Clinical presentation of immune checkpoint inhibitor-induced inflammatory arthritis differs by immunotherapy regimen

https://doi.org/10.1016/j.semarthrit.2018.02.011Get rights and content

Abstract

Introduction

Immune checkpoint inhibitors (ICIs) are a class of cancer immunotherapy, increasingly utilized to treat malignancies. Inflammatory arthritis (IA) is a potential consequence of ICI use, but there is limited information to guide evaluation and management of this immune-related adverse event (irAE). This study aimed to characterize clinical phenotypes, IA treatment and response in the largest cohort of patients with ICI-induced IA reported to date.

Methods

Patients with rheumatologist-confirmed IA occurring during or after ICI treatment with no prior history of autoimmune disease were included. Data were analyzed by ICI treatment regimen; treatments included combination CTLA-4/PD-1 inhibition, anti-PD-1 or anti-PD-L1 monotherapy. Relationship to the development of other irAEs, management of IA, and outcomes of IA management were evaluated.

Results

Of 30 patients identified, those treated with combination ICI therapy were more likely to present with knee arthritis, to have higher levels of C-reactive protein, to have already had another irAE, and to have a reactive arthritis-like phenotype. In contrast, patients treated with ICI monotherapy were more likely to have initial small joint involvement and to have IA as their only irAE. Ten patients required additional immunosuppression beyond corticosteroids, with TNF-inhibitors and/or methotrexate. Tumor progression while on non-corticosteroid immunosuppression was not seen in those with initial tumor response to ICIs.

Conclusion

These data suggest that distinct IA phenotypes may emerge with exposure to different ICI regimens. The majority of patients referred to rheumatology required systemic immunosuppression to manage their IA symptoms. Tumor progression was not seen in patients requiring TNF-inhibitors.

Introduction

Immune checkpoint inhibitors (ICIs), used in the treatment of advanced stage cancers, have revolutionized the field of oncology. They act by blocking negative co-stimulatory molecules on T cells, antigen presenting cells, and tumor cells [1]. The blockade of these inhibitory molecules allows for unchecked T cell activation and a subsequent immune response targeting tumors. There are currently six FDA-approved ICIs targeting cytotoxic lymphocyte antigen 4 (CTLA-4: ipilimumab), programmed cell death protein 1 (PD-1: nivolumab, pembrolizumab), or programmed death ligand 1 (PD-L1: atezolizumab, durvalumab, avelumab) for an ever increasing range of indications and with many more ICI agents in development.

The growing use of ICIs has created a new and increasing population of patients referred to rheumatology for management of immune-related adverse events (irAEs). Immune-related AEs broadly refer to inflammatory or immune-mediated off-target tissue effects that occur as a result of ICI use. These toxicities may involve nearly every organ system, and range widely in severity and management requirements [2]. Rheumatologic irAEs have been described in case series and reports including inflammatory arthritis (IA), sicca syndrome, myositis, vasculitis, and polymyalgia rheumatic [3], [4], [5]. Epidemiologic data, such as the incidence of rheumatologic irAEs, is lacking, but IA appears to be the most common type of rheumatologic event [6], [7].

Although well established guidelines exist for management of irAEs like colitis and pneumonitis, there have been only preliminary recommendations for evaluating and treating ICI-induced IA [8], [9]. This may stem from a lack of consistent reporting of rheumatologic irAEs in clinical trials, the non-life threatening nature of IA, or a lack of recognition of musculoskeletal symptoms by treating providers. The rate of arthralgia reported in clinical trials in agents targeting CTLA-4, PD-1, or PD-L1 has ranged from 1% to 43% [6], but no accurate estimates exist for the incidence of IA. The requirement of immunosuppression for treatment of ICI-induced IA has been documented in case series of 12 or fewer [3], [4], [10], [11] as have the unique clinical features of ICI-induced IA, including a group of patients with a clinical phenotype similar to reactive arthritis [4]. Treating patients for ICI-induced IA is complicated by their history of active or recently treated cancer and concerns of using immunosuppression in the context of ICI therapy, especially given the lack of published evidence on long-term outcomes.

With this study, we aim to characterize the presentation and longitudinal course for a cohort of patients with the novel rheumatologic entity, ICI-induced IA. Specifically, we evaluated the detailed clinical presentations of ICI-induced IA, whether these phenotypes differed by ICI regimen, long-term outcomes including persistence of arthritis, and possible effects of anti-rheumatic drugs on tumor progression.

Section snippets

Patients

Patients in this retrospective longitudinal cohort study were seen for clinical care in the Johns Hopkins Division of Rheumatology. They were included if they were age 18 or older and were treated for any malignancy with either anti-PD-1 or anti-PD-L1 monotherapy, or combination immunotherapy with anti-PD-1/CTLA-4. No patients with arthritis from anti-CTLA-4 monotherapy were referred. All patients underwent comprehensive rheumatologic evaluation and had rheumatologist confirmed IA as determined

Patient demographic features, oncologic history and family history

Thirty patients with ICI induced IA were included. Patients had a median age of 59 years (range: 36–83) and 40% were female (Table 1). Tumor types included metastatic melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), Hodgkin or cutaneous lymphoma, renal cell carcinoma (RCC), duodenal carcinoma, Merkel cell carcinoma, basal cell carcinoma of the skin, and squamous cell carcinoma of the skin. Sixteen patients were treated with anti-PD-1/PD-L1

Discussion

In this retrospective cohort study, the clinical features of patients with ICI-induced IA differed by the ICI regimen used to treat their cancers. Specifically, combination therapy was associated with higher levels of CRP and higher likelihood of having a large joint affected first in the arthritis course. All instances of reactive arthritis-like presentation were also in the combination therapy group and were noted in patients who had previously had colitis. Patients on PD-1 or PD-L1

References (18)

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Funding: Financial support provided by the National Institute of Arthritis and Musculoskeletal and Skin Disease (K23-AR061439, P30-AR070254) and the Jerome L. Greene Foundation (Scholar Award, Discovery Award).

Financial interests: L.C.C. received research funding from Bristol-Myers Squibb. J.R.B. has received research funding from Bristol-Myers Squibb, Medimmune/AstraZeneca and Merck and has consulted for Bristol-Myers Squibb, Celgene, Eli Lilly and Merck. P.M.F. has received research funding from Bristol-Myers Squibb, Medimmune/AstraZeneca, Novartis and Kyowa and has served as an uncompensated consultant for Bristol-Myers Squibb, Medimmune/AstraZeneca, Novartis, Merck, EMD Serono, and Eli Lilly. D.T.L. has served on advisory boards for Merck and Bristol-Myers Squibb and received speaking honoraria from Merck. E.J.L. has received research funding from Bristol-Myers Squibb and Merck and has served as a consultant for Bristol-Myers Squibb, EMD Serono, Merck, and Novartis. J.N. has received research funding from Merck and Astra Zeneca/Medimmune, served as a consultant for Bristol-Myers Squibb and Astra Zeneca/Medimmune, and received honoraria from Bristol-Myers Squibb, Astra Zeneca/Medimmune and Takeda. L.Z. has received research funding from Bristol-Myers Squibb and Merck. C.O.B. has received research funding and served as a consultant for Bristol-Myers Squibb. AAS has served as a consultant for Bristol-Myers Squibb.

1

Both authors contributed equally to the manuscript.

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