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Background: Rheumatologists are well versed with T cell co-stimulation with abatacept, a CTLA-4 inhibitor being a licenced therapy for Rheumatoid Arthritis, Psoriatic Arthritis and Juvenile Idiopathic Arthritis. Since the first in vivo evidence of CTLA-4 upregulation for cancer therapy in 1996 molecules involved in T cell cross-talk: termed ‘checkpoint inhibitors’, are now used to treat a variety of cancers. 11 checkpoint inhibitors have received FDA approval for use across 13 different organ systems.There are an increasing number of adverse events from CPI use amongst various organ systems with common examples being colitis, myocarditis, myositis and arthritis. Corticosteroids, Interleukin-6 (IL-6)and Tumour necrosis factor (TNF) inhibitors have been widely used to manage such immune reactions.
Objectives: There is emerging evidence for the use of Janus Kinase Inhibitors (JAKi) in these situations. The role of JAK inhibitors in immune mediated adverse events (irAE’s) were not included in either the EULAR 2021 guidance on the management of rheumatic immune-related adverse events from CPI’s or the society of immunotherapy of cancer (STIC) guidelines on this topic. We aim to describe the role of JAKi for the management of irAE’s with a review of case reports/series including the use of JAKi in this area.
Methods: Pubmed, EMBASE and MEDLINE searches were performed from inception till 01 September 2024 for case reports/series of the use of JAK inhibitors to treat checkpoint inhibitor induced immune adverse events. The four EMA licenced JAK inhibitors (Tofacitinib, Baritinib, Upadacitinib and Filgotinib) were included in addition to Peficitinib. The checkpoint inhibitors that were included within the search were Ipilumab, Tremeliumab, Nivolumab, Pemrbolizumab, Atezolizumab, Avelumab, Durvalumab, Cempilumab and Dostraliumab.
Results: Published Case reports, case series and cohort data included 80 patients. The characteristics of the included patients are shown in Table 1. 64% were male and the average median age was 65.5 years (IQR 58-71). Most patients (95%) received tofacitinib, of which 53/76 (70%) patients received 5mg twice a day, 20% received 5mg four times a day, and 20% received a different regimen (e.g. 10mg BD). 3 (4%) of patients received baricitinib whilst 1 (1%) patient received 15mg Upadacitinib daily. No reports included either filgotinib or peficitinib use. Pembrolizumab monotherapy represented the most common ICI therapeutic choice, given to 9 (11%) patients, with other patients receiving ipilimumab/nivolimuman (5%), cambrelizumab (8%) and sintilimab (3%). Notably, one cohort study, involving 53 patients did not explicitly state the nature of ICI, with 46/53 (87%) patients in this study receiving an unspecified anti-PD-1 treatment. The primary cancer for which patients were receiving ICI varied, with the most common diagnoses being gastric cancer (23%), followed by lung cancer (19%) and hepatic cancer (13%). The frequency of other cancer diagnoses are shown in Table 1. The indication for JAK inhibitor therapy for irAE’s was predominantly myocarditis (78%), followed by myositis (38%) and hepatitis (28%). Other less common irAEs included colitis (9%), thyroiditis (9%) and those affecting the nervous system (8%) and skin (8%). Prior to commencement of a JAK inhibitor, most patients received corticosteroid therapy (99%). Across all patients, 41 (51%) patients received intravenous immunoglobulin (IVIG) with small proportion of patients receiving infliximab (8%) and/or vedolizumab (5%). Following JAKi, 66% of patients achieved remission of their irAE, and an additional 18% experienced clinical improvements. Notably, 7 (9%) of patients died due to progression of their irAE, despite initation of JAKi. Time to symptom resolution after starting JAK inhibitor therapy was only reported across 16 patients (20%). Across these patients, the median time to improvement and/or remission of irAE was 28 days (IQR: 16-37.5). Regarding adverse outcomes associated with JAKi initiation, 7 (9%) experienced infection-related adverse events, including 3(4%) patients developing pneumonia. No adverse events linked to JAKi were reported for the majority of patients (90%). Data on oncological outcomes was not widely available, however, tumour progression was observed in 36 (45%) of patients, with 9 (11%) remaining in remission. Across all patients, 3 (4%) died due to progression of their cancer.
Conclusion: Using case reports and series data, we demonstrated that JAK inhibitors are an effective modality in the management of immune checkpoint inhibitor associated adverse events, and appear well tolerated. Although current international guidelines provide limited direction on the use of JAK inhibitors in irAE, it is worth questioning whether the absence of extensive evidence truly equates to a lack of efficacy or safety data. Although clinical trials are needed to answer this, there is some reassuring evidence in case reports JAK inhibitors have a potential role in the treatment paradigm for irAE’s as demonstrated by the evidence from case reports in this review. Due to heterogenicity of irAE’s and ethical considerations, it is unlikely that randomised controlled trials for this particular disease area will ever occur. Where exactly JAK inhibitors fit in the treatment ladder and whether they should be used before the use of TNF inhibitors is yet to be determined.
REFERENCES: [1] Gossec L, Kerschbaumer A, Ferreira RJO, et al. EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2023 update. Ann Rheum Dis 2024; 83(6): 706-19.
Acknowledgements: NIL.
Disclosure of Interests: None declared.
© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (