Team: MSU and NLRP3, aka “The Inflammasome Slama Jam-masome”
Region: Mechanism Madness
Base article: Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440(7081):237-241. doi:10.1038/nature04516. PMID 16407889.
Authors: Geisinger Medical Center Rheumatology Fellowship. Melissa Band, DO, 2nd year rheumatology fellow, David Bulbin, DO, RhmSUS, Program Director.
We know that gout has crystalized history for centuries – even historians have mentioned that the acute gout flares of many influential leaders, from King Henry VIII to Benjamin Franklin, may have played a role in the outcome of major historical events including the Constitution.1 Prior to the understanding of gout pathophysiology, the disease put the “full court press” on the 1st MTP, making the lives of those afflicted turn purines and pyrimidines into a uric acid “Havoc” defense.
These monosodium urate and calcium pyrophosphate crystals were known to increase the ill humors of joint inflammation, devastating the competition. However, scientists and physicians prior to Martinon et al. did not know how to crack this “Havoc” inflammatory response.
Martinon et al. was the sentinel study identifying the mechanism that swarmed the opponent. This was the advent of the offensive juggernaut stomping down the inflammation, which helped paved the way for further research and development of IL-1 inhibition for gout and autoinflammatory syndromes.
They extrapolated that increased production of the cytokine IL-1B, as identified in different autoinflammatory diseases, can also be a part of the pathogenesis of gout, the greatest offense to date for defeating the “Havoc” from IL-1. They studied this by injecting monosodium urate and calcium pyrophosphate crystals in mice deficient in the IL-1B pathway. They found that MSU or CPPD crystals engage caspase-1, activating the NLRP3 or NALP3 inflammasome’s “Havoc defense.” This resulted in production of IL-1B in acute gout flares, and the legend of Inflammasome Slama Jam-masome was born.
Impact on Rheumatology
The NLRP3 inflammasome’s impact has expanded far beyond the field of rheumatology, the playbook finally breaking the neutrophil’s IL-1 Havoc defense. This revolutionized the way the game was played and helped our understanding of defeating the powerful inflammatory driven defenses including the dreaded heart disease matchup zone, which is the leading cause of mortality in the United States.2 Beyond coronary artery disease, the NLRP3 inflammasome’s defenses have held up strong against pericarditis as shown in the AIRTRAP trial and against the chronic smoldering effects of atherosclerosis in the CANTOS trial.3,4
One of the NLPR3 inflammasome’s superstar players, the Inflammasome Slama Jam-masome Anakinra, has been a hidden gem that the offensive strategy turned into a juggernaut. Anakinra’s skillset is the perfect counterpoint to the effects of IL-1 and the inflammasome.5 He is quick in his decisions, weaving through the neutrophilic “Havoc” defense and throwing down a tomahawk jam posterizing the inflammasome. He is consistent, agile and the best weapon on the floor, washing out the fiery pain generated by IL-1. Anakinra is potential number one pick in the FDA draft, making life easier for fans with refractory gout relieving the competition. The Inflammasome Slama Jam-masome brought the playbook that stopped the “Havoc” dead in its tracks.
Chances in the Tournament
The NLRP3 inflammasome pathway in gout paved the way for Anakinra, the superstar diamond in the rough, that will lead the small conference Cinderella, Inflammasome Slama Jam-masome, through the competition of RheumMadness 2023. Coming from humble beginnings and its effect through history, the 11 seed in the tournament shocks the world in the first round. The understanding of NLRP3 was the move needed to escape defenses with fast paced, quick movement quelling the inflammation generated. “Abs before SLE” is a tough matchup, but they are no match for the heroics of the NLRP3 inflammasome. The Cinderella club has final four aspirations and will fly over the competition, leaving its mark on the history of RheumMadness.
Next scouting report: Abs before SLE
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- Marson, P., & Pasero, G. (2011). Some historical remarks on microcrystalline arthritis (gout and chondrocalcinosis). Reumatismo – The Italian Journal of Rheumatology, 63(4), 199–206. https://doi.org/10.4081/reumatismo.2011.199.
- Abbott, RD., Brand, FN., Kannel, WB., & Catelli, WP (1988). Gout and coronary heart disease: The framingham study. Journal of Clinical Epidemiology, 41(3), 237-242. https://doi.org/10.1016/0895-4356(88)90127-8.
- Brucato A, Imazio M, Gattorno M, Lazaros G, Maestroni S, & Carraro M (2016). Effect of anakinra on recurrent pericarditis among patients with colchicine resistance and corticosteroid dependence: the AIRTRIP randomized clinical trial. Journal of the American Medical Association. 316(18), 1906–1912. https://doi.org/10.1001/jama.2016.15826.
- Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, & Ballantyne C (2017). Anti-inflammatory therapy with canakinumab for atherosclerotic disease. The New England Journal of Medicine. 377(12), 1119–1131. https://doi.org/10.1056/NEJMoa1707914.
- Saag KG, Khanna PP, Keenan RT, Ohlman S, Osterling Koskinen L, Sparve E, Åkerblad AC, Wikén M, So A, Pillinger MH, & Terkeltaub R (2021). A Randomized, Phase II Study Evaluating the Efficacy and Safety of Anakinra in the Treatment of Gout Flares. Arthritis & Rheumatology. 73(8), 1533-1542. https://doi.org/10.1002/art.41699.