Clinical Rheumatology Year in Review—2022

PHILADELPHIA—To appreciate just how far we’ve come in the past year, one needs to look no further than the colleague sitting next to you at ACR Convergence 2022, which occurred in person for the first time in three years. For most, this would be enough to celebrate. But there’s more.

On Nov. 11, 2022, Carol A. Langford, MD, MHS, FACP, director, Center for Vasculitis Care and Research, professor of medicine, Harold C. Schott Endowed Chair, Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, presented an overview of clinical updates in rheumatology from November 2021 to November 2022. To craft her talk, Dr. Langford reviewed high-impact journals in rheumatology and internal medicine, noting that several important studies couldn’t be included due to time constraints. Featured articles were those that helped us weigh risks and benefits, directly impacted clinical practice or described innovative therapeutic approaches. She concluded her talk with COVID-19 updates pertinent to patients with rheumatic disease.

Risks & Benefits

The GLORIA trial was a randomized, double-blind, placebo-controlled trial that examined the benefits and harms of 5 mg of prednisolone given daily for two years added to standard of care in patients aged 65 years or older with active rheumatoid arthritis (RA).¹ This was a pragmatic trial, a design that focuses on examining treatments and outcomes in a real-world practice setting. “This means that co-treatments and changes in therapy were permitted,” Dr. Langford explained.

The co-primary outcome for benefit and harm revealed a Disease Activity Score-28 of 0.37 points lower on prednisolone than placebo (95% confidence level 0.23, P<0.0001) and a number needed to harm of 9.5. The addition of prednisolone was associated with lower disease activity and reduction in joint damage, but the tradeoff was a 24% increase in adverse events—the majority of which were due to infections.

Dr. Langford

Dr. Langford cautioned, “We need to consider the study population here. In younger patients newly diagnosed with RA, this might not be generalizable. It was also only a two-year study, which is long in terms of clinical trials but not in the grand scheme of RA.”

Dr. Langford also discussed the ORAL Surveillance trial, which resulted in a revised U.S. Food & Drug Administration (FDA) indication in RA and an added boxed warning for tofacitinib, baricitinib and upadacitinib.² Findings from this trial and others have been featured this year in The Rheumatologist. Further safety data will be particularly important given several new FDA indications for these drugs in psoriasis and spondyloarthritis, as well as a new medication that inhibits Janus kinase (i.e., deucravacitinib).

Clinical Practice

Dr. Langford turned next to studies of particular interest to the practicing rheumatologist. She discussed the MIRROR randomized, controlled trial, which resulted in the expanded FDA labeling of pegloticase to include co-administration with methotrexate (MTX) in July 2022.³ Co-administration of 15 mg of MTX weekly improved pegloticase response rates at month six (MTX 71% vs. placebo 39%, P<0.0001) and significantly decreased the development of infusion reactions (MTX 4% vs. placebo 31%) and anti-drug antibodies (MTX 23% vs. placebo 50%). Though results were positive, Dr. Langford reminded the audience to consider the general impact of immunosuppression and MTX-specific side effects when taking this approach.

In July 2021, intravenous immunoglobulin (IVIG) was the first agent to be FDA approved for any inflammatory myopathy (specifically, dermatomyositis) after a randomized, double-blind, placebo-controlled trial demonstrated its efficacy and safety.⁴ Dr. Langford noted that during the open-label extension phase of the trial, patients in the placebo arm who were switched to IVIG had improvements similar to those who had received IVIG from study start. Further studies are needed to determine when to use IVIG (e.g., first-line treatment vs. refractory disease). Cost and safety (especially in those at risk for thromboembolic events) should also be considered.

Finally, we saw positive results in the use of intravenous tocilizumab in patients with polymyalgia rheumatica who had a demonstrated inability to reduce prednisone below 10 mg per day after eight weeks.⁵ Tocilizumab was associated with a lower mean prednisone dose and greater ability to discontinue prednisone, though infections were more common with tocilizumab (47%) vs. placebo (39%). “The main consideration here remains the risk of prednisone compared to the risk of the adjunctive agent,” Dr. Langford said. We look forward to further data in this regard.

Clinical Innovations

The past year saw several novel mechanistic approaches in systemic lupus erythematosus (SLE). Of particular interest are chimeric antigen receptor (CAR) T cells, which Dr. Langford concisely described. “First, lymphopheresis is performed to remove the patient’s T cells. Then, lentivirus vector containing the gene sequence (in this case, antihuman CD19) is prepared in the lab. When placed with the patient’s T cells, there is transformation to CD19 CAR T cells. These are then grown in the laboratory while the patient receives lymphodepleting therapy. When the CAR T cells are reinfused, they bind to the CD19 antigen on the surface of the patient’s B cells, leading to B cell lysis and depletion.”

A fascinating study of five young patients with refractory, active, multi-organ SLE demonstrated improvement in all patients, with four achieving an SLE Disease Activity Index-2K (SLEDAI-2K) of zero by only three months.⁶ Complement levels normalized and anti-double-stranded DNA antibodies disappeared. All immunomodulatory drugs could be discontinued in all patients, and drug-free remission was maintained at eight months even after reappearance of B cells. “Concerns remain for costs and risks, but this is an innovative approach for which longer follow up in larger numbers will be needed to determine if remission persists,” Dr. Langford concluded.

Dr. Langford briefly touched on litifilimab, a monoclonal antibody that binds blood dendritic cell antigen 2 to suppress the production of type I interferons; iberdomide, an immunomodulatory imide drug that promotes degradation of transcriptional factors Ikaros and Aiolos, reducing B cell activity and type I interferon pathways; and obinutuzumab, a humanized type II anti-CD20 monoclonal antibody that provides greater B cell cytotoxicity and depletion than rituximab. All three therapies were studied in phase 2 randomized trials this year.^7-10 “Further studies are needed to better understand the potential roles of these agents, and we look forward to these results in the future,” she said.

Update on COVID-19

“Throughout this year, we’ve continued to learn about the impact of [COVID-19] on rheumatic disease patients through entities like the Global Rheumatology Alliance, the ACR COVID-19 Task Force and many others,” Dr. Langford said. A systematic literature review demonstrated that patients with rheumatic diseases had a relative risk of developing infection that was 52% higher compared to the general population and a higher risk of poor outcome with a 74% increased risk of death.¹¹ In partially/fully vaccinated patients, another study showed that over half of those requiring hospitalization were receiving a B cell depleting therapy or mycophenolate mofetil.¹²

Dr. Langford was careful to draw our attention to pre-exposure prophylaxis as a COVID-19 prevention strategy added to non-pharmacologic measures and vaccination. Currently only one agent has received FDA Emergency Use Authorization for pre-exposure prophylaxis (tixagevimab-cilgavimab), but others are likely to follow. This drug doesn’t prevent all COVID-19 infections, but it appears to lessen the frequency and severity with which they occur.¹³ Dr. Langford encouraged the audience to keep this often-overlooked option in mind for our vulnerable, at-risk immunocompromised patients.

Dr. Langford concluded with an enduring truth: The rheumatology practitioner has played a central role in advocating for immunocompromised patients with rheumatic diseases in the COVID-19 era and will continue to do so. Our evolving roles and contributions as rheumatologists during the changing course of the pandemic are well outlined in a recent Arthritis & Rheumatology publication in August 2022.¹⁴

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. 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(7):925–936.
2. Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022 Jan 27;386(4):316–326.
3. 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 (MIRROR RCT): Primary efficacy and safety findings. Arthritis Rheumatol. 2022 Sep 13. Online ahead of print.
4. Aggarwal R, Charles-Schoeman C, Schessl J, et al. Trial of intravenous immune globulin in dermatomyositis. N Engl J Med. 2022 Oct 6;387(14):1264–1278.
5. Devauchelle-Pensec V, Carvajal-Alegria G, Dernis E, et al. Effect of tocilizumab on disease activity in patients with active polymyalgia rheumatica receiving glucocorticoid therapy: a randomized clinical trial. JAMA. 2022 Sep 20;328(11):1053–1062.
6. Mackensen A, Müller F, Mougiakakos D, et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. 2022 Oct;28(10):2124–2132.
7. Furie RA, Aroca G, Cascino MD, et al. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: A randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2022 Jan;81(1):100–107.
8. Merrill JT, Werth VP, Furie R, et al. Phase 2 trial of iberdomide in systemic lupus erythematosus. N Engl J Med. 2022 Mar 17;386(11):1034–1045.
9. Furie RA, van Vollenhoven RF, Kalunian K, et al. Trial of anti-BDCA2 antibody litifilimab for systemic lupus erythematosus. N Engl J Med. 2022 Sep 8;387(10):894–904.
10. Werth VP, Furie RA, Romero-Diaz J, et al. Trial of anti-BDCA2 antibody litifilimab for cutaneous lupus erythematosus. N Engl J Med. 2022;387(4):321–331.
11. Conway R, Grimshaw AA, Konig MF, et al. SARS–CoV-2 infection and COVID-19 outcomes in rheumatic diseases: A systematic literature review and meta-analysis. Arthritis Rheumatol. 2022 May;74(5):766–775.
12. Liew J, Gianfrancesco M, Harrison C, et al. SARS-CoV-2 breakthrough infections among vaccinated individuals with rheumatic disease: Results from the COVID-19 global rheumatology alliance provider registry. RMD Open. 2022 Apr;8(1):e002187.
13. Kertes J, Shapiro Ben David S, Engel-Zohar N, et al. Association between AZD7442 (tixagevimab-cilgavimab) administration and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hospitalization, and mortality. Clin Infect Dis. 2022 Jul 29;ciac625. Online ahead of print.
14. Calabrese LH, Calabrese CM, Kirchner E, et al. The evolving role of the rheumatology practitioner in the care of immunocompromised patients in the COVID-19 era. Arthritis Rheumatol. 2022 Aug 26. Online ahead of print.