Gout is the most common inflammatory arthropathy in the industrialized world and is the result of having too much uric acid in the blood, which is referred to as hyperuricemia (1). Over time, as the levels of uric acid in the blood stay elevated above normal or above the limit of solubility (> 6 mg/dL), monosodium urate (MSU) crystals (gout crystals) form, depositing in the joints and soft tissues. When uric acid levels remain elevated uric acid crystals can form and deposit. Once uric acid crystals form and deposit the process continues if the uric acid levels remain above 6 mg/dL, resulting in the deposition of more uric acid crystals in and around the same area (2). Over time a microscopic collection of crystals develops into a ‘micro’ tophus, one you cannot see from the outside but can see with special imaging using a dual energy computed tomography (CT) scan (Figure 1A) or an ultrasound (3). Even though this collection of crystals is not clinically visible, it still has the same potential to cause an immune reaction, resulting in the redness, swelling, tenderness and pain that an acute gout flare is so infamously known for (Figure 1B). As the uric acid levels remain elevated, additional crystals and inflammatory debris will collect on and around the micro tophus, developing into a larger tophus, or clinically visible lump one can touch and feel (Figure 1C). Although classically a feature that occurs after years of having gout, a tophus may develop early in the disease, especially when the uric acid levels are exceedingly high.
By Rob Keenan
The term ‘tophus’ is derived from 17th century Latin meaning ‘porous stone’ (4), and while a tophus can certainly look and feel like a stone under the skin, it is much more complex (2). A tophus is not only composed of MSU crystals but also lipids, proteins, fibrous tissue, and immune cells. In patients with gout who are not flaring, it is important to recognize this collection of crystals, or tophus, is biologically active and ‘simmering’ between flares. Inflammation is occurring within and around the tophus, even when the person is not having an acute gout flare. Although at lower levels than when flaring, the same elements of the immune system that cause the pain, redness, and swelling are still active, like embers from a fire, ready to flare up again. Also, during this time those embers are slowly but surely destroying the surrounding bone and tissue (Figure 2).
In the medical community there is a term, ‘tophaceous gout’, that describes those who have at least one clinically visible tophus (plural: tophi) on examination. Tophaceous gout and gout are not two separate entities but rather part of the spectrum of all gout (5). At one end there are those that have hyperuricemia and are depositing crystals but have yet to have a gout flare for the first time (Figure 1A). There are those who are having intermittent flares but do not have any visible tophi (Figure 1B). Along the other end of the spectrum, there are those who have one visible tophus or many visible tophi that are often associated with chronic joint pain and disability, even when they are not having a gout flare (Figure 1C). Although many with gout do not have a clinically visible tophus, it would be misguided to believe their gout flares are any less severe than those with visible tophi. Whether with tophi or without, all typically describe a gout flare as one of the most painful things they have ever experienced, as bad or worse than a kidney stone, and worse than giving birth to a child. It is also misguided to believe that those without clinically visible only need to be treated for their acute flares and do not need to lower their uric acid levels. The time lower uric acid levels or start medication to lower uric acid levels is before developing a tophus you can see and feel.
The American College of Rheumatology Guidelines recommend starting medication to lower uric acid levels, urate lowering therapy (ULT) when 2 or more flares per year occur, and in some circumstances after 1 flare occurs, such as with a clinically visible tophus (6). So, it is important to start ULT before a tophus is visible. Although it is never too late to start treatment and decrease uric acid levels, and subsequently dissolve tophi, it is better to prevent clinically visible tophi from occurring. Bringing down uric acid levels to normal (less than 6 mg/dL) is paramount when you have clinically visible tophi, but it may be even more important, sparing someone a lot of pain and suffering, if you treat before a visible tophus occurs. Because all gout is tophaceous, it is best to start treating the micro tophus you cannot see before treating a tophus that you can see.
Robert T. Keenan, MD, MPH, MBA
References:
- Dehlin M, Jacobsson L, Roddy E. Global epidemiology of gout: prevalence, incidence, treatment patterns and risk factors. Nat Rev Rheumatol. 2020 Jul;16(7):380-390. doi: 10.1038/s41584-020-0441-1. Epub 2020 Jun 15. PMID: 32541923.
- Keenan RT, Toprover M, Pillinger MH. Etiology and Pathogenesis of Hyperuricemia and Gout. In Firestein and Kelley’s Textbook of Rheumatology. Philadelphia, PA: Elsevier. 2022: 1687-1709.
- Li S, Xu G, Liang J, Wan L, Cao H, Lin J. The Role of Advanced Imaging in Gout Management. Front Immunol. 2022 Jan 14;12:811323. doi: 10.3389/fimmu.2021.811323. PMID: 35095904; PMCID: PMC8795510.
- Suresh E. Diagnosis and management of gout: a rational approach. Postgrad Med J. 2005 Sep;81(959):572-9. doi: 10.1136/pgmj.2004.030692. PMID: 16143687; PMCID: PMC1743349.
- Forbess LJ, Fields TR. The broad spectrum of urate crystal deposition: unusual presentations of gouty tophi. Semin Arthritis Rheum. 2012 Oct;42(2):146-54. doi: 10.1016/j.semarthrit.2012.03.007. Epub 2012 Apr 21. PMID: 22522111.
- FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Care Res (Hoboken). 2020 Jun;72(6):744-760. doi: 10.1002/acr.24180.
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