Is Gout an Autoinflammatory Syndrome After All?

PHILADELPHIA—The term autoinflammatory syndrome was coined by Daniel L. Kastner, MD, PhD, National Institutes of Health (NIH), Bethesda, Md., not long after he discovered that mutations in the gene MEFV, which codes for the protein pyrin, are responsible for familial Mediterranean fever (FMF).¹ Early on, the term was meant to signify monogenic conditions in which a gain or loss of a gene and its protein directly involved in inflammatory states leads to dysregulation and overproduction of a single pro-inflammatory cytokine, resulting in episodic symptoms. At ACR Convergence 2022, the session titled Gout Is an Autoinflammatory Metabolic Disease sought to present arguments for why this crystalline arthritis fits into the category shared by FMF and similar conditions.

Disease Pathways

Charles Dinarello, MD

The first speaker in the session was Charles Dinarello, MD, distinguished professor, medicine-infectious disease, University of Colorado School of Medicine, Aurora. Dr. Dinarello began his presentation by describing the interleukin (IL) 1 pathway. Activation of this pathway leads to the production of cytokines and cytokine receptors, release of bone marrow leukocytes, and promulgation of COX-2, nitric oxide synthetase (NOS) and phospholipase A2. These products (i.e., COX-2, NOS and phospholipase A2) promote systemic and local inflammation, increase pain and cause cellular infiltration, tissue damage and remodeling.

If human subjects receive even miniscule injectable doses of IL-1, the results are fever, myalgias, joint pain, fatigue, neutrophilia, gastrointestinal discomfort and hypotension. Several available drugs block IL-1 in human disease, including anakinra, the recombinant form of IL-1Ra, which blocks both IL-1α and β; canakinumab, which neutralizes IL-1β; and rilonacept, an IL-1 soluble receptor that neutralizes IL-1α and β. Dr. Dinarello noted that oral NLRP3 inflammasome inhibitors prevent processing of IL-1β and IL-18 into active cytokines.

On this last topic, Dr. Dinarello expanded upon the pathophysiology of acute gout flares, in which monosodium urate (MSU) crystals are engulfed by resident synovial macrophages and activate the NLRP3 inflammasome. IL-1β is then released into the joint space and into the systemic circulation, with the former causing the first symptoms of pain and the latter resulting in bone marrow release of neutrophils and frank neutrophilia. These neutrophils enter the joint and engulf MSU crystals, and as IL-1 production increases in the joint, additional pain and swelling occur. IL-6 and C-reactive protein (CRP) serve as markers of inflammation.

Having explained this sequence, Dr. Dinarello posed the question: How can we reduce the activity of IL-1β in gout flares? He noted that traditional methods for doing so—the use of non-steroidal anti-inflammatory drugs (NSAIDs) or glucocorticoids—are non-specific, do not directly reduce IL-1β and often have side effects. Targeting IL-1β with injectable medications, such as anakinra and canakinumab, is more specific, but this requires patients to frequently administer injectable medications. An alternative approach would be to prevent the activation of the NLRP3 inflammasome, thereby preventing caspase-1 processing of IL-1β into an active cytokine.

Dr. Dinarello described work published with his colleagues that demonstrated how OLT1177, a beta-sulfonyl nitrile compound, can inhibit the NLRP3 inflammasome, reduce active IL-1β and result in a clinical reduction of pain and swelling in affected joints.²

Flare Treatment & More

Dr. Schlesinger

The second speaker in the session was Naomi Schlesinger, MD, professor of medicine and incoming chief, Division of Rheumatology, Spencer Fox Eccles School of Medicine, University of Utah, Salt Lake City. Dr. Schlesinger discussed several key points about the treatment of acute gout flares.

The AGREE trial, she said, demonstrated that low-dose colchicine (i.e., 1.2 mg followed by 0.6 mg one hour later) is equally effective and better tolerated than high-dose colchicine.³ The CONTACT trial showed no difference in pain intensity when patients were treated with low-dose colchicine vs. naproxen over seven days.⁴

 With respect to IL-1 inhibition, Dr. Schlesinger stated that canakinumab has been shown to provide pain relief in the treatment of acute gout superior to triamcinolone injection and that anakinra has been shown to provide pain relief equivalent to triamcinolone injection.^5,6

Dr. Schlesinger went on to explain that uric acid itself plays an important role in promoting inflammatory pathways in patients. She noted that intracellular uric acid induces endothelial nitric oxide synthase dysfunction, oxidative stress and inflammation and that understanding the actions of such medications as probenecid, an inhibitor of the tubular reabsorption of urate, may provide important insights into gout as an autoinflammatory condition.

In a paper published by El-Maadawy et al., researchers showed that in rats treated with probenecid, NLRP3 signaling was downregulated, as demonstrated by reduced gene and protein expression of NLRP3 and caspase-1, as well as with suppressed IL-1 beta maturation.⁷ With these findings in mind, Dr. Schlesinger predicts that NLRP3 inflammasome inhibitors may be used routinely in the future to treat acute and chronic gouty inflammation.

Dr. Schlesinger also provided helpful references to the 2020 ACR Guideline for the Management of Gout and discussed appropriate anti-inflammatory prophylaxis. As many rheumatologists will note from their clinical practice, patients often report urate-lowering therapy has failed in that they experienced increased gout flares with the initiation of such medications as allopurinol, but this is frequently because anti-inflammatory prophylaxis was not used in these patients.

If human subjects receive even miniscule injectable doses of IL-1, the results are fever, myalgias, joint pain, fatigue, neutrophilia, gastrointestinal discomfort & hypotension.

The 2020 ACR guideline provides a strong recommendation for using concomitant anti-inflammatory prophylaxis therapy (i.e., colchicine, NSAIDs or low-dose prednisolone/prednisolone) when initiating urate-lowering therapy and continuing such prophylaxis for at least three to six months.⁸ By following this recommendation, clinicians can help prevent the increase in gout flares seen when uric acid levels are lowered quickly or aggressively.

Conclusion

Many questions with regard to gout as a clinical entity and autoinflammatory syndrome remain unanswered. One such question was posed during the question-and-answer segment of the session: How it is that flares of gout spontaneously resolve even with the persistence of urate in synovial fluid?

The insights from Dr. Dinarello and Dr. Schlesinger helped provide hypothesized responses to such perplexing inquiries, but clearly much more remains to be understood about this disease, which has been written about for centuries. As Dr. Schlesinger noted in her talk, we have come a long way from the era of Emperor Charles V, who said that, “Patience and some crying are the best drugs for gout.”⁹

More study and research are needed to truly comprehend the intricacies of gout so we can help patients across the country and the world.

Jason Liebowitz, MD, completed his fellowship in rheumatology at Johns Hopkins University, Baltimore, where he also earned his medical degree. He is currently in practice with Skylands Medical Group, N.J.

References

1. Centola M, Aksentijevich I, Kastner DL. The hereditary periodic fever syndromes: molecular analysis of a new family of inflammatory diseases. Hum Mol Genet. 1998;7(10):1581–1588.
2. Marchetti C, Swartzwelter B, Gamboni F, et al. OLT1177, a β-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):E1530–E1539.
3. Terkeltaub RA, Furst DE, Bennett K, et al. High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum. 2010 Apr;62(4):1060–1068.
4. Roddy E, Clarkson K, Blagojevic-Bucknall M, et al. Open-label randomised pragmatic trial (CONTACT) comparing naproxen and low-dose colchicine for the treatment of gout flares in primary care. Ann Rheum Dis. 2020 Feb;79(2):276–284.
5. Schlesinger N, De Meulemeester M, Pikhlak A, et al. Canakinumab relieves symptoms of acute flares and improves health-related quality of life in patients with difficult-to-treat Gouty Arthritis by suppressing inflammation: results of a randomized, dose-ranging study. Arthritis Res Ther. 2011 Mar 25;13(2):R53.
6. Saag KG, Khanna PP, Keenan RT, et al. A randomized, phase ii study evaluating the efficacy and safety of anakinra in the treatment of gout flares. Arthritis Rheumatol. 2021 Aug;73(8):1533–1542.
7. El-Maadawy WH, Hassan M, Badawy MH, et al. Probenecid induces the recovery of renal ischemia/reperfusion injury via the blockade of Pannexin 1/P2X7 receptor axis. Life Sci. 2022 Nov 1;308:120933.
8. FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology Guideline for the Management of Gout [published correction appears in Arthritis Care Res (Hoboken). 2020 Aug;72(8):1187] [published correction appears in Arthritis Care Res (Hoboken). 2021 Mar;73(3):458]. Arthritis Care Res (Hoboken). 2020;72(6):744–760.
9. Ordi J, Alonso PL, de Zulueta J, et al. The severe gout of Holy Roman Emperor Charles V. N Engl J Med. 2006 Aug 3;355(5):516–520.