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INTRODUCTION: Immune checkpoint inhibitors are a new form of immunotherapy that has transformed the treatment landscape for an ever-increasing number of malignancies. While these medications utilize and enhance the immune system to treat malignancies, they can also have significant side effects, termed immune related adverse events, that in many ways resemble autoimmune disease states. One such example is inflammatory arthritis, which has been found to resemble a number of different presentations, including rheumatoid arthritis and seronegative spondyloarthropathies. In addition to these traditional inflammatory arthritis phenotypes, worsening of pre-existing arthritis is another subgroup of inflammatory arthritis that has previously not been considered in this population. Furthermore, while the effects of these autoimmune arthropathies on functionality is well-documented, it is not known whether there is a significant effect on functionality in patients that experience immune checkpoint inhibitor-induced arthritis. Given that patient reported outcomes are a validated and routinely utilized measure of functionality and quality of life, the Health Assessment Questionnaire, pain visual analogue scale and Patient Global Assessment were used to measure these outcomes following diagnosis. Our aim here is to explore the subtypes of inflammatory arthritis that result from this type of treatment and its overall effect on functionality and quality of life. METHODS: This study was a retrospective review of patients at one academic center who experienced an inflammatory arthritis resulting from immune checkpoint inhibition and required a referral to a rheumatologist for further work-up. Patients were evaluated in clinic at which time they also completed a Health Assessment Questionnaire as part of standard of care. Once patients were evaluated, their inflammatory arthritis was classified based on which clinical arthritis that it matched most closely, including polymyalgia rheumatica, rheumatoid arthritis, seronegative spondyloarthritis, or an exacerbation or osteoarthritis. Other demographic information such as gender, age, and race were also collected. Patient questionnaires were scored and compared to the type of inflammatory arthritis to assess for any correlations. RESULTS: We found 30 patients that had an inflammatory arthritis resulting from immune checkpoint inhibition, with 12 having a polyarthritis similar to rheumatoid arthritis, 11 patients having osteoarthritis exacerbation, 4 patients with a polymyalgia rheumatica arthritis phenotype and 3 patients with a spondyloarthopathy. In terms of the patient reported outcomes, the overall score was 0.57 ± 0.47, indicating that there was little effect of these arthropathies on overall functionality. The pain visual analogue scale had an average score of 41.8 ± 31.4 mm and the Patient Global Assessment had an overall score of 25.6 ± 26.7 mm. DISCUSSION: The overall results suggest that the inflammatory arthritis phenotypes do not significantly impact the functionality or quality of life of most patients who experience this side effect. Given that the use of immune checkpoint inhibitors will continue to grow, the overall need to better understand the resulting arthritis presentations is key. This is perhaps most true for those with pre-existing osteoarthritis, given the widespread nature of the disease in the general population and the prominence of the exacerbation as seen in our cohort.

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Immunotherapy has emerged as one of the four “standard” cancer therapies, alongside surgery, chemotherapy, and radiotherapy. Immune checkpoint inhibitor (ICI) therapy is an immunotherapy that blocks inhibitory immune checkpoint interactions, allowing T cells and other immune cells to kill tumor cells. In the tumor microenvironment, there is often overexpression of immune checkpoint proteins, whose binding interaction with cytotoxic T cells and other immune cells results in the dampening of the antitumor response. Programmed cell death protein 1 (PD-1) and T-lymphocyte-associated protein 4 (CTLA-4) are the two most targeted immune checkpoint proteins. Antibodies against PD-1 and CTLA-4, as well as other checkpoint proteins, are approved for clinical use as well as in clinical trials. While ICIs have changed the treatment landscape for many cancers, particularly those with significant immunogenicity, only 20-40% of patients respond to ICI therapy. Many factors are behind the lack of response and resistance, and significant efforts are aimed at improving the response to ICI therapy. One major area is modulating the gut microbiome, as it is well-established that microbial dysbiosis is associated with various human diseases. The concept is that by modulating the microbiome, we might be able to return it to a composition more similar to that seen in healthy individuals or provide microorganisms beneficial to clinical response. In the case of ICI therapy, it is proposed that there is a connection between certain microbial species and the immune system via metabolites and other signaling effects. The microbiome can be manipulated through many methods, including fecal microbiota transplantation (FMT), transferring bacterial isolates or consortia, probiotics, antibiotics, and soluble dietary fiber. For clinical insights, it is important to consider how the pre-treatment microbiome of patients may affect their response to ICI therapy, as well as how their microbiomes can be manipulated to enhance their response. Initial clinical trials have been promising, but this is an emerging field with additional work to be done. Particularly, a better understanding of the microorganisms involved in the response to ICI therapy and the mechanism by which they communicate with the immune system is essential. Future studies will need to be much larger to reduce noise between studies and to allow for emerging computational techniques to be applied.

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Background: Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising. Materials and Methods: Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable. Results: PD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS. Conclusion: High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.