“Gout flares are painful and disabling. Understanding the central role of the NLRP3 [NOD-like receptor pyrin domain-containing protein 3, cryopyrin, or NALP3] inflammasome in the initiation of the gout flare has led to new treatment approaches for gout,” says Nicola Dalbeth, MD, FRACP, head of the Department of Medicine, University of Auckland, New Zealand. “However, ultimately, gout flares should be prevented by removing the underlying cause with urate-lowering therapy. Maintaining the serum urate below 6 mg/dL will dissolve deposited monosodium urate (MSU) crystals, which treats the underlying cause of the gout flare and prevents ongoing NLRP3 inflammasome activation.”
Dr. Dalbeth is co-author of a review that is part of a series on immunology for rheumatologists published in Arthritis & Rheumatology (A&R).1 In this new installment, Dr. Dalbeth and Raewyn Poulsen, PhD, senior research fellow and senior lecturer in the Department of Pharmacology, University of Auckland, review gout and NLRP3 (NACHT-LRR-PYD-containing protein 3) inflammasome biology.2
Insights for Rheumatologists
Dr. Dalbeth
“Understanding the molecular pathways driving the gout flare provides key insight into why gout flares only occur intermittently in joints with MSU crystal deposits, why alcohol consumption or fatty foods can trigger a gout flare, and why gout flares self-resolve even in the absence of treatment,” explains Dr. Poulsen.
“In this review, we also discuss how current pharmaceutical treatments for gout flare prophylaxis and treatment act on the pathways driving gout flare, providing mechanistic insight into their clinical efficacy,” Dr. Poulsen says.
The review initially covers the histopathology of gout. The authors describe the three stages of acute inflammation in gout: initiation, including the central role of NLRP3 inflammasome activation, NLRP3 inflammasome priming, and NLRP3 inflammasome activation; mobilization, via neutrophilic infiltration; and self-resolution. The authors present a clinical case of a patient with a typical gout flare and detail the role of the NLRP3 inflammasome in acute MSU crystal-induced inflammation. The review outlines treatment strategies for gout within the framework of NLRP3 inflammasome-mediated acute inflammation. The authors conclude with a follow-up of the clinical case.
The review includes a table displaying the anti-inflammatory mechanisms of medications used to treat gout flares, a figure and legend detailing the development and self-resolution of the gout flare, and more than 100 references.
The NLRP3 Inflammasome
Dr Poulsen
“Activation of the NLRP3 inflammasome in monocytes/macrophages is the central mechanism driving the gout flare,” Dr. Poulson says. “Normally activated in response to pathogen attack or tissue damage, the NLRP3 inflammasome drives production of the inflammatory cytokine IL [interleukin] 1β, leading to further immune cell recruitment, particularly neutrophilic infiltration.”
Inflammasome activation occurs by a two-step process, and typically, two distinct signals are needed to initiate each of these steps. In gout, “MSU crystals trigger step two in this process, but often a second factor is required to initiate step one,” Dr. Poulson explains. Factors known to trigger step one include alcohol, infection and saturated fatty acids, “all of which are also implicated as gout flare triggers.”
“The need for two signals to activate the NLRP3 inflammasome may explain why gout flares only occur sporadically in joints despite the continual presence of MSU crystals and why factors such as alcohol consumption can trigger NLRP3 inflammasome activation and gout flares in individuals with MSU crystal deposits, but not in individuals without,” Dr. Poulson says.
Gout flares will self-resolve, even in the absence of treatment, Dr. Poulson explains. Many of the mechanisms involved in initiating the inflammatory cascade in the gout flare also trigger pathways to turn it off, ensuring that inflammation can only persist for a finite period.
“For instance, NLRP3 inflammasome activation results in self-cleavage of the enzyme caspase 1. This activates caspase 1, allowing it to then activate IL-1β, a key step in initiating the inflammatory cascade in the gout flare. However, self-cleavage also targets caspase 1 for destruction, ensuring that caspase 1 activity is self-limiting,” Dr. Poulson says.
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Neutrophil activation and the resultant increased production of inflammatory cytokines plays “a central role in amplifying the inflammatory response in the gout flare and is associated with the increased intensity of symptoms during initial gout flare development. However, neutrophils are also critical for flare resolution,” Dr. Poulson explains. Aggregated neutrophil elastase traps (NETs) are “released by neutrophils sequester chemokines and inflammatory cytokines. As NETs accumulate, they also form a coating on MSU crystals, reducing the inflammasome-activating ability of the crystals. Neutrophils undergoing apoptosis at the end of their life cycle are a major source of anti-inflammatory mediators, such as TGF-β [transforming growth factor beta], which is key for driving a switch in macrophage polarization from M1 to M2.”
Case Study
In the clinical case, a 60-year-old man presented with a six-hour history of pain and swelling in his right, first metatarsophalangeal (MTP) joint. He described a throbbing sensation in his big toe joint that woke him overnight. Over one hour, he developed intense pain—described as the worst he had ever experienced, with 9/10 in severity—redness, heat and swelling in the joint. The patient could not move the joint, put weight on his foot or wear a shoe.
The previous day, the patient turned 60, celebrating his birthday with a large meal and a round of golf. Joint pain was unusual for the patient, but six months before, he experienced pain and swelling in his left ankle. With naproxen, the ankle pain resolved after one week.
The patient’s medical history disclosed hypertension, hyperlipidemia and impaired glucose tolerance. On examination, he seemed distressed with the pain and could not bear weight on the right foot. The right, first MTP joint appeared tender, swollen, warm and red. Although the other joints appeared normal on examination, a small white tophus existed on the helix of the left ear.
Laboratory tests showed a C-reactive protein of 68 mg/L (reference range [RR]: <5 mg/L), neutrophils of 12,300 cells/μL (RR: 1,900–75,000 cells/μL) and serum urate of 8.0 mg/dL (RR: 3.3–7.0 mg/dL). Point-of-care ultrasound revealed a double contour sign, grade 3 synovial hypertrophy and a color Doppler signal at the right first MTP joint. The left first MTP joint presented with a double contour sign, a tophus and bone erosion at the medial metatarsal head.
After a diagnosis of gout flare, the patient was prescribed 40 mg of prednisone daily for one week, resulting in clinical improvement and symptom resolution over 10 days. Considering the patient’s recurrent gout flares and presence of tophi, he was prescribed urate-lowering therapy—100 mg of allopurinol daily gradually increasing to 400 mg daily—which reduced the serum urate to 5.2 mg/dL. In the first six months of allopurinol treatment, the patient was also prescribed low-dose colchicine (0.6 mg daily) to prevent recurrent gout flares.
Over the first year of allopurinol treatment, the patient continued to experience mild gout flares, which were managed by a home supply of prednisone. At three years of allopurinol treatment, the patient was free of gout flares for longer than a year and the tophus on his ear had resolved. He was pain free and able to exercise regularly.
Therapeutic Interventions
The mainstay of gout flare treatment is anti-inflammatory medications, such as non-steroidal anti-inflammatory drugs (NSAIDs), colchicine and glucocorticoids.
“While NSAIDs inhibit inflammatory mediator production downstream of the NLRP3 inflammasome, both colchicine and glucocorticoids inhibit the activity of the NLRP3 inflammasome, although by different mechanisms,” Dr. Dalbeth says. Colchicine and glucocorticoids “also inhibit neutrophil and other immune cell recruitment and inflammatory cytokine production, exerting wide-ranging effects to dampen immune activity and inflammation. Despite the differences in modes of action, NSAIDs, colchicine and glucocorticoids have similar clinical efficacy for treatment of the gout flare.
“Informed by the central role of the NLRP3 inflammasome in the gout flare, trials of IL-1 inhibitors, such as anakinra and canakinumab, have shown efficacy in treating gout flares,” Dr. Dalbeth explains. “Treatment with canakinumab, the long-acting human anti-IL-1β monoclonal antibody, also prevents recurrent gout flares.
“NLRP3 inflammasome inhibitors have been investigated for gout flare treatment in early phase development; the clinical efficacy and safety of these agents is not yet established,” concludes Dr. Dalbeth.
Katie Robinson is a medical writer based in New York.
Disclosures
Dr. Dalbeth has received consulting fees, speaker fees or grants from Novartis, Horizon, Selecta, Arthrosi, LG Chem, JPI, PTC Therapeutics, Protalix, Unlocked Labs, Hikma, Dexcel Pharma, Shanton Pharma, Sobi, Avalo, BioMarin, Crystalys and MedCryst, outside the submitted work.
References
- Bucala R, Solomon DH. Immunology for the rheumatologist: Arthritis & Rheumatology introduces a new problem-based immunology review series with great educational potential. Arthritis Rheumatol. 2024 Jan;76(1):9–10.
- Poulsen R, Dalbeth N. Gout and NLRP3 inflammasome biology. Arthritis Rheumatol. Published online May 5, 2025. doi:10.1002/art.43215
