Team: Lupus Legends: The Anifrolumab Edition

Base article: Kalunian KC, Furie R, Morand EF, Bruce IN, Manzi S, Tanaka Y, Winthrop K, Hupka I, Zhang LJ, Werther S, Abreu G, Hultquist M, Tummala R, Lindholm C, Al-Mossawi H. A Randomized, Placebo-Controlled Phase III Extension Trial of the Long-Term Safety and Tolerability of Anifrolumab in Active Systemic Lupus Erythematosus. Arthritis Rheumatol. 2023 Feb;75(2):253-265. doi: 10.1002/art.42392. Epub 2022 Nov 11. PMID: 36369793; PMCID: PMC10098934.

Authors: The Medical University of South Carolina Fellowship Program

1. Rachael Werner, MD, PhD, 3^rd year fellow
2. Gretchen Santana, MD, 2^nd year fellow
3. Rashi Vora, MD, 2^nd year fellow
4. Megan Donaldson, DO, 1^st year fellow
5. Maggie Smythe, MD, 1^st year fellow
6. Brandon Lew, MD, 1^st year fellow
7. Jennifer Schmidt, MD, Associate Program Director
8. Faye Hant, DO, Program Director

Team Overview: 

In the heated competition of chronic illness treatments, “A Randomized, Placebo-Controlled Phase III Extension Trial of the Long-Term Safety and Tolerability of anifrolumab in Active Systemic Lupus Erythematosus” is the undisputed MVP!

For patients, this trial shows that anifrolumab can offer relief during the overtime of managing chronic conditions. This trial shows strong data in using anifrolumab to reduce steroid usage, at least off the court.

For researchers, this trial offers invaluable insights on how long-term treatment options like anifrolumab can shape the future of chronic illness management. This study isn’t just a win for lupus—it shines a spotlight on interferon-targeted therapies which are also being explored in conditions like dermatomyositis and systemic sclerosis (1, 2). Plus, it’s a great gameplan for running long-term placebo-controlled trials.

In the competition of managing systemic lupus erythematosus (SLE), anifrolumab has emerged as a key player. This phase III long term extension (LTE) trial was like the championship finals, where patients who completed the initial TULIP trial were either continued on anifrolumab 300 mg, switched from 150mg to 300mg dosing or remained on the bench with placebo.

This trial showed that anifrolumab maintained a strong defense against serious adverse events (SAEs), with an exposure-adjusted incidence rate (EAIR) of 8.5 per 100 patient-years, outscoring the placebo team’s 11.2. Similarly, when it came to adverse events leading to treatment discontinuation, anifrolumab had fewer fouls and less time on the sidelines (EAIR of 2.5 compared to placebo’s 3.2).

In the infection zone, both teams were evenly matched, with non-opportunistic serious infections occurring at comparable rates. On the offense, anifrolumab excelled by reducing the need for glucocorticoids and improving SLE disease activity. This strategic move helped anifrolumab outscore placebo in overall disease management.

In conclusion, this LTE study was the longest placebo-controlled clinical trial in the SLE arena, and it reinforced anifrolumab’s favorable benefit-risk profile. Whether you’re advancing treatments, improving patient outcomes, or looking for a new research breakthrough, anifrolumab is THE player to watch for patients with moderate-to-severe SLE receiving standard therapy. Don’t sit on the bench—this is the one to watch for patients now and in the future!

Related content on theMednet.org:

How will you utilize newly FDA approved anifrolumab for SLE in your practice?

References:

1. Shaw, K. S., Hashemi, K. B., Castillo, R. L., Rainone, E., Ho, A. W., Kahn, P. J., Oza, V. S., Femia, A., & Vleugels, R. A. (2024). Anifrolumab in recalcitrant cutaneous dermatomyositis: A Multicenter Retrospective Cohort study. Journal of the American Academy of Dermatology, 91(6), 1217–1219.  https://doi.org/10.1016/j.jaad.2024.07.1491
2. Khanna, D., Denton, C. P., Assassi, S., Kuwana, M., Allanore, Y., Domsic, R. T., Kleoudis, C., Xu, J., Csomor, E., Seo, C., Albulescu, M., Tummala, R., Al-Mossawi, H., Kalyani, R. N., & Del Galdo, F. (2024). A randomised, parallel-group, double-blind, placebo-controlled phase 3 study to Determine the effectiveness of the type I interferon receptor antibody, Anifrolumab, In SYstemic sclerosis: DAISY study design and rationale. Clinical and Experimental Rheumatology. https://doi.org/10.55563/clinexprheumatol/s8qcyu

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Team: The Oral Biologic Frontier

Base article: Bissonnette R, Pinter A, Ferris LK, Gerdes S, Rich P, Vender R, Miller M, Shen YK, Kannan A, Li S, DeKlotz C, Papp K. An Oral Interleukin-23-Receptor Antagonist Peptide for Plaque Psoriasis. N Engl J Med. 2024 Feb 8;390(6):510-521. doi: 10.1056/NEJMoa2308713. PMID: 38324484.

Authors:  The Chicago Collaborative

1. Maja Ivanovic, MD, first-year rheumatology fellow, University of Chicago
2. Daming Shao, MD, first-year rheumatology fellow, University of Chicago
3. Michael Macklin, MD, Assistant Professor of Medicine, University of Chicago
4. Anu Pandit, MD, first-year rheumatology fellow, Northwestern University
5. Laura Arneson, MD, Assistant Professor of Medicine, Northwestern University
6. Aliya Ahsan, MD, first-year rheumatology fellow, Loyola University
7. Mohit Gupta, MD, second-year rheumatology fellow, Loyola University
8. Melissa Briones, MD, Associate Professor, Rheumatology, Loyola University

Team Overview: 

Psoriasis is a multisystem, immune-mediated inflammatory disorder at the intersection of dermatology and rheumatology. Extensive skin involvement or concurrent arthritis may require an aggressive approach, beyond topical agents, phototherapy, or conventional synthetic DMARDs. The veteran oral options in this arena, apremilast and JAK/TYK2 inhibitors, have limitations in their efficacy and safety.

This phase 2 dose-finding randomized clinical trial introduces a promising prospect: the novel oral treatment JNJ-77242113, which exerts strong defense by inhibiting IL-23 and downstream cytokine production involved in plaque psoriasis. In this study, 255 patients with moderate-to-severe plaque psoriasis were randomized to receive the rookie therapeutic with doses of 25 mg daily, 25 mg twice daily, 50 mg daily, 100 mg daily, 100 mg twice daily, or placebo for 16 weeks. The primary endpoint was 75% reduction from baseline in the Psoriasis Area and Severity Index score (PASI 75). At 16 weeks, the young phenom, JNJ-77242113, outmaneuvered placebo, demonstrating a significant dose-response relationship, with 79% of patients reaching PASI 75 in the highest-dose group.

The stats show that this novel oral IL-23 receptor antagonist is a rising star. By combining the ease of oral administration with significant therapeutic efficacy, it opens the door to an arena of safer and more convenient treatments for psoriasis and has strong potential for psoriatic arthritis as well. The success of this therapy is a harbinger of the rising players capable of oral inhibition of cytokine targets more broadly, heralding an era where patients will not have to compromise efficacy for ease of use – a slam dunk for us all!

Related content on theMednet.org:

What circumstances would drive you to consider using an oral IL-23 inhibitor over parenteral options for management of psoriasis/PsA?

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Team: Bispecific T-Cell Engagers (BiTEs), aka “Other Drugs BiTE the Dust”

Base article: Alexander T, Krönke J, Cheng Q, Keller U, Krönke G. Teclistamab-Induced Remission in Refractory Systemic Lupus Erythematosus. N Engl J Med. 2024 Sep 5;391(9):864-866. doi: 10.1056/NEJMc2407150. PMID: 39231352.

Authors: 

1. Marwin Groener, Rheumatology Fellow, The Johns Hopkins University School of Medicine
2. Maximilian F. Konig, Assistant Professor of Medicine, The Johns Hopkins University School of Medicine

Team Overview: 

CAR-T cell therapies promise to change the game of rheumatology. But an upcoming rookie (and MVP in oncology) is our No.1 draft pick this year: Bispecific T cell-engaging antibodies.

Originally scouted by hematologists, these bispecific antibodies bind the T cell receptor-CD3 complex on any T cell with one end and a B cell surface protein (e.g. CD19 or BCMA) on B cells with the other. This dual engagement results in the destruction of B cells by the patient’s own (unmodified) T cells.

In this case study (1), teclistamab, a BCMAxCD3 bispecific T cell engager, was used to treat a patient with refractory SLE (lupus nephritis, hemolytic anemia, rash, oral ulcers, and arthritis). By six weeks, all laboratory (hypocomplementemia, anti-dsDNA) and clinical abnormalities had resolved. Her SLEDAI-2K decreased from 20 to 0, and drug-free complete remission was sustained at 16-week follow-up.

Unlike CAR-T cell therapy, bispecific antibodies offer the potential for deep depletion and “immune reset” of the B-cell compartment without the requirement for apheresis and cell engineering, without cytotoxic conditioning therapy (“lymphodepletion”), and without any risk of secondary malignancies! Like CAR-T cell therapy, side effects included cytokine release syndrome, hypogammaglobulinemia (treated with IVIg), and mild infections.

This “off-the-shelf” therapy has the potential to become the Michael Jordan of rheumatology. Blinatumomab, a CD19xCD3 bispecific T cell engager (BiTE), was also successful in patients with rheumatoid arthritis (2), and teclistamab showed promise in systemic sclerosis, Sjögren’s disease, anti-MDA5-associated dermatomyositis (3). The future holds even more for this promising player that can be engineered to beat any opponent. Bispecific antibody therapies targeting autoreactive B cells in SLE (9G4xCD3 BiTE, 4), antiphospholipid syndrome (BaiTE, 5), and even autoreactive T cells in ankylosing spondylitis (TRBV9xCD3 BiTE, 6) were presented at ACR Convergence 2024, highlighting opportunities for precision targeting without increasing the infection risk.

Related content on theMednet.org:

What factors drive you to prioritize T vs B cell inhibition when choosing therapies for patients with refractory SLE?

References

1. Alexander T, Krönke J, Cheng Q, Keller U, Krönke G. Teclistamab-Induced Remission in Refractory Systemic Lupus Erythematosus. N Engl J Med. 2024 Sep 5;391(9):864-866. PMID: 39231352.
2. Bucci L, Hagen M, Rothe T, Raimondo MG, Fagni F, Tur C, Wirsching A, Wacker J, Wilhelm A, Auger JP, Pachowsky M, Eckstein M, Alivernini S, Zoli A, Krönke G, Uderhardt S, Bozec A, D’Agostino MA, Schett G, Grieshaber-Bouyer R. Bispecific T cell engager therapy for refractory rheumatoid arthritis. Nat Med. 2024 Jun;30(6):1593-1601. PMID: 38671240.
3. Hagen M, Bucci L, Böltz S, Nöthling DM, Rothe T, Anoshkin K, Raimondo MG, Tur C, Wirsching A, Wacker J, Düsing C, Distler JHW, Kuwert T, Bozec A, Ramming A, Schett G, Grieshaber-Bouyer R. BCMA-Targeted T-Cell-Engager Therapy for Autoimmune Disease. N Engl J Med. 2024 Sep 5;391(9):867-869. PMID: 39231353.
4. Liu J, Xia Y, Ferris D, Shaw E, Mog B, Pearlman A, Moritz B, Kaeo K, Gliech C, Awosika T, DiNapoli S, Nichakawade T, Li Y, Ge J, Glavaris S, Marcou N, Ahmedna T, Bugrovsky R, Jenks S, Bettegowda C, Goldman D, Petri M, Sanz I, Kinzler K, Zhou S, Vogelstein B, Paul S, Andrade F, Konig M. T Cell-Engaging Bispecific Antibodies to Target Autoreactive 9G4 Idiotope B Cells in Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9).
5. Xia Y, Liu J, Pearlman A, Mog B, Shaw E, Kaeo K, Gliech C, Moritz B, Awosika T, DiNapoli S, Glavaris S, Ge J, Nichakawade T, Marcou N, Paul S, Pardoll D, Bettegowda C, Goldman D, Petri M, Rosen A, Kinzler K, Zhou S, Vogelstein B, Konig M. Bispecific Autoantigen-T Cell Engagers (BaiTE) to Selectively Target Autoreactive B Cells in Antiphospholipid Syndrome [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9).
6. Glavaris S, Pearlman A, Liu J, Ge J, Xia Y, Kaeo K, Awosika T, Gliech C, Nichakawade T, Marcou N, Bettegowda C, Pardoll D, Kinzler K, Zhou S, Vogelstein B, Paul S, Konig M. TRBV9-Targeted Bispecific T Cell-Engaging Antibodies to Reset the Autoreactive T Cell Compartment in Spondyloarthritis and HLA-DQ8 Celiac Disease [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9).

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Team: Abatacept for pre-RA, aka the “tendon ticklers”

Base article: Cope AP, Jasenecova M, Vasconcelos JC, Filer A, Raza K, Qureshi S, D’Agostino MA, McInnes IB, Isaacs JD, Pratt AG, Fisher BA, Buckley CD, Emery P, Ho P, Buch MH, Ciurtin C, van Schaardenburg D, Huizinga T, Toes R, Georgiou E, Kelly J, Murphy C, Prevost AT; APIPPRA study investigators. Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial. Lancet. 2024 Mar 2;403(10429):838-849. doi: 10.1016/S0140-6736(23)02649-1. Epub 2024 Feb 13. PMID: 38364839.

Authors: Allegheny Health Network Adult Rheumatology Fellowship

1. Conor O’Donnell, DO, Second year rheumatology fellow
2. Saloni Goyal, DO, Second year rheumatology fellow
3. Guru Prasad Parthiban, MD, First year rheumatology fellow
4. Mara Banez, MD, First year rheumatology fellow
5. Michael Lucke, MD, Program Director

Team Overview: 

Imagine your patient squaring off on the baseball diamond in the immunologic ballpark. Rheumatoid Arthritis (RA) is the pitcher and is ready to throw a citrullinated fast ball at your patient. Would you rather risk the long-term consequences of a strikeout, or give them the resources to prevent RA’s tendrils from infiltrating their pristine joint space? The APIPPRA trial showed that abatacept’s protective gear could stave off the inflammatory advances of rheumatoid arthritis.

This groundbreaking trial was the first of its kind to demonstrate a sustained delay in the development of RA and onset of clinical synovitis. In this multicenter placebo controlled clinical trial, abatacept showed improvement in pain scores, functional well-being, quality of life and subclinical synovitis at one year.

At 12 months, 29% of patients on placebo had development of clinical synovitis or progression to RA compared to 6% of patients on abatacept. Despite discontinuation of the abatacept in the treatment arm at 12 months, this difference was sustained at 24 months, with 38% in the placebo group compared to 25% in the abatacept group. There was no increase in side effects in the abatacept group compared to placebo.

Abatacept was a home run in potentially delaying the transition from pre-clinical RA to clinical RA, suggesting it may alter the risk state of pre-clinical RA. This low-risk, high-reward tool will empower your patient to seize victory in the battle against rheumatoid arthritis.

Related content on theMednet.org:

What is your approach to monitoring patients referred for high titer +RF and +CCP but without active symptoms of inflammatory arthritis?

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Team: CD40L Inhibitor in Sjögren’s, aka the “Sjögren Horse”

Base article: St Clair EW, Baer AN, Ng WF, et al. CD40 ligand antagonist dazodalibep in Sjögren’s disease: a randomized, double-blinded, placebo-controlled, phase 2 trial. Nat Med. 2024;30(6):1583-1592. doi:10.1038/s41591-024-03009-3

Authors: Trainees associated with the Duke Rheumatology Fellowship

1. Jamie Lim, third year medical student
2. Hannah Concannon, third year medical student
3. Robyn Guo Ku, third year medical student
4. Eric A. Wilson, MD, third year internal medicine resident
5. Lisa Criscione-Schreiber, MD, MEd, Professor of Medicine
6. David Leverenz, MD, MEd, Program Director

Team Overview: 

Currently, there are no approved targeted therapies for Sjögren’s disease (SjD). Clinical heterogeneity has made the search for efficacious treatments challenging; however, SjD may be gearing up for its Cinderella story with the development of the CD40 ligand antagonist, Dazodalibep (DAZ).

In St. Clair et al’s recently published phase 2 trial, patients with SjD received three infusions of IV DAZ 1500 mg or placebo every 2 weeks, followed by four additional doses every 4 weeks. Authors pre-defined 2 distinct SjD populations to pick and roll their way around previous challenges with heterogenity. Population 1 included those with high systemic disease activity (ESSDAI ≥5), while population 2 included patients with high symptom burden (ESSPRI ≥5) and limited systemic organ involvement (ESSDAI < 5).

Primary endpoints – change from baseline ESSDAI score in population 1 and change from baseline ESSPRI score in population 2 at 169 days – were achieved in both populations. In population 1, ESSDAI scores decreased significantly more (P = 0.0167) in the DAZ group (−6.3 ± 0.6) than in the placebo group (−4.1 ± 0.6). Similarly, ESSPRI scores were significantly lowered (P = 0.0002) with DAZ treatment ( −1.8 ± 0.2) compared to placebo (−0.5 ± 0.2; P = 0.0002) in population 2. In both populations, these outcomes also surpassed the minimal clinically important improvement in ESSDAI score (3-point reduction) or ESSPRI score (1-point reduction).

Team Sjögren’s Horse is hopeful that larger, phase 3 trials will show that DAZ is a slam-dunk for SjD!

Related content on theMednet.org:

What is your approach to managing sicca symptoms in patients not responding or not tolerating conservative measures, pilocarpine, and cevimeline?

What is your approach to immunomodulatory treatment in patients with Sjogren’s syndrome who have active serologies (i.e. elevated ESR, hypergammaglobulinemia, hypocomplementemia) but minimal symptoms?

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