Clinical Year in Review: 2023

Clinical Updates in Rheumatology Presented at ACR Convergence 2023

Philip Seo, MD, MHS

SAN DIEGO—At ACR Convergence 2023, Philip Seo, MD, MHS, associate professor of medicine, Johns Hopkins University, Baltimore, presented a humorous and engaging overview of clinical updates in rheumatology. This article summarizes many of the articles he discussed.

Updates to Key Trials from 2022

Dr. Seo began discussing updates to two sentinel trials discussed in the 2022 Year in Review: the ORAL Surveillance study and the GLORIA trial.^1-3

The ORAL study was mandated by the U.S. Food & Drug Administration (FDA) to look at the safety of tofacitinib in patients older than 50 with one cardiac risk factor and active rheumatoid arthritis (RA) despite treatment with methotrexate. Referencing the original trial, Dr. Seo noted, “This is the table that launched a thousand studies. Ever since this study, we’ve been trying to explain why tofacitinib is associated with an increased risk of cardiovascular events, venous thromboembolic events and malignancy. And these [same investigators] may have provided us with an answer.”

The ORAL Surveillance investigators conducted a post-hoc analysis that identified subpopulations with different relative risk with tofacitinib vs. tumor necrosis factor inhibitors (TNFi).⁴ Patients older than 65 with a current or prior long-time smoking history were at higher risk with tofacitinib compared with TNFi, whereas those younger than 65 who didn’t smoke weren’t. Dr. Seo remarked, “[The investigators] possibly managed to highlight a group of patients who can use tofacitinib and, by extension, other Janus kinase inhibitors relatively safely.”

The GLORIA trial demonstrated that the addition of prednisolone 5 mg daily to standard-of-care therapies in people with active RA older than 65 decreased disease activity and joint damage.³ The tradeoff was a 24% increased risk of mostly non-severe adverse events. This year, a follow-up study looked at what happened when the same patients were tapered off prednisolone over a period of three months.⁵ There was a concordant small increase in disease activity when patients were tapered, but interestingly, no one developed adrenal insufficiency.

Dr. Seo noted, “I think there are two messages here. First, if you have an older patient on low dose glucocorticoids for two years, we shouldn’t be afraid to taper. You won’t see adrenal insufficiency as a result. However, if you have a patient with low disease activity on chronic low-dose glucocorticoids, tapering is probably not the best strategy, since it might induce a disease flare.”

Arthritis

Dr. Seo continued his talk with good news: “We all have excellent job security.” He highlighted results from studies assessing the global prevalence of osteoarthritis (OA) and “other musculoskeletal disease,” like systemic lupus erythematosus (SLE) and spondyloarthritis.^6,7 These studies showed that by 2020, 595 million people had OA and 494 million had “other musculoskeletal diseases,” representing a 132% increase and 123% increase since 1990 respectively. The prevalence of knee OA is expected to increase by 75%, and other musculoskeletal diseases by 50% by 2050.

Next, Dr. Seo turned toward RA trial design, highlighting NORD-STAR, a study with an admirable approach.⁸ He said, “If you think about the classic RA trial, they take a novel compound with really interesting mechanism of action and compare it to dishwater, or something else you don’t care about, like continuing methotrexate therapy in a patient who has already failed methotrexate. What we really need are clinical trials where all the arms are looking at interventions that we might actually use.”

NORD-STAR took patients with treatment-naive early, active RA, and randomized them to receive “active conventional therapy” (methotrexate and tapered steroids, or triple therapy with methotrexate, sulfasalazine and hydroxychloroquine, as well as intra-articular glucocorticoids as needed), or methotrexate plus a biologic (e.g., abatacept, certolizumab pegol or tocilizumab).⁸ Results showed that “compared with active conventional therapy, [Clinical Disease Activity Index (CDAI)] remission rates were significantly higher for abatacept (adjusted difference +20.1%, P<0.001) and certolizumab (+13.1%, P=0.021), but not for tocilizumab (+12.7%, P=0.030).⁸

“I think that NORD-STAR really highlights that abatacept belongs higher in the hierarchy of drugs we consider when looking at patients with new RA,” said Dr. Seo.

Last, Dr. Seo discussed interesting findings from an exploratory analysis of LoDoCo2, a cardiology trial that examined the effect of colchicine in patients with coronary artery disease (CAD).⁹ The study found that patients assigned to colchicine 0.5mg daily had a decreased risk of developing a need for hip or knee replacement in the future (HR 0.69; CI 0.51-0.95). Similarly, an exploratory analysis of CANTOS, a cardiology trial examining canakinumab in patients with CAD, found a similar decreased risk of hip or knee replacement a few years ago (HR 0.58; CI 0.42-0.80).¹⁰ “None of us are going to go out and start giving canakinumab to a bunch of patients to prevent OA, but colchicine certainly raises some intriguing opportunities. I’ll be interested to see whether colchicine is effective for even earlier complications of OA besides joint replacement,” Dr. Seo remarked.

Novel Therapeutics 

Dr. Seo turned next to novel therapeutics coming down the pipeline. Peresolimab, a programmed cell death 1 (PD-1) stimulator, showed benefit in RA.¹¹ This drug does the opposite of PD-1 inhibitors (checkpoint inhibitors), which are used to treat various cancers.

“You’re probably thinking that stimulating a checkpoint maybe isn’t such a smart idea,” Dr. Seo noted. “That said, we had the same thoughts about TNFi and cancer risk decades ago and that never really panned out. We need to wait for more data to know if this is an important risk.”

ABBV-3372 is a novel hybrid molecule that also showed benefit in RA.¹² Dr. Seo explained, “Part of the molecule is basically adalimumab, and it uses that to home in on activated immune cells expressing TNF. Then, it drops off a payload of a GC receptor modulator, delivering GC doses to cells that actually need it, while leaving other cells alone.” Most interestingly, the study showed that there may be prolonged benefit even after discontinuation of the drug. “This is really exciting when we think of SLE or vasculitis, diseases commonly treated with high doses of GC. This might represent a path forward for them.”

Dr. Seo also touched on brepocitinib and bimekizumab for the treatment of psoriatic arthritis, deucravacitinib for SLE, and riociguat for diffuse cutaneous systemic sclerosis. We look forward to further data that will help determine each drug’s future role in the treatment of our patients.^13–17 Baricitinib, on the other hand, will no longer be pursued by the drug company as a potential treatment for SLE due to lack of efficacy in clinical trials.^18,19

“This brings us back to the question of whether we know what the ideal end point is for SLE clinical trials,” he said.

Polymyalgia Rheumatica

In February 2023, the FDA approved sarilumab for the treatment of adults with polymyalgia rheumatica (PMR) for whom glucocorticoids have proven inadequate or who cannot tolerate a glucocorticoid taper.²⁰

A phase 3 trial showed significant efficacy in achieving sustained remission and steroid sparing in patients with relapsed PMR.²⁰ “The most common adverse effect was neutropenia,” noted Dr. Seo, “but these patients didn’t get serious infections. It still seems well tolerated, even in an elderly population.”

A Fascinating Case Report

Dr. Seo concluded with an exciting case report that describes a potential curative therapy for ankylosing spondylitis (AS). A patient with severe, refractory AS who had failed multiple immunosuppressants, as well as hematopoietic stem cell transplantation was treated with a cytotoxic anti-TRBV9 antibody, which depletes TRBV9-positive T-cells (implicated in the pathogenesis of AS).²¹  Investigators reported that the patient achieved remission within three months, has remained in remission for four years and was able to discontinue TNFi with continuous use of the study drug (three infusions per year).

“This drug is already in phase 2 trials, and we look forward to more data in the near future,” he said.

Samantha C. Shapiro, MD, is the executive editor of Harrison’s Principles of Internal Medicine. As a clinician educator, she practices telerheumatology and writes for both medical and lay audiences.

References

1. Shapiro S. Clinical rheumatology year in review–2022. 2022 Dec 4. https://www.the-rheumatologist.org/article/clinical-rheumatology-year-in-review-2022/.
2. Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022 Jan;386(4)316–326.
3. Boers M, Hartman L, Opris-Belinski D, et al. Low dose, add-on prednisolone in patients with rheumatoid arthritis aged 65+: the pragmatic randomised, double-blind placebo-controlled GLORIA trial. Ann Rheum Dis. 2022 Jul;81:925–936.
4. Kristensen LE, Danese S, Yndestad A, et al. Identification of two tofacitinib subpopulations with different relative risk versus TNF inhibitors: An analysis of the open label, randomised controlled study ORAL Surveillance. Ann Rheum Dis. 2023 Jul;82(7):901–910.
5. Almayali AAH, Boers M, Hartman L, et al. Tapering of long-term, low-dose glucocorticoids in senior rheumatoid arthritis patients: Follow-up of the pragmatic, multicentre, placebo-controlled GLORIA trial. Ann Rheum Dis. 2023 Oct;82(10):1307–1314.
6. Gill TK, Mittinty MM, March LM, et al. Global, regional, and national burden of other musculoskeletal disorders, 1990–2020, and projections to 2050: A systematic analysis of the Global Burden of Disease Study 2021. Lancet Rheumatol. 2023 Nov;5(11):e670–e682.
7. Steinmetz JD, Culbreth GT, Haile LM, et al. Global, regional, and national burden of osteoarthritis, 1990–2020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Rheumatol. 2023 Aug;5(9):e508–e522.
8. Østergaard M, Van Vollenhoven RF, Rudin A, et al. Certolizumab pegol, abatacept, tocilizumab or active conventional treatment in early rheumatoid arthritis: 48-week clinical and radiographic results of the investigator-initiated randomised controlled NORD-STAR trial. Ann Rheum Dis. 2023 Oct;82(10):1286–1295.
9. Heijman MWJ, Fiolet ATL, Mosterd A, et al. Association of low-dose colchicine with incidence of knee and hip replacements: Exploratory analyses from a randomized, controlled, double-blind trial. Ann Intern Med. 2023 Jun;176(6):737–742.
10. Schieker M, Conaghan PG, Mindeholm L, et al. Effects of interleukin-1β inhibition on incident hip and knee replacement: Exploratory analyses from a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2020 Oct;173(7):509–515.
11. Tuttle J, Drescher E, Simón-Campos JA, et al. A phase 2 trial of peresolimab for adults with rheumatoid arthritis. N Engl J Med. 2023 May;388(20):1853–1862.
12. Buttgereit F, Aelion J, Rojkovich B, et al. Efficacy and safety of abbv-3373, a novel anti–tumor necrosis factor glucocorticoid receptor modulator antibody–drug conjugate, in adults with moderate-to-severe rheumatoid arthritis despite methotrexate therapy: A randomized, double-blind, active-controlled proof-of-concept phase IIa trial. Arthritis Rheumatol. 2023 Jun;75(6):879–889.
13. Morand E, Pike M, Merrill JT, et al. Deucravacitinib, a tyrosine kinase 2 inhibitor, in systemic lupus erythematosus: A phase II, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2023 Feb;75(2):242–252.
14. McInnes IB, Asahina A, Coates LC, et al. Bimekizumab in patients with psoriatic arthritis, naive to biologic treatment: A randomised, double-blind, placebo-controlled, phase 3 trial (BE OPTIMAL). Lancet. 2023 Jan;401(10370):25–37.
15. Merola JF, Landewé R, McInnes IB, et al. Bimekizumab in patients with active psoriatic arthritis and previous inadequate response or intolerance to tumour necrosis factor-α inhibitors: A randomised, double-blind, placebo-controlled, phase 3 trial (BE COMPLETE). Lancet. 2023 Jan;401(10370):38–48.
16. Mease P, Helliwell P, Silwinska-Stanczyk P, et al. Efficacy and safety of the TYK2/JAK1 inhibitor brepocitinib for active psoriatic arthritis: A phase IIb randomized controlled trial. Arthritis Rheumatol. 2023 Aug;75(8):1370–1380.
17. Distler O, Allanore Y, Denton CP, et al. Riociguat in patients with early diffuse cutaneous systemic sclerosis (RISE-SSc): Open-label, long-term extension of a phase 2b, randomised, placebo-controlled trial. Lancet Rheumatol. 2023;5(11):e660–e669.
18. Petri M, Bruce IN, Dörner T, et al. Baricitinib for systemic lupus erythematosus: A double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-II). Lancet. 2023 Mar;401(10381):1011–1019.
19. Morand EF, Vital EM, Petri M, et al. Baricitinib for systemic lupus erythematosus: A double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-I). Lancet. 2023;401(10381):1011–1019.
20. Kaufman MB. FDA approves sarilumab for the treatment of glucocorticoid-resistant PMR. The Rheumatologist. 2023 Mar 14. https://www.the-rheumatologist.org/article/fda-approves-sarilumab-for-the-treatment-of-adults-with-glucocorticoid-resistant-pmr/#:~:text=On%20Feb.,cannot%20tolerate%20a%20glucocorticoid%20taper.&text=Sarilumab%20is%20an%20interleukin%20(IL)%206%20receptor%20antagonist.
21. Britanova OV, Lupyr KR, Staroverov DB, et al. Targeted depletion of TRBV9+ T cells as immunotherapy in a patient with ankylosing spondylitis. Nat Med. 2023 Oct 23. Online ahead of print.