superficial articular cartilage as the ‘double contour sign’ and tophi may appear as hypoechoic, hyperechoic or mixed echogenicity nodules.
Magnetic resonance imaging (MRI) can demonstrate joint effusion, synovitis, tendon disorder, tophus, cartilage disorder or bone oedema. Computed tomography (CT) scan may reveal discrete tophi at multiple sites adjacent to bone and within soft tissues and is helpful in scoring bone erosions.
Dual-energy CT (DECT) analyses using a 3D material decomposition algorithm that allows characterisation of uric acid (allocated a specific colour) to be contrasted with calcium and soft tissue (allocated other colours). This allows MSU crystals detection with a high degree of accuracy as DECT scans detect fourfold more deposits than physical examination.

Utility of SUA beyond gout

Elevated SUA is associated with fourfold increased odds of Pulmonary Artery Hypertension (PAH) in Systemic Sclerosis (SSc) patients and is being increasingly recognised as a valuable biomarker in its non-invasive assessment for severity, and outcomes.
Elevated serum uric acid in pregnancy may not only be a valuable biomarker for preeclampsia but may also have a contributory role in the pathogenesis of the maternal and fetal manifestations.

Hyperuricemia is an independent risk factor for cardiovascular and ischaemic stroke mortality, non-alcoholic fatty acid disease, diabetes, obesity and hypertension.

When to use ULTs in gout?

Since gout is a chronic deposition disease with body MSU crystal burden, the goal for treatment is to significantly reduce the SUA level below the solubility threshold allowing crystal dissolution. An SUA level <6.0 mg/dl (360 mmol/l), is widely considered as the target. Indications of urate-lowering therapy (ULTs) in gout include:

Patients with more than two attacks per year
Chronic tophaceous gout
Chronic gout associated with renal impairment or urate calculi
Radiographic changes of gouty arthropathy
Adjunct to cytotoxic therapy to prevent tumour lysis syndrome

However, mainly due to “clinical inertia” and low patient adherence, gout remains undertreated globally. Overall, only 20- 40% of gout patients are treated with ULTs; <30% with 6.0 mg/dl SUA level as a target.