Gout Year in Review: 2022

As a part of our Year in Review series, Rheumatology Network interviewed Theodore Fields, MD, FACP, to discuss the top highlights of gout in the year 2022. Fields discusses the stand out studies, including the MIRROR trial, a study pinpointing the role of lubricin deficiency in the pathogenesis of gout, and a Korean study that compared febuxostat and allopurinol treatment and the impact they had on adverse cardiovascular reactions. He goes on to discuss regulatory news updates and the most pressing news issues that he hopes will be addressed in 2023. Fields is Attending Rheumatologist, Professor of Clinical Medicine, Weill Cornell College of Medicine, Hospital for Special Surgery, and a medical advisor to CreakyJoints.

Rheumatology Network: What studies or new data related to gout stand out most when looking back at 2022?

Theodore Fields, MD, FACP:

The MIRROR trial showed success in a randomized, controlled trial for the combination of methotrexate and pegloticase in reaching goal (71%) in significantly more patients than pegloticase alone (39%).This is a significant advance, since the potent medication pegloticase only succeed in prior trial at approximately 40%, as in this trial, due to antibody formation. Methotrexate appears able to block this antibody formation.Infusion reactions were also markedly less in the methotrexate group.¹

A population study in Korea looked at ~160,000 users of febuxostat vs allopurinol in terms of adverse cardiovascular (CV) reactions, with propensity score matching for multiple co-morbidities.² Febuxostat was found to be non-inferior to allopurinol for risk of CV events. There was actually an unexpected finding of 16% reduced risk of all-cause mortality for febuxostat vs allopurinol. This was especially interesting since the FAST trial³ had also found a trend in this direction, as opposed to the CARES trial4 which had found a death rate higher with febuxostat. Putting all the data together, the concerns about febuxostat appear more and more to not be significant, and this medication can be used when needed without excessive concern about cardiovascular issues.

A study looked at the effectiveness in stopping gout erosions of lowering the uric acid goal in severe gout from <5.0 to < 3.4.5 This was important because we had no prior studies of urate goal and its outcomes. At 2 years, they did not find significant difference in gouty erosions between the <5.0 and the <3.4 group, and they found it challenging to get to the <3.4 goal. At 2 years, the tophus count and index tophus area were less in the <3.4 group, but not statistically significantly different. There were 52 patients in each group.Overall, it was a major contribution to look at a 2 year outcome of different gout treatment goals, but I don’t think this study is sufficient to rule out considering a goal even less than <5.0 for patients with especially severe tophaceous gout.

Robert Terkeltaub, MD, and a large group of authors reported that lubricin deficiency may be a significant player in the pathogenesis of gout.6 They studied a young adult woman with erosive urate-induced erosion with normal uric acid level, seeking gout mechanisms that were independent of uric acid. In vitro, they found blunted urate precipitation by lubricin. The patient studied has markedly decreased serum lubricin and genetic studies found provocative results for further analysis. This study raises the question as to whether strategies to increase lubricin could be future therapeutic options in gout.

RN: What regulatory news or updates related to gout stand out most when looking back at 2022?

TF: The major issue was the US Food and Drug Administration (FDA) approval of the combination of methotrexate and pegloticase. This was especially based on the findings of the MIRROR study, as discussed above.

RN: Two years removed from the ACR's latest gout guidelines, how have you seen the new recommendations impact care?

TF: The guidelines seem to increase my rheumatology colleagues interest in checking the HLA-B*5801 marker in patients with Asian (but not Japanese) background, and to also consider this testing in African American patients. I believe that the guidelines have moved the primary care community more towards a treat-to-target approach to gout, rather than the treat-to-symptoms approach noted in the American College of Physicians' (ACP) guideline. Also, since the ACR guidelines came out 2 years ago, there have been several articles published further demonstrating the benefits of a treat-to-target approach to gout, so hopefully any future ACP guideline will recommend this approach.

RN: What are the most pressing issues in gout you hope to see addressed or receive a greater focus in 2023?

TF:

Longer-term studies of larger number of gout patients are ongoing and should help to further support a treat-to-target approach, and better define that target. As discussed above, I still feel that a very intensive urate lowering approach is likely helpful in shrinking tophi faster, but we need proof in appropriate studies.

Great efforts have been made to educate the physician community, especially the primary care community, about the dramatic benefits to gout patients from an aggressive and targeted approach. Still, many studies still show less than 50% of gout patients receiving appropriate urate-lowering therapy. The educational process needs to continue!

References:

1. Botson JK, Saag K, Peterson J, et al. A Randomized, Placebo-Controlled Study of Methotrexate to Increase Response Rates in Patients with Uncontrolled Gout Receiving Pegloticase: Primary Efficacy and Safety Findings [published online ahead of print, 2022 Sep 13]. Arthritis Rheumatol. 2022;10.1002/art.42335. doi:10.1002/art.42335
2. Shin A, Choi SR, Han M, et al. Cardiovascular safety associated with febuxostat versus allopurinol among patients with gout: Update with accumulated use of febuxostat. Semin Arthritis Rheum. 2022;56:152080. doi:10.1016/j.semarthrit.2022.152080
3. Mackenzie IS, Ford I, Nuki G, et al. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. Lancet. 2020;396(10264):1745-1757. doi:10.1016/S0140-6736(20)32234-0
4. White WB, Saag KG, Becker MA, et al. Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout. N Engl J Med. 2018;378(13):1200-1210. doi:10.1056/NEJMoa1710895
5. Dalbeth N, Doyle AJ, Billington K, et al. Intensive Serum Urate Lowering With Oral Urate-Lowering Therapy for Erosive Gout: A Randomized Double-Blind Controlled Trial. Arthritis Rheumatol. 2022;74(6):1059-1069. doi:10.1002/art.42055
6. Elsaid K, Merriman TR, Rossitto LA, et al. Amplification of inflammation by lubricin deficiency implicated in incident, erosive gout independent of hyperuricemia [published online ahead of print, 2022 Dec 1]. Arthritis Rheumatol. 2022;10.1002/art.42413. doi:10.1002/art.42413