A case of connective tissue disease-related interstitial lung disease following immune checkpoint inhibitor therapy: Lessons on managing rheumatology respiratory disorders in the context of comorbidity.
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All Authors
Sharrack, S.
Harnden, K.
Sugden, H.-J.
Howell, K.
Horgan, L.
Bradley, J.
Mankia, K.
LTHT Author
Sharrack, Sana
Mankia, Kulveer
Howell, Keith
Bradley, Jessica
Mankia, Kulveer
Howell, Keith
Bradley, Jessica
LTHT Department
Rheumatology
NIHR Leeds Biomedical Research Centre
Oncology
Leeds Cancer Centre
Cardio-Respiratory
Respiratory Medicine
Interstitial Lung Disease Service
NIHR Leeds Biomedical Research Centre
Oncology
Leeds Cancer Centre
Cardio-Respiratory
Respiratory Medicine
Interstitial Lung Disease Service
Non Medic
Publication Date
2025
Item Type
Conference Abstract
Language
Subject
Subject Headings
Abstract
Introduction: Immune checkpoint inhibitors (ICIs) have revolutionised cancer treatment over the past decade and have been increasingly used in cancer management. They work by preventing cancer cells from hijacking immune tolerance pathways. However, due to this immune system activation, immune-related adverse events (irAEs) frequently occur and can range from mild to life-threatening. ICI-induced or accelerated connective tissue diseases (CTDs) and their associated manifestations are rarely reported in the literature. We present what we believe may be the first case of ICI-induced CTD-ILD in a young female patient with metastatic melanoma and discuss the challenging diagnostic and management decisions we faced. Case description: An otherwise fit and well 38-year-old Caucasian female presented to her general practitioner with a two-month history of right upper quadrant pain. She had a significant past medical history of double mastectomies and a bilateral salpingo-oophorectomy at the age of 29 for BRCA1 mutation. She was a non-smoker and had no family history of autoimmune disease. Initial investigations including an ultrasound scan of the abdomen and upper and lower endoscopic examinations were normal, but computed tomography (CT) imaging identified an indeterminate 5cm left adrenal mass. Biopsy confirmed malignant melanoma and subsequent positron emission tomography-computed tomography (PET-CT) imaging revealed widespread disease, with no primary lesion identified. The patient was commenced on combination ipilimumab and nivolumab immunotherapy three-weekly. After the second dose of immunotherapy, the patient developed new onset pain, stiffness and swelling of the small joints of her hands and was referred to the regional ICI-induced joint toxicity service for suspected ICI-induced inflammatory arthritis. On review, the patient described clear inflammatory joint symptoms. On further questioning, the patient described Raynaud's symptoms since commencing immunotherapy but had no other CTD or respiratory symptoms. On examination, she had synovitis of several of the small joints of the hands, and clear evidence of Raynaud's stigmata (including thumb cracking). She also had fine inspiratory crackles bi-basally. Cardiac and neurological examinations were normal and there was no rash. Initial investigations revealed ANA (via Bioplex) and anti-Ro 52 antibody positivity with a slightly elevated creatine kinase (454 IU/L). Serial cross-sectional chest imaging since initiation of immunotherapy showed rapidly progressive fibrotic lung changes, predominantly in the lower lobes but grossly normal PFTs. Whole body multi-joint MRI, conducted as part of a research study, revealed significant synovitis of several joints and myofascial inflammation in the pelvis. ICI-induced CTD was considered, and immunosuppressive treatment offered (steroid in the first instance), but not commenced, following patient-centred informed decision making (lack of chest symptoms and risk of negatively affecting cancer outcome). Discussion(s): This patient's rapidly progressive (over weeks) fibrotic lung changes prompted referral to the local ILD multi-disciplinary team (MDT), where differentials of immunotherapy-induced pneumonitis versus ICI-induced/accelerated CTD-ILD were discussed. Interestingly, it was identified that our patient had very subtle basal lung changes even at cancer diagnosis (pre-ICI), raising the possibility that the patient may have had very early CTD features even before initiation of ICI that were simply accelerated by the immunotherapy. Serology was undertaken for the first time only after she was seen by respiratory and rheumatology, so no pre-immunotherapy antibody results were available. Trying to manage significant autoimmune disease that would require immunosuppressive treatment, in the context of active, aggressive and metastatic cancer, where immunosuppression could be detrimental to patient outcome and survival, was extremely challenging. Our patient had strong views and anxieties surrounding ICI cessation and immunosuppression initiation which could have the potential to negatively influence her cancer outcome. We worked closely with our oncology and respiratory colleagues through multiple inter-specialty and even cross-hospital MDT meetings, in order to provide an optimal management plan for this patient. Ultimately, given our patient had no respiratory symptoms and a strong preference to prioritise her cancer treatment, we decided to continue ICI and monitor lung function closely with the understanding that ICI cessation and immunosuppression initiation may need to be reconsidered if the clinical picture changed. This case is interesting and relevant because it highlights two common challenges we as rheumatologists are increasingly facing in today's world: (i) diagnostic uncertainty in the context of new and emerging treatments and (ii) weighing up benefits and risks of immunosuppressive treatment in the context of increasing comorbidity, including cancer. Key learning points: There are several learning points from this case. Firstly, it demonstrates how complex some of the patients we need to manage as rheumatologists can be. With the increasing discovery of novel and complex immune-modulating treatments such as ICIs, we are encountering situations that historically rheumatologists may not have encountered. As a result, it becomes very important to share knowledge about rare and important cases with the wider rheumatology community (e.g. through such case-based conferences!), especially with the rise in cancer worldwide and the increasing use of ICIs for multiple cancer indications. The case also reiterates the diagnostic uncertainty that we commonly face as rheumatologists, and the importance of inter-specialty working. In this case, we relied heavily on discussions and expertise from our oncology and respiratory colleagues to ensure we interpreted investigation results appropriately and came to a unanimous decision regarding this patient's management. Finally, this case demonstrates the importance of involving patients in decision making about their care. This patient was very clear that she wanted to prioritise her cancer treatment above everything else, even if it meant risking worsening CTD-ILD to the extent that it would cause her significant breathlessness even on minimal exertion (that could be life-threatening). As doctors, we need to make sure our clinical decisions are in our patients' best interests and first do no harm. However, at the same time, we also need to make sure that patients have some control over their long-term outcomes - every patient's priority is different. At the conference, I hope to learn more about managing rheumatology respiratory disorders in the context of comorbidities such as cancer and infection. I would like to hear expert speakers' opinions on how to tackle diagnostic uncertainty in the face of novel treatments and pathologies, and how best to make challenging inter-specialty decisions on management.
Journal
Rheumatology Advances in Practice