Gout: updates in diagnosis and treatment

Gout diagnosis is rendered less invasive and more practical in the general clinical setting and treatment more sustainable by recent advances.

Diagnosis without joint fluid analysis

Analysis of synovial fluid for monosodium urate (MSU) crystals is the 'gold standard' for diagnosis of gout, but this is often not feasible in general practice. A study just published in the journal Rheumatology further validates an easy-to-use rule for diagnosing gout that can be relied upon in both the primary and secondary care settings. The authors state:

"The gold standard for diagnosing gout is the identification of MSU crystals in joint fluid. In secondary care, the facilities or expertise to analyse joint fluid are not always available and gout is diagnosed clinically. To improve the predictive value of the clinical diagnosis of gout in secondary care, a diagnostic rule developed in primary care could be helpful. The aim of this study was to validate this diagnostic rule in a secondary care population with the gold standard as reference test."

The study validating the use of this diagnostic rule in primary care was published a few years ago in Archives of Internal Medicine (now JAMA Internal Medicine). For the current study the authors examined data for 390 patients with monoarthritis according to the variables of their diagnostic rule: male sex, previous arthritis attack, onset <1 day, joint redness, involvement of the first MTP joint, hypertension or one or more cardiovascular disease, and serum uric acid >5.88 mg/dl. Fluid was aspirated from the affected joint and analyzed for the presence of MSU crystals.

"In 219 patients (56%) MSU crystals were found. The positive predictive value of a score of ≥8 points was 0.87, the negative predictive value of a score of ≤4 points was 0.95. The area under the receiver operating characteristic curve for the diagnostic rule was 0.86. The Hosmer–Lemeshow goodness-of-fit test showed that the difference between the expected and the observed probability was non-significant, indicating good agreement."

In other words, a score of 8 points or higher has a positive predictive value for gout and 4 points or lower means a low probability, mandating consideration of other diagnoses. Note that serum uric acid over 5.88 mg/dl scores a point.

Handy Gout Calculator

The team of rheumatologists in the Netherlands who first developed the diagnostic rule and tested its validity in primary care have kindly made a convenient online gout calculator available to healthcare professionals.[Practitioners in the US note that serum uric acid of 0.35mmol/L = 5.9 mg/dL.]

Treating Gout By Calming IL-1β Driven Inflammation

MSU crystals trigger the NALP3 inflammasome

All the pain and misery of gout are due to the immune system's inflammatory reaction to monosodium urate crystals that have precipitated in tissues subject to high uric acid levels. A paper published in Immunological Reviews describes how MSU elicits production of the pro-inflammatory cytokine IL-1β (interleukin-1 beta) by triggering the NALP3 inflammasome (a multiprotein patten recognition receptor that activates the inflammatory cascade):

"Uric acid crystals [monosodium urate (MSU)] have emerged as an important factor for both gouty arthritis and immune regulation. This simple crystalline structure appears to activate innate host defense mechanisms in multiple ways and triggers robust inflammation and immune activation... Upon contact with host cells, MSU induces a set of membrane events that trigger Syk and PI3K activation, phagocytosis, and cytokine production. Having entered the cell, MSU further triggers NALP3 inflammasome activation and induces the production of IL-1 beta, likely inducing a full spectrum of inflammation."

The NALP3 inflammasome activates IL-1β

A paper published in the esteemed journal Nature further describes this process that is common to other autoinflammatory diseases:

"The notion of autoinflammatory diseases delineates a heterogeneous group of pathologies characterized by spontaneous periodic inflammation and fever in the absence of infectious or autoimmune causes. Hereditary periodic fevers, systemic onset juvenile idiopathic arthritis, Still's disease, Behçet's disease and the metabolic disorders gout and pseudogout are examples of such inflammatory maladies. Increased production of the inflammatory cytokine IL-1β was recently identified as the cause of several autoinflammatory diseases, providing clear evidence for a pivotal role of this cytokine in triggering autoinflammation. IL-1β, also known as the endogenous pyrogen, is a highly inflammatory cytokine whose production is tightly controlled by at least three distinct steps....The middle step, processing of pro-IL-1β, involves the activation of a caspase-1-activating complex, the best characterized being the inflammasome."

Specifically in regard to gout and pseudogout:

"Development of the acute and chronic inflammatory responses known as gout and pseudogout are associated with the deposition of monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals, respectively, in joints and periarticular tissues....Here we show that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1β and IL-18...These findings provide insight into the molecular processes underlying the inflammatory conditions of gout and pseudogout, and further support a pivotal role of the inflammasome in several autoinflammatory diseases."

Treating gout by blocking IL-1β

Of particular interest to practitioners using low dose cytokine therapy is the notion of treating gout and other autoinflammatory disorders by blocking IL-1β. This is suggested in a paper published in the journal Joint Bone Spine:

"The inflammasome is a proteolytic complex that regulates IL1β and IL-18 secretion in macrophages and dendritic cells. Its plays a vital role in the control of the inflammatory and cellular responses to infectious and danger signals and is an essential part of the innate immune system. Four different inflammasomes have been identified so far, and the NLRP3-inflammasome has been the best-studied in relation to human disease. Activation of the NLRP3-inflammasome by microcrystals, such as monosodium urate (MSU) and basic calcium phosphate (BCP) crystals, leads to IL1β release, which in turn triggers local inflammation. Dysfunction of the NLRP3-inflammasome due to mutations of the NLRP3 gene is the cause of the auto-inflammatory syndrome CAPS. The symptoms and signs of inflammation in both conditions respond to IL1 blockade. IL1 inhibitors have also been used successfully in other idiopathic inflammatory diseases, suggesting that dysregulated inflammasome activity contributes to the pathogenesis of multiple diseases, but the precise underlying mechanisms remain to be identified."

A paper recently published in Seminars in Immunology further stokes enthusiasm for the use of anti-IL1 low-dose cytokine therapy:

"IL-1 is a master cytokine of local and systemic inflammation. With the availability of specific IL-1 targeting therapies, a broadening list of diseases has revealed the pathologic role of IL-1-mediated inflammation. Although IL-1, either IL-1α or IL-1β, was administered to patients in order to improve bone marrow function or increase host immune responses to cancer, these patients experienced unacceptable toxicity with fever, anorexia, myalgias, arthralgias, fatigue, gastrointestinal upset and sleep disturbances; frank hypotension occurred. Thus it was not unexpected that specific pharmacological blockade of IL-1 activity in inflammatory diseases would be beneficial. Monotherapy blocking IL-1 activity in a broad spectrum of inflammatory syndromes results in a rapid and sustained reduction in disease severity. In common conditions such as heart failure and gout arthritis, IL-1 blockade can be effective therapy...By specifically blocking IL-1, we have learned a great deal about the role of this cytokine in inflammation but equally important, reducing IL-1 activity has lifted the burden of disease for many patients."

IL-1 blockade in other metabolic inflammatory disorders

Besides autoinflammatory disorders such as gout and pseudogout, the authors of a paper published in Annual Review of Medicine recognize the therapeutic potential for blocking IL-1 in inflammatory conditions including diabetes and coronary artery disease:

"Monogenic autoinflammatory syndromes present with excessive systemic inflammation including fever, rashes, arthritis, and organ-specific inflammation and are caused by defects in single genes encoding proteins that regulate innate inflammatory pathways....The discovery of the mutations that cause CAPS and DIRA led to clinical and basic research that uncovered the key role of IL-1 in an extended spectrum of immune dysregulatory conditions. NLRP3 encodes cryopyrin, an intracellular "molecular sensor" that forms a multimolecular platform, the NLRP3 inflammasome, which links "danger recognition" to the activation of the proinflammatory cytokine IL-1β...The fact that the accumulation of metabolic substrates such as monosodium urate, ceramide, cholesterol, and glucose can trigger the NLRP3 inflammasome connects metabolic stress to IL-1β-mediated inflammation and provides a rationale for therapeutically targeting IL-1 in prevalent diseases such as gout, diabetes mellitus, and coronary artery disease."