Beyond Glucocorticoids: The Current Landscape and Prospects for Treating Immune Checkpoint Inhibitor‐Induced Autoimmunity

Abstract

The rapid integration of immune checkpoint inhibitors (ICIs) into standard oncology protocols has birthed a new frontier in clinical rheumatology: immune‐related adverse events (irAEs). By disrupting the programmed cell death‐1 (PD‐1)/PD‐L1 and cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) axes to restore antitumor T cell activity, these therapies inadvertently breach peripheral tolerance. This results in a spectrum of de novo autoimmune and inflammatory syndromes that frequently mimic established rheumatic diseases, including inflammatory arthritis and myositis. Although ICIs have revolutionized survival outcomes, the resultant irAEs pose a significant clinical challenge, affecting nearly 50% of patients and often necessitating the expertise of rheumatologists for management. This manuscript explores the unique rheumatologic phenotype of ICI‐induced toxicities, emphasizing the urgent need for a shift from broad‐spectrum glucocorticoid use toward targeted, mechanism‐driven therapies that do not compromise the abscopal antitumor effect. We review the current landscape of clinical trials investigating the repurposing of traditional disease‐modifying antirheumatic drugs and advanced biologics. Specifically, we discuss the efficacy and safety of tumor necrosis factor–alpha inhibitors, interleukin‐6 receptor antagonists, and JAK inhibitors in the context of steroid‐refractory irAEs. We further analyze the molecular commonalities between idiopathic autoimmune diseases and ICI‐induced inflammation. As the patient population receiving ICIs grows, the rheumatologist's role as a co‐manager is increasingly essential. This review highlights the need for standardized grading and treatment algorithms for rheumatologic irAEs and advocates collaborative research to separate immunotherapy toxicities from its oncological benefits.

Introduction

Cancer is one of the leading causes of death worldwide, ranking as the second most common cause in the United States. ¹ Immune checkpoint inhibitors (ICIs) have recently become a leading treatment option for cancer, with about 50% of cancer patients in developed countries receiving this type of therapy. ² Unlike nonspecific treatments, ICIs target immune‐evasion mechanisms used by tumor cells, thereby restoring T cell‐mediated antitumor immunity. Tumors often evade immune surveillance by exploiting inhibitory immune checkpoints, such as programmed cell death‐1 (PD‐1) and its ligand PD‐L1, which suppress tumor‐specific T cell activity. ICIs work by reinvigorating T cell immune responses against tumor cells. Two key immune checkpoints targeted by ICIs are cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) and PD‐1, both inhibitory receptors on T cells that enable tumors to escape immune detection. Antibodies targeting CTLA‐4, PD‐1, and PD‐L1 disrupt receptor‐ligand interactions, allowing T cells to recognize and destroy cancer cells. ³ The Food and Drug Administration has approved these drugs for the treatment of over 25 cancer types, including melanoma, non–small cell lung cancer (NSCLC), bladder, kidney, liver, head/neck, colorectal, and Hodgkin lymphoma, and have led to significant improvements in patient survival. CTLA‐4 and PD‐1 regulate immune responses at different stages of T cell activation. CTLA‐4 primarily acts during early T cell priming, whereas PD‐1 acts later by limiting Teff cell activity. Anti–CTLA‐4 antibodies, in part, boost T cell activation by suppressing Treg cells, whereas anti–PD‐1 therapies restore exhausted CD8⁺ and CD4⁺ Teff cells. The timing difference between these treatments may explain why anti–CTLA‐4 therapy often causes higher rates and more severe side effects. By acting earlier in immune activation, anti–CTLA‐4 provokes a broader and more intense immune response, increasing the risk of serious side effects compared with anti–PD‐1 therapy. ⁴

Although ICIs have transformed cancer therapy, they come with notable limitations, especially immune‐related adverse events (irAEs), which can lead to treatment discontinuation. Over 50% of patients treated with ICIs develop irAEs, usually within the first three months, although they can occur at any point during treatment. ¹ IrAEs result from increased immune activation across organs and often mimic autoimmune diseases clinically.

Mechanistically, ICIs enhance the immune system's ability to target tumor cells; however, this boost can also lead to off‐target inflammation affecting normal tissues. These adverse effects can manifest in various forms, impacting the skin, gastrointestinal tract, endocrine glands, musculoskeletal system, kidneys, liver, nervous system, and eyes. In some cases, multiple organs are affected simultaneously, whereas in others, toxicity is limited to a single system. Different irAEs, such as pulmonary toxicities, peripheral nervous system toxicities, myocarditis, and arthritis, have been reported to be caused by different disordered T cell subsets. Bronchoalveolar lavage fluid collected from ICI‐pneumonitis patients showed an increase in the CD8⁺ T cell population and activation of Th17/interleukin (IL)‐17A and Th1/Type II Interferon (IFN‐g) pathways. ⁵ , ⁶ A variety of other irAEs, including colitis, nephritis, pneumonitis, and dermatological complications, involve CD4⁺ T cell infiltration, particularly Th1 and Th17 ⁷ cells. Another mechanism for irAEs is autoreactive B cell activation, leading to the production of self‐antibodies that bind antigens and trigger the classical complement cascade, causing damage. Furthermore, a third mechanism is cytokine‐mediated inflammatory damage, as supported by patients’ responses to cytokine signaling blockade, such as anti–IL‐6R treatment. ⁸ The onset of rheumatic irAE‐arthritis is specifically attributed to a combination of T cell dysregulation, B cell activation with autoantibody production, cytokine‐mediated inflammation, and impaired immune tolerance due to Treg dysfunction. ⁹

The variability in irAE presentation and severity makes patient management particularly challenging. Three urgent issues related to irAEs need attention. First, preventing or halting the development of secondary autoimmune disorders caused by drugs is crucial. Second, protecting patient safety from irAEs is essential for the continued use of ICIs, which can be lifesaving. Third, it is important to recognize that some immunosuppressive treatments for irAEs may raise the risk of tumor progression. Addressing these challenges underscores the need to deepen our understanding of irAE mechanisms and to develop targeted therapies that manage these side effects effectively and minimize risks. Consequently, expanding knowledge of irAE mechanisms and developing more precise treatments, especially for rheumatic irAEs, is urgently required.

There are differing opinions and evidence regarding the correlation between irAEs and tumor responses in patients. Numerous studies have suggested a strong link between the occurrence of irAEs and improved tumor responses to ICIs, likely attributed to a more vigorous immune response in these patients. ¹⁰ However, some research indicates that patients experiencing irAEs, such as pneumonitis, have a diminished response to ICIs like nivolumab or pembrolizumab when treating lung cancer. ¹¹ Additional studies suggest that immune activation may be associated with beneficial antitumor immune responses, as exemplified by cases of vitiligo, which demonstrate the antitumor effects of ICIs in melanoma. Furthermore, evidence such as shared T cell receptor sequences and increased organ‐specific transcripts found in tumors and noncancerous tissues affected by toxicities supports this correlation. ² Conversely, some evidence indicates that irAEs are not directly associated with antitumor effects. This divergence in perspectives may be attributed to the various types of irAEs and their distinct underlying mechanisms. IrAEs may be influenced by both tumor‐related and unrelated factors, complicating the process of drawing definitive conclusions. This intricacy underscores the need for further research in this domain. ²

Clinical Manifestations of Immune‐Related Adverse Events

ICIs target the PD‐1 pathway to augment T cell activity against neoplastic cells. However, the immune response may occasionally be nonspecific to organs. Even with targeted PD‐1 blockade, the heightened immune response may inadvertently affect normal tissues across multiple organs, leading to irAEs that are not confined to a single organ. Such reactions can precipitate autoimmune and autoinflammatory responses that affect various organ systems. ⁴ These irAEs can be classified by the affected organ, including dermatologic, gastrointestinal, hepatic, endocrine, pulmonary, musculoskeletal, and other less common inflammatory types. Although irAEs generally manifest within the first three months of treatment, they can occur at any point during therapy or even after its conclusion. Acute irAEs occur during treatment, whereas delayed irAEs develop after treatment ends. ¹² , ¹³ Conversely, chronic irAEs, defined as organ damage that persists beyond three months after ICI discontinuation, are associated with improved survival (30+ months post‐treatment) in some cancers such as NSCLC and melanoma. ¹⁴ , ¹⁵ Patients frequently develop enduring inflammatory diseases resulting from chronic irAEs, which necessitate long‐term immunosuppressive therapy and pose increased management challenges. ¹⁰ The most prevalent chronic irAEs include arthritis, dermatitis, and neuropathy. ² Furthermore, the endocrine system is particularly susceptible to chronic toxicities across various irAE types. In cases where inflammation affects the thyroid, pituitary, adrenal glands, or beta‐islet cells, T cell‐mediated injury often results in persistent hormone deficiencies because these hormone‐secreting cells generally lack regenerative capacity. Although these chronic toxicities occur less frequently and have a more insidious onset than acute irAEs, they can lead to significant morbidity and should not be undervalued. ¹³

The emergence of irAEs has fundamentally redefined the scope of modern rheumatology, establishing a novel category of ICI‐induced systemic inflammatory syndromes. ¹⁶ Observed in approximately 5% to 14% of patients receiving therapies targeting the CTLA‐4 and PD‐1/PD‐L1 axes, these toxicities result from a systemic breach of peripheral tolerance that manifests as phenocopies of traditional autoimmune disease. ¹⁷ The spectrum of rheumatic irAEs is notably diverse (Figure 1). Manifestations range from the most prevalent conditions, such as inflammatory polyarthritis (present in 1.5%–22% of patients) and arthralgia (ranging from 1%–43%), to more localized pathologies such as tendinitis and enthesitis. ¹⁸ , ¹⁹ Although additional frequently observed rheumatic irAEs include myalgias (prevalence 2%–20%) and polymyalgia rheumatica (PMR)‐like syndromes (prevalence ~2.1%), rheumatologists must also manage high‐acuity complications such as inflammatory myositis (prevalence ~1%). ¹⁹ PMR has been reported to occur at a higher frequency in patients treated with anti–PD‐1/PD‐L1 (single agent or combination) compared with patients treated with anti–CTLA‐4 at a ratio of 15:1. ²⁰ Although less frequently reported, other documented rheumatic irAEs include sicca syndrome (prevalence up to 24%), characterized by severe xerostomia, as well as rare instances of vasculitis, sarcoidosis, and systemic sclerosis (<1% incidence). ²¹ This clinical intersection is particularly complex because these drug‐induced syndromes often exhibit distinct serological profiles, frequently lacking traditional biomarkers like rheumatoid factor (RF) or anti‐Cyclic Citrullinated Peptide, and may persist chronically even after the cessation of immunotherapy. Consequently, the rheumatologist's role is critical in implementing a nuanced, multidisciplinary management strategy that uses targeted immunosuppression to mitigate disability and life‐threatening inflammation without compromising the patient's antitumor immune response. ²²

Figure 1.

Rheumatic irAEs and their treatments. Most common ICI‐induced rheumatic irAE manifestations include sicca syndrome, myalgia/PMR, arthralgia, inflammatory polyarthritis, and myositis. Figure shows their respective prevalence as well as first and second line treatments for all grades irAE. Unless specifically mentioned, ICI treatment can be continued if irAE remains Grade 1 to 2. ICI, immune checkpoint inhibitor; irAE, immune‐related adverse event; PMR, polymyalgia rheumatica.

Management Principles for Immune‐Related Adverse Events

There are multiple general recommendations for treating irAEs, including those published by the EULAR, the European Society for Medical Oncology, the American Society of Clinical Oncology (ASCO), the Society for Immunotherapy of Cancer, and the Institut National du Cancer. The ASCO, in particular, provided a previous guideline detailing the recommendation for the management of immunotherapy‐related toxicities. Based on ASCO's recommendation, the management of irAEs depends on the severity of toxicity, which is graded 1 to 4, with higher scores indicating greater severity. Generally, patients with grade 1 toxicities from ICIs can continue treatment, except in cases involving neurologic, hematologic, or cardiologic adverse effects. ³ For grade 2 toxicities, the approach varies slightly; clinicians may temporarily suspend ICIs and restart them once symptoms decrease to grade 1. If symptoms persist for more than one week, patients should begin glucocorticoids (initial dose of 0.5–1 mg/kg/day of prednisolone or an equivalent) for symptom relief. ³ For grade 3 toxicities, health care providers are advised to immediately stop ICI treatment and begin high‐dose glucocorticoids, typically 1 to 2 mg/kg/day of prednisolone or its equivalent, with a gradual taper over 4 to 6 weeks. If symptoms persist for more than three days despite glucocorticoid therapy, clinicians may consider initiating immunosuppressive therapies such as antitumor necrosis factor–alpha (TNF‐α) as an alternative to glucocorticoids. If symptoms improve to grade 1, physicians may cautiously consider resuming ICIs. ⁴ For grade 4 toxicities, patients must discontinue ICI therapy. Hormone replacement therapy can be effective for endocrinopathy cases. ³

Currently, glucocorticoids are the main treatment for irAEs. Common glucocorticoids used for managing irAEs include prednisone and methylprednisolone. If severe irAE symptoms (grade 3+) do not improve within 72 hours of glucocorticoid treatment, consider increasing the initial dose or adding additional immunosuppressive therapy. ²³ Furthermore, using high doses of nonspecific steroids can cause various side effects, including increased infection risk, osteoporosis, hyperglycemia, and adrenal suppression, all of which can significantly affect patients’ health and quality of life.

Nonetheless, a subgroup of patients with ICI‐induced irAEs do not adequately respond to steroids and have steroid‐refractory irAEs (sr‐irAEs). Another subgroup of patients cannot be tapered off steroids without the recurrence of side effects, referred to as steroid‐dependent irAEs (sd‐irAEs). ²⁴ Patients experiencing sr‐ or sd‐irAEs are relatively common, with an incidence between 2% to 7% among individuals treated with ICIs. This rate rises to approximately 15% for those undergoing combined therapy with anti–PD‐1 and anti–CTLA‐4 antibodies. ²⁵ , ²⁶ The significant occurrence of steroid‐refractory and steroid‐dependent cases highlights the need for a more targeted approach as a second‐line treatment option. Although steroids are effective for many, their limitations in treating organ‐specific irAEs stress the pressing necessity for new therapies. Furthermore, extended steroid use can potentially undermine the effectiveness of ICI treatments, which goes against the goal of managing cancer with these therapies. ²⁷ Current data, including large meta‐analyses, indicate that although baseline steroid use (~10 mg of prednisone equivalent) for cancer‐related symptoms like brain edema or fatigue is associated with poorer overall survival and progression‐free survival, steroids initiated specifically to manage irAEs do not typically compromise antitumor outcomes. This distinction suggests that the development of an irAE is a biomarker of a robust immune response that is not easily extinguished by standard immunosuppressive tapers. However, the timing and dose remain critical variables; high peak doses (>60 mg) or prolonged administration during the early T cell priming phase may theoretically blunt the expansion of tumor‐specific effector cells. Overall, the consensus in cardio‐oncology and rheumatology is that the judicious use of steroids to treat rheumatic toxicities is a safe and necessary intervention that maintains the delicate balance between systemic immune tolerance and antineoplastic activity.

For sr‐irAEs and sd‐irAEs, alternative treatments such as anti–IL‐6 and anti–TNF‐α medications may be considered. A multicenter retrospective study reported that more than 70% of patients experienced resolution or a return to grade 1 irAEs following IL‐6 treatment, with a median onset of two months among 92 patients who had received either PD‐1 antibodies or a combination of anti–PD‐1 and anti–CTLA‐4 therapies. ⁸ In cases of myocarditis induced by ICIs, patients typically receive glucocorticoids as the initial therapy. Nevertheless, steroid‐refractory or steroid‐resistant myocarditis cases are frequent, and in such circumstances, TNF‐α agents can serve as a treatment alternative. It is important to note that TNF‐α agents should not be administered to patients with moderate‐to‐severe heart failure. ²⁸

Although general guidelines for the management of irAEs exist, they may be too broad. Current management principles for rheumatic toxicities of ICIs rely on expert opinion, likely based on the management of classical rheumatic conditions they mimic. More specifically, EULAR guidelines recommend that the initial management of mild‐to‐moderate rheumatic irAEs should focus on symptomatic treatment, including nonsteroidal anti‐inflammatory drugs and/or analgesics. ¹⁷ In the event of monoarthritis or oligoarthritis, intra‐articular glucocorticoids can provide more targeted first‐line treatment. ⁹ Also, ICI‐induced PMR requires lower glucocorticoid doses for a shorter duration than classical PMR. ²⁹ , ³⁰ On the other hand, because of its potential severity, ICI‐induced myositis requires ICI discontinuation and a much more aggressive therapeutic strategy with an initial prednisone range from 0.5 to 1 mg/kg/day to intravenous pulses of 1 g methylprednisolone, potentially in combination with intravenous Ig. ²⁹ Moreover, symptomatic treatment for ICI‐induced sicca syndrome is similar to that for Sjögren disease, with saliva substitutes for dry mouth and artificial tears and punctal plugs for dry eyes. Prednisone is suggested for ICI‐induced sicca syndrome because it may help restore some salivary function. Case studies also provide insight into the successful treatment of ICI‐induced arthralgia with systemic glucocorticoids or prednisolone (10 mg/day) as first‐line treatment and higher doses of prednisolone (15–20 mg/day) or addition of methotrexate or sulfasalazine to glucocorticoids as second‐line treatment. ³¹ Management for common rheumatic irAEs has been summarized in a graphic illustration (Figure 1).

Predictive Biomarkers for Immune‐Related Adverse Events

Broad‐spectrum autoantibodies, including antinuclear antibodies, antithyroid antibodies, and RF, are associated with an increased risk of developing irAEs across all categories. ³² Conversely, organ‐specific autoantibodies are practical tools for screening irAEs confined to specific organs. ³³

Several hematologic parameters routinely evaluated, such as absolute lymphocyte count, neutrophil‐to‐lymphocyte ratio (NLR), and platelet‐to‐lymphocyte ratio, are associated with the risk of irAEs. For example, a higher NLR indicates an increased risk of severe irAEs. ³³ In a study of patients with malignant melanoma, increased white blood cell counts and decreased relative lymphocyte counts were significantly associated with grade 3 to 4 irAE. ³⁴ Similarly, among patients with various solid tumors, elevated absolute lymphocyte and eosinophil counts following anti–PD‐1 therapy were linked to the occurrence of irAEs. ³⁵ Elevated C‐reactive protein (CRP) levels in patients with malignant melanoma have been associated with the development of irAEs in individuals receiving anti–PD‐1 or anti–CTLA‐4 therapies, in the absence of concurrent infectious diseases. ³⁶

Cytokines are vital for predicting susceptibility to irAEs in patients undergoing ICIs therapy. TNF‐α is among the most extensively studied biomarkers associated with irAEs, and lower levels may enhance antitumor immune responses. ³³ Another significant cytokine is IL‐6; patients with some types of irAE, such as Crohn disease or psoriasiform dermatitis, have elevated IL‐6 levels following ICI treatment. ³⁷ In patients with malignant melanoma, reduced IL‐6 levels correlated with the development of irAEs, such as colitis. ³⁸ This contradictory observation may stem from IL‐6's dual role in both fostering tumor progression and facilitating tumor suppression. IL‐6 assumes a complex role in innate and adaptive immunity by activating helper T cells, inhibiting Treg cells, and supporting B cell differentiation. ³⁹ Besides promoting anti‐inflammatory molecules, IL‐6 raises CRP levels, which can increase during stronger inflammatory responses. This overall immune activation might significantly contribute to the development of irAEs, although the exact mechanisms are still unclear.

IL‐17, a pro‐inflammatory cytokine produced by T helper 17 (Th17) cells, has become an important biomarker in immune responses to immune checkpoint inhibition. ⁴⁰ , ⁴¹ Elevated IL‐17 levels have been linked to a higher risk of developing colitis in patients treated with Ipilimumab, an ICI. ³³ This association underscores the potential of targeting IL‐17 pathways as a therapeutic approach; IL‐17 antagonists may effectively reduce IL‐17–related irAEs, thereby improving patient outcomes and reducing treatment complications.

Other increased cytokine/chemokine levels in patients with multiple solid tumors after anti–PD‐1/PD‐L1 or anti–CTLA‐4 therapy strongly correlated with the progression of irAEs, particularly with C‐X‐C motif chemokine ligands 9, 10, 11, and 1. ⁴² In patients with malignant melanoma, significant up‐regulations of cytokines such as Granulocyte Colony‐Stimulating Factor, Macrophage Colony‐Stimulating Factor, Fractalkine, Fibroblast Growth Factor–2, IFN‐g, IL‐12p70, IL‐1a, IL‐3 1B, Interleukin‐1 Receptor Antagonist, IL‐2, and IL‐13 were observed among those who developed severe irAEs.

Research indicates that single‐nucleotide polymorphisms (SNPs) within genes such as CTLA‐4 and PD‐1 are associated with susceptibility to irAEs. ⁴³ For instance, specific SNPs in PD‐1, including PD1.3 (rs11568821), PD1.5 (rs2227981), PD1.6 (rs10204525), PD1.7 (rs2227982), PD1.10 (rs5582977), and 804 (rs2227981) have been identified as factors linked to either protection against or increased risk of irAEs. ⁴³ , ⁴⁴ , ⁴⁵ , ⁴⁶ These genetic variations can influence individual responses to ICIs, potentially affecting the development and severity of adverse events. Understanding these SNPs enhances our understanding of personalized medicine approaches to managing irAEs in patients undergoing immunotherapy.

Using single‐cell RNA sequencing, specific T cell subsets have been linked to organ‐specific irAEs. For example, patients with immune‐related arthritis had lower levels of CD8 central memory T cells (TCM) before therapy. Conversely, those with immune‐related pneumonitis had higher baseline levels of CD4 T helper 2 (Th2) cells. ⁴⁷ Furthermore, a study suggested that the expansion of CD38hi cytotoxic CD8 T cells and high interferon responses could serve as biomarkers for predicting the development of ICI‐related arthritis. ⁴⁸ Additionally, patients with immune‐related thyroiditis showed elevated baseline levels of CD4 Th17 cells. ⁴⁷

Clinical Trials in Treating Immune‐Related Adverse Events

There are over 20 clinical trials worldwide evaluating the safety and efficacy of different treatments for irAEs (Table 1). Several of these treatments under investigation are monoclonal antibodies that inhibit T cell activation by modulating cytokine or cell‐surface ligand‐receptor signaling (Figure 2).

Table 1.

irAE treatments in clinical trial^*

Type of Treatment	Name of the Drug	Clinical Trial
Anti–TNF‐α	Adalimumab	NCT06037811 Phase II London, Canada irAE‐arthritis
	Certolizumab	NCT03293784 Phase I Toulouse, France Advanced melanoma
	Infliximab		NCT04305145 Phase II MGH irAE‐colitis	NCT04407247 Phase I/II MD Anderson irAE‐colitis
Anti‐α4β7 Integrin	Vedolizumab	NCT04797325 Phase II University of Copenhagen irAE‐colitis
Anti–IL‐6	Siltuximab	NCT06470971 Phase II Ohio State University ICI rechallenge
Anti–IL‐6R	Tocilizumab	NCT03999749 Phase II NYU Unresectable stage III, IV melanoma	NCT04940299 Phase II MD Anderson Melanoma, urothelial carcinoma, NSCLC	NCT04375228 Phase II Columbia University Advanced solid tumors
Anti‐CD20	Rituximab
CTLA‐4 Analog	Abatacept	NCT05335928 Phase III MGH irAE‐myocarditis
JAK1 Inhibitor	Golidocitinib	NCT07303881 Phase II Guangzhou, China
	Itacitinib	NCT05660421 Phase II Vanderbilt University
CD24 fusion protein	CD24Fc	NCT04060407 Phase Ib/II Huntsman Cancer Institute Stage III/IV metastatic melanoma
5‐aminosalicylic acid	Mesalamine	NCT05663775 Phase II Alberta, Canada Stage III/IV malignant melanoma irAE‐diarrhea
Thymosin α‐1	Thymalfasin	NCT06178146 Phase IV Shandong, China irAE‐dermatitis, irAE‐enteritis, irAE‐pneumonia, irAE‐hepatitis
Statins	Atorvastatin	NCT06785974 Phase IV South Holland, Netherlands Melanoma irAE‐atherosclerosis
	ECP	NCT05700565 Munich, Germany irAE‐refractory
Dietary fiber supplement	FORX (Food intervention to Reduce immunotherapy toXicity)	NCT05832606 Jette, Belgium Adjuvant and metastastic cancers irAE‐prophylaxis
Anti–IL‐17A	Secukinumab	NCT07237594 Phase I Duke University Metastatic melanoma irAE‐colitis, irAE‐hepatitis, irAE‐skin rash, irAE‐psoriatic arthritis; ICI‐reinitiation
Anti–IL‐17RA	Brodalumab	NCT06673329 Phase I Columbia University

^*CD, cluster of differentiation; CTLA‐4, cytotoxic T‐lymphocyte–associated protein 4; ECP, extracorporeal photopheresis; ICI, immune checkpoint inhibitor; IL‐6, interleukin 6; irAE, immune‐related adverse event; NSCLC, non–small cell lung cancer; TNF‐α, tumor necrosis factor alpha.

Figure 2.

Cell drug interactions. (A) Th1 cells secrete IL‐6 and TNFα. Th17 cells secrete IL‐17A. Siltuximab binds IL‐6 and inhibits signaling. Tocilizumab binds and blocks IL‐6 receptor signaling. Adalimumab, Certolizumab, Infliximab, and Golimumab inhibits TNF‐α signaling. Secukinumab binds and blocks IL‐17A signaling. (B) Brodalumab is an IL‐17RA antagonist that inhibits IL‐17RA heterodimers’ signaling on T cells. (C) Abatacept is a CTLA‐4 analog and binds to CD80 and CD86 molecules on APC to prevent T cell activation. (D) Rituximab is an anti‐CD20 antibody that leads to B cell depletion. (E) Vedolizumab (anti‐α4β7 integrin) binds to CD49d and integrin beta‐7 heterodimer on T cells. APC, antigen‐presenting cell; CD, cluster of differentiation; CTLA‐4, cytotoxic T‐lymphocyte–associated protein 4; IL‐6, interleukin 6; TNF‐α, tumor necrosis factor alpha.

Multiple clinical trials evaluate the safety and efficacy of anti–TNF‐α agents for irAEs. The Institut Claudius Regaud in France completed an open‐label phase 1b study (NCT03293784) in August 2023. This study examined the combined use of Nivolumab and Ipilimumab with either Certolizumab or Infliximab, both anti–TNF‐α agents, in patients with advanced melanoma. The study's unique two‐part design further emphasizes its distinctiveness. The first part included two parallel patient cohorts, each receiving a different treatment combination. The second part, which was the expansion phase selecting the most promising combination from phase I, followed afterward. Results from this trial show that, although the two combinations were both found to be safe, lower irAEs were observed with Infliximab compared with Certolizumab. It concludes that the high response rate in the Certolizumab treatment cohort deserves further investigation. NCT04305145 is another phase II clinical trial currently being conducted at Massachusetts General Hospital. This study aims to compare the safety and effectiveness of Infliximab (anti–TNF‐α) with steroids for the treatment of irAE‐colitis in patients with stage III/IV skin cancer. Steroids evaluated in this trial include methylprednisolone and prednisone. It is expected that this study will be completed in 2030.

Phase II clinical Trial NCT06037811, conducted by the Lawson Health Research Institute, is currently active. This trial aims to evaluate the safety and effectiveness of early Adalimumab (anti–TNF‐α) induction in combination with prednisolone for treating ICI‐associated inflammatory arthritis. Researchers expect that early administration of Adalimumab will alleviate symptoms and consequently decrease the reliance on steroids. Patients are divided into two groups: one receiving standard steroid treatment (prednisolone alone) and the other receiving Adalimumab combined with prednisolone. The trial is estimated to be completed in December 2025.

NCT04407247 is an active phase I/II clinical trial to assess the safety and tolerability of Infliximab (anti–TNF‐α) and Vedolizumab (anti‐α4β7 Integrin) in patients experiencing ICI‐related colitis. Researchers at MD Anderson Cancer Center have recruited and divided the patients into two groups to evaluate the effectiveness of Infliximab and Vedolizumab. They administer intravenous Infliximab or Vedolizumab to treat and induce remission of immune‐related diarrhea and colitis. This study is anticipated to conclude in December 2027. Vedolizumab (anti‐α4β7) is also evaluated in another phase II clinical trial, NCT04797325, conducted by the University of Copenhagen for the treatment of irAE‐colitis. Although the status is unknown, this trial should have been completed in April 2025.

More research focuses on the targeted inhibition of cytokine signaling, such as IL‐6, to treat irAEs. Phase II trial NCT06470971 at The Ohio State University Comprehensive Cancer Center aims to study the prophylactic effect of Siltuximab (anti–IL‐6) for irAEs in patients rechallenged with ICIs. Patients recruited in this trial have previously stopped ICI treatment because of severe irAEs. Nonetheless, these patients need ICI rechallenge because of cancer progression. In this trial, Siltuximab is given together with anti–PD‐1 or anti–PD‐L1. It is estimated that this study will be completed by December 2030.

The phase II trial NCT03999749, led by NYU Langone Health Hospital, aims to evaluate the safety and tolerability of Tocilizumab (anti–IL‐6R) combined with Ipilimumab and Nivolumab in patients with stage III or IV melanoma. This study, which enrolled 71 patients, is a single‐arm study examining the antitumor effects of Tocilizumab in combination with Ipilimumab and Nivolumab in patients with unresectable stage III or IV melanoma. The trial is set to conclude in April 2030.

The other IL‐6 receptor antagonist phase II clinical trial, NCT04940299, led by MD Anderson Cancer Center, is currently active and not recruiting. This trial aims to evaluate the safety and effectiveness of Tocilizumab in combination with Ipilimumab and Nivolumab for treating patients with advanced melanoma, urothelial carcinoma, or epidermal growth factor receptor mutant NSCLC that has spread locally to nearby tissues or lymph nodes. Researchers organized participants into three cohorts based on cancer types: melanoma, urothelial cancer, and NSCLC. The melanoma cohort was further subdivided into two groups to receive different dosages of Tocilizumab. This trial's primary outcome measure is the dose‐limiting toxicity rate according to tumor type. Additionally, for the cohort of melanoma patients, another primary outcome is the identification of one or more grade 3+ severe adverse events. The study has enrolled 35 patients and is projected to conclude in December 2027.

The safety and effectiveness of Tocilizumab (anti–IL‐6R) and Rituximab (anti‐CD20) are being evaluated in another active phase II clinical trial, in which Columbia University recruited patients with side effects of ICI treatment who require long‐term steroid use (NCT04375228). Extended steroid use can lead to various issues, including sleep disorders, weight gain, diabetes, muscle atrophy, and elevated cholesterol levels. Therefore, this study seeks to determine whether these medications can reduce the need for prolonged steroid treatment. It will assess how effective these drugs are in allowing patients to stop using steroids by measuring the proportion of participants who successfully discontinue steroid use following treatment with Tocilizumab or Rituximab. Patients will be divided into two groups: one receiving four weekly doses of intravenous Rituximab and the other receiving up to two monthly doses of intravenous Tocilizumab. This trial is estimated to be completed in December 2026.

The safety and tolerability of CTLA‐4 analog Abatacept have been evaluated in clinical trials NCT05335928 and NCT05195645 for the treatment of ICI‐induced myocarditis. NCT05335928 is a thoughtfully structured phase III clinical trial at Massachusetts General Hospital, in which participants were randomized to receive either 10 mg/kg of Abatacept by intravenous infusion or placebo. The primary outcome measure for this trial is the occurrence of major adverse cardiac events, which encompass rates of a composite of cardiovascular death, nonfatal sudden cardiac arrest, cardiogenic shock, significant ventricular arrhythmias, or the emergence of heart failure. This study is projected to conclude in April 2027.

In Clinical Trial NCT05195645, conducted by Pitie‐Salpetriere Hospital, patients with ICI‐induced myocarditis were assigned to one of three groups receiving intravenous doses of Abatacept at 10 mg/kg, 20 mg/kg, or 25 mg/kg. This phase II study focused on circulating monocytes’ CD86 receptor occupancy as its primary outcome measure. This receptor occupancy serves as a vital biomarker for assessing Abatacept's efficacy in blocking T cell activation via CD86 binding and is crucial for evaluating the drug's ability to modulate the immune response. This study, which should have been completed in September 2025, aimed to define the most appropriate starting dose of Abatacept to treat irAE‐myocarditis in combination with Ruxolitinib and glucocorticoids. ⁴⁹

Clinical trials NCT07303881 and NCT05660421 evaluate JAK1 inhibitor golidocitinib and itacitinib, respectively, for the treatment of irAEs. NCT07303881 is a phase II trial at The First Affiliated Hospital of Guangzhou Medical University. It is estimated that this trial will be completed by December 2028. Phase II trial NCT05660421 is the other phase II clinical trial at Vanderbilt University that aimed to test the JAK1 inhibitor itacitinib in grad 2+ patients with irAE who do not respond to steroids. Nonetheless, the second trial has been withdrawn.

Phase Ib/II clinical trial NCT04060407 aimed to test the safety and efficacy of combining CD24Fc with Ipilimumab and Nivolumab to decrease irAEs in patients with metastatic melanoma. This study was planned to be conducted at Huntsman Cancer Institute in Salt Lake City, Utah. However, this trial has also been withdrawn.

Mesalamine, also known as 5‐aminosalicylic acid, is a medication approved for the treatment of inflammatory bowel diseases. Phase II clinical trial NCT05663775 in Alberta, Canada, aims to test whether prophylactic mesalamine reduces the incidence and severity of irAE‐associated diarrhea induced by Nivolumab or Ipilimumab in patients with stage III or IV malignant melanoma. This study aims to enroll 20 patients and should be completed by August 2027.

Thymosin alpha‐1 (Tα‐1), also known as thymalfasin, has immunomodulatory effects. Clinical trial NCT06178146 in Shandong, China, is a phase 4 interventional trial investigating the efficacy and safety of Tα‐1 for the treatment of irAEs. Tα‐1 has previously also been evaluated in management of radiation pneumonitis in patients with locally advanced NSCLC treated with concurrent chemoradiotherapy. ⁵⁰ This post‐marketing surveillance trial recruited patients with grade 2 to 4 skin toxicity, enteritis, pneumonia, and hepatitis following ICI therapy, and should have been completed by now, although no published results were found.

Statins block an enzyme called HMG‐CoA reductase that is involved in the synthesis of mevalonate, a naturally occurring substance that is used by the body to make sterols, including cholesterol. The phase 4 clinical trial (NCT06785974) in South Holland, the Netherlands, aims to test whether atorvastatin prevents accelerated atherosclerosis progression in melanoma patients receiving ICI therapy (nivolumab, pembrolizumab, or a combination of anti–PD‐1 and Ipilimumab). This study plans to recruit 140 patients and is estimated to be completed in February 2030.

Extracorporeal photopheresis (ECP) consists of leukapheresis, photoactivation, and reinfusion, resulting in immunomodulatory effects. Clinical trial NCT05700565 in Munich, Germany, recruits patients with irAE refractory to standard therapy as well as patients for whom glucocorticoids cannot be tapered. This study evaluates ECP and other immunosuppressive/immunomodulatory drugs as treatment in the irAE‐refractory patient population. It is estimated that this study will be completed by January 2027.

FORX (Food intervention to Reduce immunotherapy toXicity) involves supplementing dietary fiber intake by providing weekly boxes containing 30 different plants. The clinical trial NCT05832606 in Jette, Belgium, is currently recruiting patients with various types of cancer in both adjuvant and metastatic settings to evaluate the preventive effect of a high‐fiber diet on irAE development. These patients receive weekly boxes of a high‐fiber diet during the first 12 weeks of ICI therapy involving anti–PD‐1 and/or anti–CTLA‐4. This trial is estimated to be completed in December 2026.

In a preclinical study of thyroid‐infiltrating immune cells in mice undergoing ICI treatment, investigators found that blocking IL‐17A significantly reduced thyroiditis associated with ICI therapy without diminishing its antitumor effect. ⁵¹ IL‐17A‐neutralizing antibodies reduced both the frequency and severity of autoimmune infiltrates, effectively managing thyroiditis‐related immune adverse events. Furthermore, in a syngeneic murine colon carcinoma MC38 model, the combination of IL‐17A‐neutralizing antibodies with dual ICIs did not result in inferior tumor control compared with mock isotype controls in B6 mice. In summary, neutralizing IL‐17A during ICI therapy successfully alleviates ICI‐related thyroid autoimmune infiltrates and preserves the effectiveness of anti–PD‐1 and anti–CTLA‐4 treatments. Clinical trial NCT07237594 is a phase I interventional trial currently being conducted at Duke University to assess the safety and efficacy of the anti–IL‐17A monoclonal antibody Secukinumab for the treatment of irAEs in patients with metastatic melanoma. This trial is estimated to be completed in June 2030.

It was previously reported that, in vivo, B6/Lpr mice treated with an IL‐17 receptor A (IL‐17RA) inhibitory antibody showed reduced or prevented ICI‐induced hepatitis and pneumonitis, as demonstrated by hematoxylin and eosin staining of immune infiltration. ¹ The findings also indicate that high IL‐17RA expression correlates with lower survival rates, suggesting that neutralizing IL‐17RA may be effective in treating irAEs. The phase I clinical trial NCT06673329 at Columbia University, which is investigating the safety and efficacy of anti–IL‐17RA antibody (Brodalumab) as treatment for irAEs in patients with solid tumors, is anticipated to be completed in November 2026.

Future Directions of Treatments for Immune‐Related Adverse Events

Neutralization of IL‐25 using a single intraperitoneal injection of an anti–IL‐25 antibody in mice, given at either a high dose (400 μg) or a low dose (200 μg) was previously shown as effective prophylactic treatment for irAEs. ¹ The mice treated with the anti–IL‐25 antibody showed reduced immune cell infiltration compared with untreated mice, with effects that depended on the dose. Additionally, tumor data from the mouse model showed benefits, including tumor regression and improved survival, when treated with the anti–IL‐25 antibody. These experimental results support further research into anti–IL‐25 antibodies as potential treatments for irAEs.

Side‐by‐side comparison of anti–IL‐6, anti–TNF‐α, and anti–IL‐25 demonstrates that although all treatments effectively prevented irAEs such as pneumonitis and hepatitis, only anti–IL‐25 demonstrated antitumor effects in the mouse colon adenocarcinoma model. ¹ This research highlights the distinct potential of anti–IL‐25 to enhance ICI‐mediated tumor suppression while also reducing irAE‐related autoimmune effects. Moreover, in mice treated with anti–IL‐25, levels of specific cytokines, including IL‐4, IL‐5, IL‐6, IL‐25, and IL‐12p70, increased, whereas TNF‐α levels decreased.

Therefore, directly targeting IL‐25 to suppress off‐tumor immune responses while maintaining the antitumor effects of ICIs presents a hopeful direction for future ICI treatments. However, the current studies on IL‐25 signaling blockage for irAEs have limitations, especially because mouse models cannot completely predict human diseases. Furthermore, the animal model IL‐25 neutralization was tested in does not show manifest irAE‐arthritis or irAE‐dermatitis. Additionally, the study of anti–IL‐6 and anti–TNF‐α treatments was limited to melanoma and NSCLC. As a result, more preclinical research in different tumor and irAE mouse models and future clinical trials in patients are urgently needed to assess the effectiveness and safety of IL‐25 blockade as a preventive or therapeutic approach to ICI‐induced irAEs.

Conclusions

The emergence of irAEs has fundamentally redefined the scope of modern rheumatology, establishing a novel category of ICI‐induced systemic inflammatory syndromes. Observed in approximately 5% to 10% of patients receiving therapies targeting the CTLA‐4, PD‐1/PD‐L1, and LAG‐3 axes, these toxicities result from a systemic breach in peripheral tolerance that manifests as clinical phenocopies of traditional autoimmune diseases. The spectrum of rheumatic irAEs is notably diverse, ranging from highly prevalent conditions like inflammatory polyarthritis (1.5%–22%) and arthralgia (up to 43%) to high‐acuity complications such as inflammatory myositis (~1%) and sicca syndrome (up to 24%). This clinical intersection is particularly complex because these syndromes often exhibit distinct serological profiles and may persist chronically even after the cessation of immunotherapy, requiring prolonged rheumatologic surveillance and long‐term monitoring. A primary management concern remains the impact of glucocorticoids on oncological outcomes; however, data indicate that although baseline steroid use for supportive care is associated with poorer survival, steroids initiated specifically to manage irAEs do not typically compromise antitumor efficacy.

As ICIs become a mainstay for nearly 40% of patients with cancer, the medical community must shift toward a multidisciplinary management strategy that prioritizes both oncological survival and quality of life. Future research directions must focus on identifying predictive biomarkers, such as cytokine profiles or HLA associations, to risk‐stratify patients before treatment begins. Furthermore, there is an urgent need for clinical trials investigating targeted steroid‐sparing agents, including JAK inhibitors, TNF‐α inhibitors, and IL‐6 receptor antagonists, early in the irAE course to prevent permanent structural damage. Transitioning from broad‐spectrum immunosuppression to precision‐targeted therapies will be essential to selectively quench organ‐specific inflammation while preserving the systemic antineoplastic immune response. Finally, addressing the health care resource requirements of this growing patient population will be vital because the rising economic burden of managing chronic irAEs necessitates the establishment of specialized, sustainably funded multidisciplinary clinics to ensure that the successes of cancer survivorship are not overshadowed by the burden of chronic, treatment‐induced autoimmune disease. ⁵²

AUTHOR CONTRIBUTIONS

All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr Mor confirms that all authors have provided the final approval of the version to be published and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Declaration of Helsinki requirements.

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