Immune Checkpoint Inhibitors and Lupus Erythematosus

Immune checkpoint inhibitors (ICIs) are the standard of care for a growing number of malignancies. Unfortunately, they are associated with a broad range of unique toxicities that mimic the presentations of primary autoimmune conditions. These adverse events are termed immune-related adverse events (irAEs), of which ICI-lupus erythematosus (ICI-LE) constitutes a small percentage. Our review aims to describe the available literature on ICI-LE and ICI treatment for patients with pre-existing lupus. Most diagnoses of ICI-LE had findings of only cutaneous lupus; four diagnoses of ICI-LE had systemic lupus manifestations. Over 90% (27 of 29) of cases received anti-PD-1/PDL-1 monotherapy, 1 received combination therapy, and 1 received only anti-CTLA-4 treatment. About three-fourths (22 of 29 or 76%) of patients with ICI-lupus were managed with topical steroids, 13 (45%) received hydroxychloroquine, and 10 (34%) required oral corticosteroids. In our case series, none of the patients with pre-existing lupus receiving ICI therapy for cancer had a flare of their lupus, but few had de novo irAE manifestations, all of which were characterized as low-grade. The review of the literature yielded seven ICI-LE flares from a total of 27 patients with pre-existing lupus who received ICI. Most flares were manageable without need for ICI cessation.


Introduction
Immune checkpoint inhibitors (ICIs) are immunomodulatory monoclonal antibodies that have revolutionized cancer treatment.Ipilimumab was the first approved ICI in 2011 to treat malignant melanoma [1].ICIs primarily block the interaction between T lymphocyte checkpoint proteins and their partner proteins on tumor cells.Programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) are two types of checkpoints expressed on the surface of T cells, functioning as "off" switches to regulate T-cell-mediated immune responses [2].Checkpoint blockade includes three large classes of medications: PD-1 antibodies (pembrolizumab, nivolumab, dostarlimab, retifanlimab, and cemiplimab), antibodies to the ligand of PD-1 or PDL-1 antibodies (atezolizumab, durvalumab, and avelumab), and CTLA-4 antibodies (ipilimumab and tremelimumab).
While the benefits of harnessing the immune system to attack malignant cells have been demonstrated across numerous trials, a substantial risk exists for a unique group of toxicities referred to as immune-related adverse events (irAEs) [3].irAEs can affect essentially any organ system in the body.Individual irAE severity is measured by the Common Terminology Criteria for Adverse Events (CTCAE) and is graded from 1 to 5 [4].Among the less common toxicities are ICI-induced rheumatic conditions, the most common of which are inflammatory arthritis and polymyalgia rheumatica (PMR) [5,6].This article reviews the current literature on one of the rarer rheumatic irAEs (R-irAEs): ICI-induced lupus erythematosus.
There is a paucity of data on lupus erythematosus (LE) in the setting of checkpoint inhibitor usage.LE is a chronic inflammatory disease characterized by autoantibodies, immune complex (IC) deposition, and immune dysregulation, and it can impact multiple organ systems [7].Treatment of LE involves a range of different immunosuppressant medications, often guided by the organ systems affected [7].Here, we present a review of ICI-associated LE.The majority of published accounts are limited to small case reports and case series.The following terms were used to identify PubMed and Google Scholar publications: checkpoint and systemic lupus erythematosus, checkpoint and cutaneous lupus erythematosus.We examined the associations between immune checkpoints and lupus erythematosus, focusing on de novo lupus associated with ICI usage.We further summarize the data available for lupus patients receiving ICIs and whether it influences the risk for disease flares.Finally, we present a small case series of LE patients at our own institution who received immunotherapy between 2011 and the present day.

Role of Checkpoints in the Pathogenesis of Lupus Erythematosus 2.1. PD-1 and PDL-1 and Lupus Erythematosus
PD-1 and its ligands (PDL-1 and PDL-2) are immune regulatory molecules that have been implicated in the pathogenesis of LE, contributing to the loss of immune tolerance and the development of autoimmunity.Expression of these proteins is dysregulated in lupus, though the exact repercussions of this dysregulation remain undetermined [8,9].Functioning as membrane-bound proteins, normal interactions between PD-1 and its ligands lead to attenuation of the adaptive immune response and allow for self-tolerance [2,10].As tumor cells express PDL-1 and PDL-2 to avoid the immune system, this pathway emerged as a prime target for immunotherapy [2].Soluble forms of these proteins are also referred to as sPD-1, sPDL-1, and sPDL-2 [11].These soluble forms are believed to interact across the PD1 axis by binding to the membrane-bound PD1, PDL-1, and PL-2 and may additionally be linked to lupus [11].
Low levels of sPDL-2 and elevated expression of PDL-2 have been associated with SLE disease activity [11].In particular, patients with SLE suffering from arthralgias, kidney disease, oral ulcers, and hypocomplementemia have significantly lower sPDL-2 than patients without such manifestations [11].Murine models have also demonstrated a role for the PD-1 axis in SLE.For example, mice lacking PD-1 expression develop spontaneous lupus-like autoimmune arthritis and glomerulonephritis accompanied by IgG3 and C3 deposition, suggesting loss of peripheral self-tolerance [12].An additional mouse study found that injecting PDL-1 immunoglobulin into SLE-prone mice demonstrated a protective function, with reduced proteinuria, decreased production of abnormal cytokine levels, and lower anti-dsDNA antibodies [13].In turn, SLE patients would be expected to express reduced levels of PD-1 and PDL-1.However, contrary to this, PD-1 and PDL-1 expression on immune cells are significantly higher in SLE patients when compared to healthy donors [14,15].One proposed explanation for these findings is that a defect in tolerance mediated by the PD-1 axis, rather than a lack of PD-1, defines the roles of PD-1s and their ligands in SLE [15].This hypothesis is bolstered by a study examining the serum levels of autoantibodies against PD-1, which found that elevated levels of anti-PD-1 IgG correlated with increased disease activity and T-cell proliferation in new SLE patients [16].The PDCD1 gene, a member of the immunoglobulin gene superfamily, codes for PD-1 and is thought to play a direct role in self-tolerance, the suppression of autoreactive B lymphocytes, and immunity as polymorphisms involving the gene are associated with an increased relative risk for SLE [17,18].Finally, two other pathways that play significant roles in regulating the PD-1 axis, type-I IFN and the Toll-like receptor (TLR) pathways, are also highly active in the pathophysiology of LE [19][20][21][22][23]. Overall, there is evidence that the PD-1 axis influences lupus.However, the exact role of PD-1 and its ligands (both membrane-bound and soluble) in LE and the implications of this relationship on therapy are areas that need further investigation.

CTLA-4 and Lupus Erythematosus
CTLA-4 is a T-cell-specific protein receptor implicated in lupus development and activity.Expressed constitutively on regulatory T-cells (Tregs) and upregulated in conventional T-cells following activation, it plays an important role in immune tolerance through several mechanisms [24].The exact function of CTLA-4 in lupus development and activity is unclear; however, genetic, serological, and mouse studies provide evidence for its role in autoimmune diseases.Genome-wide studies originally detected CTLA-4 as a potential susceptibility gene for SLE [25].These reports, in turn, led to investigations of the CTLA-4 gene locus, with multiple studies finding associations between the CTLA-4 gene and promoter region polymorphisms and the development of SLE [26,27].
Furthermore, CTLA-4 knockout mice develop a dysregulated T-cell immune response, resulting in autoimmune disease and severe lupus-like syndrome [28].An additional murine model examined the effects of blocking CTLA-4 ′ s costimulatory protein CD28, which led to the prevention of lupus nephritis development, prolonged animal survival, and reduced production of dsDNA antibodies [29].Finally, multiple studies suggest that abnormal expression and function of CTLA-4 contribute to the amplified conventional T-cell responses seen in SLE patients and contribute to the onset and progression of disease [30][31][32].These investigations have, in turn, led to clinical trials investigating the efficacy of abatacept, a CTLA-4 analog, in SLE treatment, though without great efficacy [33].

ICI-CLE
Among the patients afflicted with CLE, subacute CLE (SCLE) is the predominant diagnosis, with 25 out of 29 cases in total (Table 2).All cases of SCLE in the literature were supported by biopsy.Two cases of chilblain lupus are identified in the literature [38,39].Both patients received pembrolizumab and were clinically diagnosed rather than receiving biopsies (Table 1).A single case of de novo discoid lupus erythematosus (DLE) is reported in the literature (Table 2) [40].

ICI-SLE
From a SLE standpoint, four cases are reported in the literature (Table 2).Three of the four cases were in the setting of anti-PD-1 therapy, and manifestations also included CLE [38,39,52].The other SLE case was attributed to the anti-CTLA-4 antibody ipilimumab.This is the single case of anti-CTLA-4 SLE in the literature and the only case of lupus nephritis identified [41].Diagnosis was confirmed in the setting of proteinuria, positive autoantibodies, and suggestive biopsy findings (Table 1) [41].

Management of ICI-LE
The treatment of ICI-associated lupus erythematosus (ICI-LE) varied across cases and is summarized in Table 1.Hydroxychloroquine (HCQ), oral and topical steroids were the most common treatment regimens.A total of 22/29 (75.8%) patients received topical steroids, 13/29 (44.8%) received HCQ, and 10/29 (34.4%) received oral steroids.There was one report of treatment with quinacrine amongst the cases [42].In another single report, infliximab plus prednisone was initiated, but symptoms did not resolve until infliximab was discontinued and topical corticosteroids were added [43].In one case, no treatment beyond halting pembrolizumab was required [44].

Pre-Existing Lupus and Treatment with Immune Checkpoint Inhibitors Case Series of Patients with Lupus Receiving Immunotherapy
To expand the available literature on patients with lupus receiving cancer immunotherapy, we queried our institution's electronic medical record (EMR).We conducted a retrospective case series of patients who had a diagnosis of lupus erythematosus and then subsequently received ICI therapy for their cancer at The University of Chicago Medical Center between January 2011 and July 2023.The study was approved by the Institutional Review Board at the University of Chicago Medical Center.Patients included in the study were at least 18 years old, had a confirmed diagnosis of lupus erythematosus by the treating rheumatologist, received ICI therapy, and had follow-up available in the EMR.Patients were excluded if their symptoms did not meet the diagnosis for lupus erythematosus if they did not have a diagnosis of lupus before ICI initiation, or if the patient did not have any follow-up and clinical annotation available within our EMR.We used at least two ICD search codes to identify patients with lupus and ICI treatment receipt.ICI therapy regimens included monotherapy with an anti-CTLA-4 agent, anti-PD-1/PDL-1 therapy, or a combination of both.For the included patients, abstracted data included demographic characteristics, prior history of LE, details of LE diagnosis, information on cancer diagnosis, ICI treatment regimen and development of pre-existing autoimmune disease flare and/or de novo irAE(s).ICI toxicities were graded according to the CTCAE rubric.
Our data are summarized in Tables 3 and 4 below.A total of six patients were identified that met the criteria.Two (33.3%) of these patients were diagnosed with SLE alone, while one (16.6%)carried a diagnosis of DLE, and three (50%) had SLE with cutaneous manifestations (Table 4).Our patients' prior and current disease manifestations were generally mild and included arthritis, fatigue, and photosensitivity (Table 3).A single patient had biopsy-proven lupus nephritis over a decade prior to commencing immunotherapy.Of note, at the time of ICI initiation, this patient was not on lupus nephritis treatment as his disease was considered quiescent but had received rituximab in the past as part of chronic lymphoblastic leukemia treatment a number of years prior.At the time of ICI initiation, no patients were reporting severe disease manifestations, and all were on minimal therapy (Table 3).Four of six (66.6%) patients received hydroxychloroquine alone, one received topical desonide cream, and one was on no therapy at all.No patients had changes to their LE regimen after initiating their respective cancer therapy.The mean age at LE diagnosis was 49.5 years, though two patients did not have such data available, while the mean age at cancer diagnosis was 60.83 years (Table 4).Malignancies included NSCLC in 4/6 (66.6%) patients, SCC in one patient, and a neuroendocrine tumor in one patient.Four patients (66.6%) were female, while two patients (33.3%) were male (Table 4).As reported in Table 4, all six patients received immunotherapy with either a PD-1 or PDL-1 targeted therapy and received concurrent chemotherapy.All concurrent chemotherapy included a platinum-based component.Three patients (50%) developed a total of five de novo irAEs, none of which constituted flares of their lupus (Table 4).IrAEs included vitiligo, thrombocytopenia, myocarditis, colitis, and arthritis.Four (80%) of the reported irAEs were CTCAE grade 1-2, while there was a single grade 3 irAE in a patient diagnosed with ICI myocarditis.Of note, this patient was the individual with a prior history of more extensive disease manifestations, including lupus nephritis.Treatment of above-mentioned irAEs all included at least temporary discontinuation of ICI (Table 3).Two patients required permanent discontinuation of immunotherapy due to their toxicities (Table 4).The first of these patients was our individual with myocarditis, while the second was the patient suffering from grade 2 thrombocytopenia (Table 3).All other patients either continued to undergo treatment with their ICI or completed their full therapy course.Table 3 reports individual toxicity treatments, which included topical steroids (for vitiligo), oral steroids, intravenous steroids, leflunomide, mesalamine, and vedolizumab.The latter two treatments were for ICI colitis.Three (60%) of reported irAEs, including ICI-myocarditis, improved or resolved with treatment, while two (40%) persisted despite treatment (Table 3).Two (33.3%) of the patients had cancer progression, two (33.3%) had stable disease, and two (33.3%) had disease response at the time of our query (Table 4).Legend: LE-lupus erythematosus; M-male; F-female; NSCLC-non-small-cell lung cancer; SCC-squamous cell carcinoma; SLE-systemic lupus erythematosus; DLE-discoid lupus erythematosus; CLE-cutaneous lupus erythematosus; irAE-immune-related adverse event; ICI-immune checkpoint inhibitor; HCQ-hydroxychloroquine; OA-osteoarthritis; IA-inflammatory arthritis; CR-complete response; PD-progressive disease; PR-partial response; NR-not reported; NA-not applicable; Tx-treatment.Legend: aPD-1-Anti-programmed cell death protein 1; aPDL-1-Anti-programmed death ligand 1; LE-lupus erythematosus; IQR-interquartile range; M-male; F-female; NSCLC-non-small-cell lung cancer; SCC-squamous cell carcinoma; SLE-systemic lupus erythematosus; DLE-discoid lupus erythematosus; CLE-cutaneous lupus erythematosus; irAE-immune-related adverse event; ICI-immune checkpoint inhibitor; #-number.

Review of Pre-Existing Lupus and ICI Treatment
We then looked at pre-existing lupus and the use of ICIs in literature.Current publications are mostly confined to retrospective analyses, and case reports with the single aforementioned prospective study that included one case of CLE.Our findings are summarized in Table 5.There is one report of a severe SLE flare in the setting of pembrolizumab treatment [56].This patient had a history of severe disease manifestations, including seizures and renal involvement, though at the time, was well controlled with mild arthralgias [56].There are two reports of DLE in the literature [53,57].Initially, ICIs had been avoided in both of these DLE patients due to the fear of disease flares.Blakeway et al. reported a case of a 55-year-old woman's DLE flaring while on anti-PD-1 therapy [53].Of note, this patient's DLE had previously required multiple systemic therapies to control [53].
Zakharian and Lee also reported a patient with lupus treated with pembrolizumab with a mild DLE flare [57].In contrast to the case reported by Blakeway et al., this patient's DLE had not required immunosuppressive therapy before ICI initiation.Among all studies and case reports of patients with autoimmune diseases on ICIs, a total of 27 patients had lupus [53,[56][57][58][59][60][61][62][63][64][65].Unfortunately, reported demographics, details on disease activity, current lupus therapy, and other characteristics of this group are sparse.A total of seven patients had lupus flares, six of which were graded 1-2 by CTCAE, while one flare was grade 3. Additionally, five de novo irAEs (in five separate patients) occurred in this cohort of 27.Three of these were graded 1-2, while two grade 3-4 irAEs were graded.Of these higher grade irAEs, one patient with DLE developed grade 3 central diabetes insipidus, while a separate patient with SLE was diagnosed with grade 4 immune thrombocytopenia (ITP) [56,58].Of interest, the individual who developed ITP was also one of the patients with a grade 3 lupus flare, and had a history of severe lupus manifestations, including neurologic involvement, Libman-Sacks endocarditis, and renal involvement, amongst others [56].Two patients developed both a lupus flare and a new irAE simultaneously [56,60].All patients who developed irAEs or lupus flares were undergoing treatment with anti-PD1/PDL1 therapy.In total, 21/27 (77.7%) patients were treated with anti-PD1/PDL-1 therapy, while 3/27 (11.1%) patients received ipilimumab, and 3/27 (11.1%) patients did not have the type of immunotherapy reported in the literature.A total of 11/27 (40.7%) patients were on no therapy at the time of ICI initiation, 3/27 (11.1%) were on HCQ alone, while one (3.7%)patient was on HCQ and oral steroids, and one (3.7%)patient was on oral steroids alone.No data regarding LE treatment was available for 11/27 (40.7%) patients.
When looking at lupus specifically, the literature is limited at this point, and it is difficult to make definitive claims regarding the risk of lupus flares or irAE occurrence.However, the fact that most patients were either on minimal or no therapy suggests that baseline disease activity in these patients was low at ICI initiation.As mentioned above, the only individual with a grade 3 SLE flare had a history of severe disease manifestations, though at the time, had mild disease by SLE Disease Activity Index (SLEDAI) score, and developed a grade 4 irAE in the form of ITP [56].Whether or not patients with more active disease at baseline or in the past are at a higher risk of lupus flares and more severe irAEs needs further investigation.

Review of Any Pre-Existing Autoimmune Disease and ICI Treatment
We then searched more broadly in the literature for patients with any pre-existing autoimmune disease who had subsequently received ICI therapy for cancer.Patients with autoimmune diseases have historically been excluded from immunotherapy clinical trials, largely due to concerns that ICIs may exacerbate their established diseases [66].With the ever-growing usage of ICIs, their connection with R-irAEs, and the increased risk of malignancy in patients with autoimmune conditions, there is substantial concern over whether these therapies can lead to flares of disease and/or increased risk of irAEs [67].One retrospective study of 462 patients with pre-existing autoimmune diseases (pAIDs) found that patients with pAIDs were at an increased risk for irAEs (HR 1.81, 95% CI 1.21-2.71)and received a higher amount of systemic corticosteroids for irAEs (HR 1.93, 95% CI 1.35-2.76)when compared to those without pAIDs [68].Another retrospective study comparing 85 patients with pAIDs to 666 without pAIDs further supported these findings, reporting that irAEs of any grade were more frequent with ICI treatment (65.9% vs. 39.9%)[59].Importantly, these authors found that there was no difference in risk of high-grade ICI toxicities compared to patients without pAIDs [65].One prospective study on 45 patients with pAIDs found an increased risk of irAEs and shorter irAE-free survival time when compared to 352 patients without pAIDs [64].Of note, they found no significant difference between overall survival time and malignancy response rate in their population [64].Overall, the literature suggests that immunotherapy confers an increased risk of disease flares and irAEs in all autoimmune diseases, with the majority of flares being mild in nature.

Clinical Trial Studying ICI for Patients with pAIDs
There is an ongoing clinical trial for the prospective study of patients with pre-existing autoimmune diseases who require ICI treatment for cancer.This multi-institutional clinical trial, titled AIM-NIVO (Study of Nivolumab in Patients With Autoimmune Disorders and Advanced Malignancies), is a phase 1b study to assess the overall safety of using anti-PD-1 in patients with various autoimmune diseases, including SLE (NCT03816345).

Discussion
As ICIs become the standard of care for an increasing number of indications, more patients, including those with pre-existing autoimmune diseases, will be at risk for irAEs.Amongst these, ICI-associated lupus erythematosus is an infrequent but emerging entity.The majority of cases appear confined to CLE, with rare presentations of SLE.Of the ICIs, far more de novo cases of lupus are found in patients on therapy influencing the PD-1 axis.
For patients with pre-existing lupus, the literature suggests that there is a risk of lupus flares while on ICIs.While the vast majority of reported flares have been mild, there is a paucity of data on whether higher baseline disease activity or prior severe disease influences the risk of flares.Notably, the one higher grade flare in the literature occurred in a patient with significant prior disease manifestations, who also developed a significant grade 4 irAE [56].Our case series did not report any disease flares.However, our sample was only six patients.In line with the available literature, most reported irAEs in our patient population were low grade, with a single incidence of a grade 3 irAE.Similar to aforementioned patient in the literature, this individual had a history of more severe LE manifestations in the past, having been diagnosed with Class V lupus nephritis.Further research is necessary to ascertain which individuals with lupus are more at risk for flares and high-grade irAEs with ICI treatment.We recommend assessing patients' baseline lupus status before starting ICI treatment.This assessment should include a detailed history of their rheumatic symptoms, prior immunosuppressive regimens, and labs, including urinalysis and characteristic autoantibodies.
While treatment for ICI-LE in previously published literature has been limited to topical or systemic steroids and hydroxychloroquine, other potential treatments to consider include mycophenolate mofetil, tacrolimus, or other medications used to treat lupus, which has already been successfully utilized for other irAEs.A well-powered, prospective study with systemic steroids and steroid-sparing immunomodulating agents will be essential to identify effective therapy that does not abrogate ICI's anti-tumor immunity.Different immunosuppressants have their concerns: systemic glucocorticoids nonspecifically decrease the immune system and may have a negative impact on anti-tumor immunity, whereas TNF inhibitors can be worrisome to use for ICI-LE as they themselves can cause drug-induced lupus.

Conclusions
Immune checkpoints play a notable but complicated role in lupus pathogenesis.ICI-LE is a rare toxicity of checkpoint inhibitor therapy but may lead to deleterious cessation of an efficacious cancer treatment.Patients with pre-existing LE should not be indiscriminately precluded from ICI treatment as most cases of LE flares and irAEs were mild with successful symptom resolution, often with the resumption of therapy and, in some cases, without the halt of the offending ICI.Future large, centralized databases and standardized reporting systems for both ICI-lupus and patients with pre-existing LE requiring ICIs will allow for a better understanding of which patients are at risk and provide more direction for the care of these patients.

Table 1 .
ICI-Induced Lupus Erythematosus.Characteristics of patients diagnosed with immune checkpoint inhibitor-induced lupus erythematosus.

Table 2 .
Descriptive Data ICI-Induced Lupus Erythematosus.Descriptive data of the patients with ICI-induced Lupus Erythematosus.

Table 3 .
Patients with Lupus Erythematosus on Checkpoint Inhibitors.Case series patients from the University of Chicago on checkpoint inhibitors.

Table 4 .
Descriptive Data of Lupus Patients on Checkpoint Inhibitors.Descriptive data of University of Chicago patients with lupus erythematosus who received checkpoint inhibitors.

Table 5 .
Literature Review Lupus Erythematosus Patients on Checkpoint Inhibitors.Data on lupus erythematosus patients obtained through a literature review.