Case report
Patient’s perspective
Learning points
In January 2018, I was on holiday in Austria with my wife for a week enjoying the beautiful scenery, fresh air and good food after a hectic Christmas…life was good and my wife and I were both enjoying our lives with very few worries. During our holiday we decided to take a day trip to Salzburg and took a coach to the city that morning little did I know that on this day my whole life would change forever. On the morning of arriving to Salzburg I began to get a numbing sensation on my right side and thankfully my wife got me to a hospital pretty quickly, I was taken for a MRI scan of the brain thinking I might be having a stroke but when the results came back I was diagnosed with a cancerous tumour in the brain and the doctors wanted to know where the cancer started and with some more tests it showed up in the right lung. I was diagnosed with non-small cell carcinoma of the right lung with brain metastases, a very frightening prognosis for me. I returned to Ireland and was under the guidance of the oncology team. I started radiotherapy to the tumour in the brain and right lung in early March of 2018 and after a biopsy of the lung I got the good news that I was eligible to receive the new immunotherapy treatment - Pembrolizumab, this news gave me a lot of hope during these frightening times as I was aware of the good results that were coming from patients on it. I started this treatment in May 2018 and over the next few months things were going really well for me, I was responding to the treatment really well and thankfully the cancer was not spreading. After several immunotherapy treatments, however I began to notice my right knee swelling up with fluid and causing me acute pain. As time went on I had to get my right knee drained a few times to relieve the discomfort and not long after my left knee started to swell as well and the pain was so bad that at times I was unable to walk. I felt really low during this time, I noticed soon after, the joints in my hands and elbows were stiffening and swelling and I found it hard to bend them, the pain was indescribable, usually I have a strong resistance to pain but this really affected me deeply and I felt I was losing the fight. It was at this point that my oncologist stopped all treatments for the cancer and referred me to a and his to a rheumatologist to do a more in-depth study of the side effects from Pembrolizumab. The rheumatology team did a biopsy to my right knee and I was diagnosed with Inflammatory Arthritis. I felt a glimmer of hope knowing I was under a superb team. With this diagnosis I started on methotrexate, and tofacitinib and my progress was monitored closely. Over the next few months on these drugs I was responding really well, swelling was reducing, movement was returning and I could walk again without an aid. The methotrexate was reduced substantially and I am now on only a small dose along with tofacitinib. I can happily say that over the last few months my life has returned to a form of normality that I probably could have only dreamed of in early 2018 but thanks to the amazing immunotherapy drug Pembrolizumab that has put my cancer under control and thankfully I have not received treatment since mid 2019 and of course the rheumatoid drugs, I can exercise again, work again and enjoy my life with my wife again. I cannot thank my consultants enough, they have given me hope and a new lease of life that I cherish so much now. Thank you to all the amazing medical staff I owe my life to.
examined 13 721 patients on ICI for a range of malignancies. 4 They demonstrated a significant survival benefit for immuno- therapy compared with other systemic therapies (HR, 0.75, 95%CI, 0.70 to 0.81; p<0.001; I2=61%). 4 ICIs can trigger inflammation in almost any organ. Indeed, ICI- induced colitis, pneumonitis, hepatitis, neurotoxicity, hypophysitis and myocarditis can cause mortality. 3 4 T-cell antibody and cytokine responses appear to contribute to the disruption of immune homeo- stasis and irAEs linked with ICIs. 3 The PD-1 pathway regulates thymic T cell development and provides an activation threshold for T cell receptor (TCR) mediated signals. 8 Several studies have demon- strated the key role of PD-1 in regulating autoreactive T cell response in the periphery by limiting activation and proliferation of autoreac- tive T cells. 9 Different ICIs are associated with specific irAEs, colitis and hypophysitis are more frequent with CTLA-4 inhibition and pneumonitis and thyroiditis more frequent with PD-1 inhibitors. 3 The mechanisms underlying the aforementioned distinction remain elusive, therefore further characterisation of the immune response in patients receiving ICIs will be crucial in minimising irAEs prevalence in the future. Inflammatory arthritis is characterised by immune cell infiltra- tion, activation leading to synovial hyperplasia, with subsequent joint destruction and disability. 10 We have recently reported increased levels of PD-1 in the serum and synovial tissue of RA patients, with down-regulation of its ligand PD-L1 preventing overactivity of the PD-1 pathway. 11 In this patient, PD-L1 inhibition triggered arthritis, as evident at both the clinical, macroscopic and microscopic level. This was further confirmed following single cell analysis of synovial tissue which showed an increase in immune cell infiltrates in the joint, particularly polyfunctional T cells and pathogenic Tfh cells, with defects observed for Treg phenotypes also. There remain no RCTs to determine the optimal treatment for ICI-induced synovitis. Evidence for methotrexate, Non-steroidal anti-inflammatory drugs (NSAIDs), prednisolone, Tumour Necrosis Factor (TNF) blockade, and interleukin-6 (IL-6) inhibition is limited to small, uncontrolled case series. 12 13 The recently published ‘EULAR points to consider’ provides significant clarity and a stepwise symptomatic treatment approach using glucocorticoids, conven- tional synthetic disease-modifying antirheumatic drugs and biologic agents. 14 However, some patients will not respond to these therapies or experience significant adverse effects thus, other treatment strategies do need to be explored. We and others have previously shown tofacitinib to regulate synovial inflammation and cellular metabolism in inflammatory arthritis. 15 16 Janus kinase/signal transducer and activator of transcription (JAK/STAT) blockade regulates pro-inflammatory responses, invasive mechanisms and cellular bioenergetics that we and others have shown to be highly pathogenic. 17 18 Furthermore, ► ► Immune checkpoint inhibitors (ICIs) have transformed the outcomes of many cancers. ► ► Inflammatory adverse reactions including arthritis do occur and may be debilitating in some patients. ► ► Conventional therapies, including steroids, may not provide significant benefit. ► ► Small molecular inhibitors of the JAK/STAT pathway such as tofacitinib, as in this case, may provide swift and sustained remission from inflammatory arthritis associated with ICI treatment.
DISCUSSION ICI have dramatically improved prognosis in many cancers through manipulation of T-cell pathways involved in cellular activation/deactivation. A 2018 meta-analysis of 23 RCT
Murray K, et al . BMJ Case Rep 2021; 14 :e238851. doi:10.1136/bcr-2020-238851
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