In Brief | Autoimmune Diseases | Rheumatoid Arthritis
Immune Checkpoint Inhibitors Linked to Increased Risk of Rheumatoid Arthritis
Time to read: 04:42Time to listen: 08:21
Originally Published: 7 January 2025
Sourced: ACR Open Rheumatology
Type of article: In Brief
MedED Catalogue Reference: MAIB002
Category: Autoimmune Diseases
Cross Reference: Oncology, Inflammatory Arthritis
Keywords: rheumatoid arthritis, immune checkpoint inhibitors, ontology, gene therapy
A study of over five million patients with a neoplasm found that those treated with immune checkpoint inhibitors (ICIs) had a 26% increased risk of developing rheumatoid arthritis (RA) compared to those receiving other cancer therapies. This highlights the importance of monitoring for autoimmune conditions in patients undergoing ICI treatment.
This article is a of a clinical trial originally published in ACR Open Rheumatology, 7 January 2025. This article does not represent the original research, nor is it intended to replace the original research. Access the full Disclaimer Information.
Recent advancements in cancer biology have led to significant progress in immuno-oncology, particularly with the development of immune checkpoint inhibitors (ICIs).
Since ipilimumab’s approval for melanoma in 2011, ICIs targeting key immune checkpoints, such as CTLA-4 and PD-1, have shown promising results in various cancers, improving patient outcomes.
CTLA-4, with its ligands CD80/CD86 and PD-1, with PD-L1 and PD-L2 ligands, are vital regulators of T-cell activation, maintaining immune balance and preventing self-reactivity.
Research has highlighted the effects of ICIs in patients with preexisting autoimmune conditions (ACs), though data remains limited.
The researchers of this study, published on January 24, 2025, in ACR Open Rheumatology, aimed to address this gap by examining the prevalence of new ACs diagnosed after ICI treatment using a real-world database.
Editors Note
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is an inhibitory receptor which belongs to the CD28 immunoglobulin subfamily. It is expressed primarily by T-cells. Its ligands, CD80 and CD86, are found on the surface of antigen-presenting cells and can either bind CD28, resulting in a costimulatory response, or to CTLA-4, resulting in a co-inhibitory response.1
Programmed death-1 (PD-1) is an immune checkpoint receptor on T cells that regulates immune responses by regulating T cell exhaustion. When PD-1 binds to its ligand, programmed death-ligand 1 (PD-L1), it triggers signalling pathways that suppress T cell activation, reducing immune responses.2
Tumour cells can exploit the dysregulation of these checkpoints, particularly by upregulating PD-L1, to evade immune detection.
While blocking these checkpoints enhances the antitumor immune response, it may also disrupt self-tolerance, resulting in immune-related adverse effects (irAEs).
Study Purpose
To evaluate the prevalence of new-onset autoimmune conditions following the commencement of immune checkpoint inhibitors.
Study Methodology
The patients were divided into two groups: those who received ICIs (including atezolizumab, pembrolizumab, nivolumab, and others) and those who did not.
The prevalence of autoimmune conditions such as vasculitis, lupus, rheumatoid arthritis, and others was assessed.
Multivariate Cox proportional hazard models and Kaplan-Meier methods were used to determine the risk of ACs in each group.
Subgroup analysis further compared the risk of ACs among different ICI classes, including CTLA-4 inhibitors (CTLA4i), PD-1 inhibitors (PD1i), PD-L1 inhibitors (PDL1i), and combination therapies (CT)
Findings
Of the total cohort of 5,259,415 patients, 106,809 (2.03%) were receiving ICIs.
The patients who received immune checkpoint inhibitors (ICIs) were younger (68.7 ± 12.6 years vs. 71.8 ± 13.9 years), more likely to be male (54% vs. 41%;)and predominantly White (68% vs. 58%) compared to those who did not receive ICIs.
ICIs were associated with a lower likelihood of developing systemic lupus erythematosus (SLE) (0.366% vs. 0.437%, [OR] 0.837; P = 0.0005) and systemic sclerosis (0.108% vs. 0.135%, OR 0.796; P = 0.0151).
However, the odds of developing rheumatoid arthritis (RA) were higher in the ICI group (2.194% vs. 1.752%, OR 1.258; P < 0.0001; HR 1.746; P < 0.0001).
There were no significant differences in the development of vasculitis, dermato-polymyositis, or psoriatic arthritis between the two groups.
After adjusting for variables using propensity score matching, the prevalence of autoimmune conditions remained similar, except for no significant difference in SLE prevalence (0.37% vs. 0.393%, OR 0.942, P = 0.3970).
Immune checkpoint inhibitors have become the standard treatment for many cancers due to their ability to harness the immune system against tumours.
However, as illustrated by this study, they are associated with immune-related adverse effects, including inflammatory arthritis. The researchers found that rheumatoid arthritis was more prevalent in ICI-treated patients, especially those receiving combination therapy.
While other inflammatory arthritis, such as psoriatic arthritis (PsA), showed no significant differences, combination therapy was linked to more severe disease courses.
Surprisingly, systemic lupus erythematosus was less common in ICI patients, though not significantly so after adjustment. This contrasts with some murine studies which found that ICIs may offer protective effects in lupus. Limited cases of ICI-induced systemic sclerosis have been reported, with atypical features in ICI cases.
Vasculitis and myositis were also studied, with no significant differences in vasculitis rates between ICI and non-ICI groups.
Myositis (especially dermatomyositis) showed higher odds in ICI patients, though it was not statistically significant.
Overall, while ICIs offer significant clinical benefits, the researchers conclude that their role in inducing autoimmune conditions remains an area requiring careful monitoring, with early diagnosis being key to managing these adverse effects effectively.
Conclusion
Additionally, there is a need for increased training for prescribers of ICIs in identifying unconventional features of ICI-induced ACs, to reduce the delay in diagnoses and treatment. Further prospective studies are needed to confirm causality and fully understand the relationship.
Importance of this study for South Africa
A 2023 study on cancer immunotherapy in sub-Saharan Africa highlighted the region's limited use of this treatment, with only 29% of the clinics surveyed having easy access to the treatment and even fewer using biomarker testing.
While 46% of healthcare providers surveyed were familiar with immunotherapy, only 11% felt adequately trained to administer it, and fewer still were trained to manage severe side effects.
Despite the low usage, immunotherapy is critical for addressing the growing cancer burden in SSA, projected to exceed 1 million deaths by 2040.3
However, as highlighted by this study, its adoption must be approached cautiously, with more training, biomarker testing, and patient access needed for safe implementation.
Access the Original Trial
Khandwala P, Desai D, Lau A. Prevalence of Autoimmune Diseases in Patients Treated With Immune Checkpoint Inhibitors: An Epidemiological Study Using A Global Network of Health Care Organizations. ACR Open Rheumatol. 2025 Jan;7(1):e11787. doi: 10.1002/acr2.11787. PMID: 39854167; PMCID: PMC11760991.
Additional References
1. Van Coillie, S., Wiernicki, B., & Xu, J. (2020). Molecular and Cellular Functions of CTLA-4. Advances in experimental medicine and biology, 1248, 7–32. https://doi.org/10.1007/978-981-15-3266-5_2
2. Jiang Y, Chen M, Nie H, Yuan Y. PD-1 and PD-L1 in cancer immunotherapy: clinical implications and future considerations. Hum Vaccin Immunother. 2019;15(5):1111-1122. doi: 10.1080/21645515.2019.1571892. Epub 2019 Mar 19. PMID: 30888929; PMCID: PMC6605868.
3. Olatunji E, Patel S, Graef K, Joseph A, Lasebikan N, Mallum A, Chigbo C, Jaffee E, Ngwa W. Utilization of cancer immunotherapy in sub-Saharan Africa. Front Oncol. 2023 Dec 21;13:1266514. doi: 10.3389/fonc.2023.1266514. PMID: 38179176; PMCID: PMC10765613.
Back to top
Disclaimer
This article is compiled from several resources researched and compiled by the contributor. It is in no way presented as an original work. Every effort has been made to attribute quotes and content correctly. Where possible all information has been independently verified. The Medical Education Network bears no responsibility for any inaccuracies which may occur from the use of third-party sources. If you have any queries regarding this article contact us
Fact-checking Policy
The Medical Education Network makes every effort to review and fact-check the articles used as source material in our summaries and original material. We have strict guidelines in relation to the publications we use as our source data, favouring peer-reviewed research wherever possible. Every effort is made to ensure that the information contained here is an accurate reflection of the original material. Should you find inaccuracies, out of date content or have any additional issues with our articles, please make use of the contact us form to notify us.
