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Abstract
Background Immune checkpoint inhibitors (ICIs) have significantly improved outcomes for patients with cancer. However, these therapies are associated with adverse events including de novo immune-related adverse events or flare of pre-exiting autoimmune disorders. Up to 80% of patients with cancer and pre-existing psoriasis (PsO) or psoriatic arthritis (PsA) experience PsO/PsA flare after initiating ICIs. Targeting the interleukin (IL)-17/IL-23 axis is a mainstream of the PsO/PsA treatment. However, whether this treatment can effectively control PsO/PsA with ICI exposure while preserving anti-tumour efficacy remains unknown.
Case reports We report three patients with PsA and cancer, who received ICIs for their cancer treatment. All patients were male. Two patients had clear cell renal cell carcinoma, and one had melanoma. Two patients received anti-PD-1 antibody monotherapy, while one patient received combined anti-CTLA-4 and PD-1 antibody therapy. One patient had been receiving anti-IL-17A antibody (secukinumab), while the other two patients started anti-IL-17A antibody (ixekizumab) and anti-IL-23 antibody (guselkumab) after their PsA flared up during ICI treatment. Of note, with the anti-IL-17A or anti-IL-23 antibody treatment, their PsA remained in remission, and they well tolerated the ICI therapy. Importantly, all three patients showed persistent tumour responses to ICI therapy, including two complete remissions and one stable disease, respectively.
Conclusions These three cases suggest that targeting the IL-17/23 axis may be an effective and safe approach for patients with cancer and pre-existing PsA being considered for ICI therapy.
- arthritis, psoriatic
- T-lymphocytes
- cytokines
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Up to 80% of cancer patients with pre-existing psoriasis (PsO) or psoriatic arthritis (PsA) develop PsO/PsA flares following an immune checkpoint inhibitor (ICI) therapy. The agents targeting the interleukin (IL)-23/IL-17 axis are extensively used for managing classical PsO/PsA.
WHAT THIS STUDY ADDS
The efficacy of targeting the IL-23/IL-17 axis for PsO/PsA while maintaining anti-tumour immunity mediated by ICIs remains uncertain. Our case series suggests that for patients with PsO/PsA and concomitant cancer necessitating ICIs, targeting the IL-23/IL-17 axis could present an effective approach to manage PsO/PsA without compromising the anti-tumour efficacy of ICIs.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Consideration of agents targeting the IL-23/IL-17 axis is warranted for the management of PsO/PsA in patients with concurrent cancer necessitating ICIs. However, due to the limited number of patients in this study, further research involving a larger number of patients is needed to substantiate and validate these observations.
Introduction
Targeting T cell-inhibitory molecules including cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed death-1 (PD-1), immune checkpoint inhibitors (ICIs) have revolutionised cancer therapy.1 However, ICIs are often associated with adverse events, distinct from conventional chemotherapies and radiotherapies, including de novo immune-related adverse events (irAEs) and flares of pre-existing autoimmune diseases (ADs).2 Up to 80% of cancer patients with psoriasis (PsO) and psoriatic arthritis (PsA) have PsO/PsA flares following the initiation of ICIs.3
Interleukin (IL)−17, mainly produced by T helper (Th) 17 cells, play a pivotal role in host defence against extracellular pathogens by recruiting neutrophils to the inflamed tissues and enhancing angiogenesis.4 IL-23 stabilises Th17 cells but also induces the Th17 cells to adopt a pathogenic phenotype.4 Pathogenic Th17 cells play a critical role in numerous ADs, particularly PsO and PsA.
While agents targeting the IL-23/IL-17 axis are used for the treatment of PsO and PsA,4 it is unknown whether they are effective for patients with cancer and pre-existing PsO/PsA, who receive ICIs. Here, we report three cases of melanoma (n=1) and renal cell carcinoma (n=2) with pre-existing PsA. One patient had initiated treatment with the anti-IL-17A antibody (secukinumab) before the initiation of ICI therapy, while the other two patients were started on the anti-IL-17A antibody (ixekizumab) or the anti-IL-23 antibody (guselkumab) after they experienced PsA flares following ICI exposure. PsA of all patients remained under control with IL-23/IL-17 blockades. Importantly, all of them achieved durable anti-tumour responses to the ICIs.
Case report
Case 1
Our first case is a 72-year-old male with a history of PsA, osteoarthritis (OA) and metastatic melanoma. The patient was diagnosed with PsA in his 30s and treated with methotrexate (discontinued in few years due to loss of efficacy), etanercept and ultraviolet therapy. He was diagnosed with melanoma at the age of 65, and etanercept was discontinued. The patient was treated with Mohs surgery (figure 1A). Two years later, his melanoma recurred to the lungs, which was treated with surgery and radiation. The patient had PsA flares every few weeks, and few months later, to better control his PsA, secukinumab (150 mg every 4 weeks subcutaneous) was initiated. With secukinumab, his PsA was relatively well controlled with 1–2 times mild flares annually. Four years later, he was found to have lesions in his oesophagus, which were treated with proton therapy, and subsequent immunotherapy was planned. The patient was referred to the rheumatology clinic before administering the anti-PD-1 antibody (pembrolizumab). At the initial rheumatology visit, he was asymptomatic, and his physical examination was unremarkable. Given his 5 year history of secukinumab treatment and the potential impact of its discontinuation on anti-tumour immunity, alongside the risk of ICI-induced PsA flare with undesired usage of steroids,3 after the meeting with the multi-disciplinary team, the decision was made to continue secukinumab. Two weeks after the initial rheumatology evaluation, pembrolizumab was initiated. Four weeks after the first cycle of pembrolizumab, he developed neuritis-irAE that warranted intravenous immunoglobulins and plasmapheresis. At 4 and 7 months after the initiation of pembrolizumab, the patient developed PsA flares that were treated with a short course of prednisone while continuing secukinumab. At 10 months, the patient underwent bilateral knee replacements for his OA, and secukinumab was on hold while continuing low-dose prednisone (5 mg daily). At 20 months, secukinumab was resumed, and prednisone was tapered off at 32 months. The patient successfully completed pembrolizumab and proton therapy to the oesophageal metastases. At the last rheumatology clinic visit, 32 months after the initiation of pembrolizumab, his psoriatic arthritis was under control and melanoma was in remission (figure 1B).
(A) Clinical course of case 1. We defined the date of the first cycle of pembrolizumab as Day 0. Mets, metastasis; irAE, immune-related adverse events; PLEX, plasmapheresis; PsA, psoriatic arthritis; PtGA, patient global assessment (0–10); PGA, physician global assessment (0–10); Mo, month; Pembro, pembrolizumab; IVIg, intravenous immunoglobulin. (B) PET images at baseline and month 32. The oesophageal lesion at baseline (indicated by the arrow) was completed resolved at month 32.
Case 2
Our second case is a 47-year-old man with PsA and clear cell renal cell carcinoma (ccRCC). The patient was diagnosed with PsA in his 40s. Adalimumab was started, and his PsA was brought under control. However, 3 years later, he was diagnosed with left-sided ccRCC and treated with partial nephrectomy (figure 2A). Adalimumab was also discontinued. One month later, he was found to have metastases to the brain that were treated with radiation therapy. His cancer aggressively progressed despite of two tyrosine kinase inhibitor (TKI)-based regimens. Subsequently, he referred to the rheumatology clinic before starting pembrolizumab in combination with the TKI (axitinib). At his initial rheumatology evaluation, the patient did not exhibit active PsA symptoms, and physical exam was unremarkable. As his PsA was in remission, the decision was made to hold any immunosuppressive medications. One week later, pembrolizumab and axitinib were initiated. In month 7, he developed PsO as well as PsA flare. Given the aggressive nature of his ccRCC and negative impacts of steroids on ICI-efficacy,5 6 a steroid-sparing agent was warranted to minimise the use of steroids. From rheumatologic perspectives, since his PsO and PsA were both flared, disease-modifying antirheumatic drugs (DMARDs) were also indicated. Among the DMARDs for PsO/PsA,7 methotrexate and apremilast were relatively contraindicated due to his nephrectomy status. Janus kinase inhibitors (JAKi) were not preferred because of their potential negative impact on anti-tumour immunity. Subsequently, ixekizumab (160 mg subcutaneous once followed by 80 mg every 4 weeks subcutaneous) was initiated along with a short course of prednisone, while pembrolizumab and axitinib were continued. Two months later, he was found to have new brain metastases on routine monitoring. Given the persistently excellent extracranial control of the metastatic ccRCC, he remained on pembrolizumab, axitinib and ixekizumab while receiving gamma knife radiotherapy to the new brain lesions. At the most recent rheumatology clinic visit, 22 months after the initiation of pembrolizumab plus axitinib, his PsA remains well controlled with ixekizumab monotherapy. He continues his pembrolizumab and axitinib treatment. Most recent images demonstrated persistent response of the ccRCC with no evidence of recurrent brain metastases (figure 2B).
(A) Clinical course of case 2. We defined the date of the first cycle of pembrolizumab as Day 0. Mets, metastasis; PsA, psoriatic arthritis; PsO, psoriasis; PtGA, patient global assessment (0–10); PGA, physician global assessment (0–10); Mo, month. (B) CT images at baseline and month 26. Note the complete resolution of the hepatic and right gluteal lesions (indicated by arrows) and the stable lesion in the left acetabulum (indicated by the arrowhead) at month 26.
Case 3
Our third case is a 60-year-old male with PsA, metastatic ccRCC and remote history of melanoma status post excision and cryoablation in remission. The patient developed PsO in his late 30 s and developed inflammatory arthritis about 15 years later and was subsequently started on sulfasalazine. He was diagnosed with ccRCC at the age of 56 for which he underwent left partial nephrectomy (figure 3A). However, his cancer recurred three times, and he was considered for potential ICI therapy with the anti-CTLA-4 antibody (ipilimumab) in combination with the anti-PD-1 antibody (nivolumab). During the initial visit to the rheumatology clinic, he was asymptomatic, and his physical exam was unremarkable. The decision was made to continue sulfasalazine. On the same day, he had the first cycle of ipilimumab and nivolumab. The anti-IL-6 receptor antibody (tocilizumab) was added due to the patient’s history of melanoma and the potential synergic anti-cancer effects of tocilizumab when combined with ICI. Two weeks later, the patient was found to have transaminitis-irAE and thyroiditis-irAE. Tocilizumab was subsequently put on hold. After his transaminitis was resolved, tocilizumab was resumed. However, 1 month later, the patient developed PsA flare that required prednisone. In addition, tocilizumab was also discontinued for potential paradoxical PsA flare. As the patient had difficulty in tapering prednisone for PsA, 1 month later, a decision was made to initiate a DMARD. Like in our second case, methotrexate, apremilast and JAKi were not preferred due to either his nephrectomy status or potential abrogation of ICI efficacy. In addition, we were concerned about the risk of colitis-irAE associated with combined ICI therapy8 and the negative impact of IL-17i on colonic mucosa.9 Therefore, the anti-IL-23 antibody (guselkumab) was initiated (100 mg subcutaneous injection at weeks 0, 4 and then every 8 weeks). The patient responded well to guselkumab and was successfully tapered off prednisone over 3 months while being able to continue his ICI therapy. At the most recent rheumatology clinic visit, 10 months after the initiation of the ICI therapy, his PsA remains well controlled with guselkumab monotherapy. The patient continues his ICI treatment, and images revealed that his ccRCC is in remission (figure 3B).
(A) Clinical course of case 3. We defined the date of the first cycle of ipilimumab and nivolumab as day 0. Mets, metastasis; irAE, immune-related adverse events; PsA, psoriatic arthritis; PtGA, patient global assessment (0–10); PGA, physician global assessment (0–10); Mo, month. (B) CT images at baseline and month 15. The images show complete resolution of the lesion in the hilar region (indicated by the arrow).
Discussion
Although ICIs are revolutionising cancer treatment, they are also associated with life-/organ-threatening adverse events including de novo irAEs and flare of pre-existing ADs. It has been observed that up to 80% of PsO/PsA patients with cancer experience flare of their pre-existing PsO/PsA after ICI therapy.3 In this study, we reported three cases in which PsA was effectively managed with either an anti-IL-17A antibody or an anti-IL-23 antibody. Importantly, the ICI therapy was well tolerated and has produced durable long-term anti-tumoural responses (15, 26 and 32 months after initiation). Of note, a case with ICI-induced PsA successfully managed with IL-23i without compromise of anti-tumour efficacy has also been reported,10 supporting our observations. The role of the IL-23/IL-17 axis in cancer is controversial.11 IL-17 supports tumour growth by prompting tumour angiogenesis12 and activating IL-6/STAT3 pathway in tumour cells, a key pathway in cancer development and progression.13 Likewise, the genetic or pharmacologic depletion of IL-23 has been found to significantly mitigate tumour formation during chemical carcinogenesis by increasing the infiltration of cytotoxic T cells into tumours.14 In contrast, IL-17 assumes an anti-tumorigenic role by prompting cancer cells to secrete CC-chemokine ligand 20, which recruits CC-receptor six expressing dendritic cells (DCs) into the tumour sites.15 IL-17 also stimulates expression of CXC-chemokine ligand 9 (CXCL9) and CXCL10 on tumour cells, which attract anti-tumoral CD8 T cells and Th1 cells.16 Similarly, IL-23 overexpression by DCs, T cells or cancer cells has been shown to enhance anti-tumour immunity.17 Of note, contrary to our patients, a case with PsA and metastatic colon cancer, who lost tumour response to anti-PD-1 antibody with the initiation of anti-IL-17A antibody, has been reported.18 Taken together, clinical, translational and basic research are required to identify risk factors associated with the attenuation of ICI anti-tumour efficacy due to IL-23/17 inhibition.
Our first case had received secukinumab for 5 years before the initiation of ICIs. He experienced two flares, at 4 and 7 months after the initiation of pembrolizumab, suggesting that secukinumab might not have prophylactic benefits for PsA. Studies have shown that the levels of serum pro-inflammatory cytokines such as interferon gamma, IL-1β, IL-4, IL-5, IL-6, IL-8, GM-CSF and TNFα are increased after ICI therapy,19 20 which might have diminished the efficacy of secukinumab; however, this hypothesis needs to be proven. Clinically, our first case suggests that rheumatologists and oncologists should closely monitor co-existing autoimmune diseases regardless of the status of DMARDs before initiatiing ICIs. The prophylactic effects of pre-ICI DMARDs are a critical topic for future research.
Our study has several limitations. Given the limited number of cases, drawing definitive conclusions would be premature. Second, our cases were heterogenous in terms of primary cancer types, ICI regimen and PsA treatment before the ICIs. Third, due to the COVID-19 pandemic, their rheumatologic follow-ups were often conducted virtually, which kept us from assessing PsA disease activity through standard measurements.21 22 Lastly, in case 3, we cannot exclude the possibility that tocilizumab might have contributed to his durable anti-tumour efficacy.
As ICIs increasingly become therapeutic mainstays for multiple malignancies, clinicians will encounter challenging cases, including managing PsO/PsA during ICI therapy. Our case series suggests that targeting the IL-23/IL-17 axis could be a promising therapeutic strategy in this setting. However, with a small number of cases and the controversial role of the IL-23/IL-17 axis in cancer, we cannot make definitive conclusions at this moment. Future studies with larger numbers of patients, standardised measurement of PsO/PsA and concurrent analyses of the patients’ samples are warranted.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants. We inquired with our institution (MD Anderson) and were informed that case series are deemed 'not human subject research' and do not require IRB-approved protocols. Participants gave informed consent to participate in the study before taking part.
References
Footnotes
Contributors All authors were involved in the management of each case. YL and STK wrote the manuscript. All authors read, edit and approved the final manuscripts.
Funding This work was supported by NIH K08 grant (STK: K08AR079587), Rheumatology Research Foundation Fund (STK: 1012231) and the University of Texas MD Anderson Cancer Center (MDACC) Division of Internal Medicine IOTOX program (STK). PM was supported by the Andrew Sabin Family Foundation Fellowship, Gateway for Cancer Research, a Translational Research Partnership Award (KC200096P1) by the United States Department of Defense, an Advanced Discovery Award by the Kidney Cancer Association, a Translational Research Award by the V Foundation, the MD Anderson Physician-Scientist Award, as well as philanthropic donations by the family of Mike and Mary Allen.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.