JAK inhibitors for the treatment of life-threatening and refractory immune-related adverse events secondary to immune checkpoint inhibitors: a prospective cohort study
Bibliographic record
Abstract
BACKGROUND: Immune checkpoint inhibitors have revolutionized cancer treatment but can induce immune-related adverse events (irAEs), which are sometimes severe, life-threatening, or refractory to corticosteroids. Current management is largely empirical and adapted from autoimmune disease protocols. Dysregulation of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway has been implicated in irAE pathogenesis, positioning JAK inhibitors (JAKi) as potential therapeutic agents. We hypothesized that JAKi may offer therapeutic benefit in treating corticosteroid-refractory or life-threatening irAEs. METHODS: We conducted a prospective cohort study at the Jewish General Hospital (Montreal, Canada) within the Montreal Immune-Related Adverse Events biobank, enrolling patients who developed grade ≥3 or persistent grade 2 irAEs unresponsive to corticosteroids or life-threatening irAEs requiring urgent intervention. RESULTS: 29 patients received JAKi; 5 were excluded due to death within 30 days of initiation, leaving 24 evaluable patients (median age 69 years; 37.5% female). The majority received anti-programmed cell death protein-1 (PD-1) monotherapy (79.2%), with some receiving combination anti-cytotoxic T-lymphocyte antigen-4/PD-1 therapy (16.7%). Indications for JAKi use included myocarditis (n=8), arthritis (n=4), colitis (n=3), hepatitis (n=3), encephalitis (n=2), pneumonitis (n=2), myasthenia gravis (n=1), and sicca syndrome (n=1). JAKi were employed as second-line therapy in 7 patients, third-line in 11, and fourth-line or later in 6. Clinical response, defined as irAE resolution to grade ≤1 while on ≤10 mg prednisone equivalent without relapse for ≥30 days, was observed in 17 patients (70.8%), with median time to resolution of 41 days. Response rates were highest for myocarditis (75%) and arthritis (100%). No opportunistic infections or JAKi-related hepatotoxicity occurred; thrombotic events were identified in three individuals (10.3%). CONCLUSIONS: These findings suggest that JAKi are a promising, well-tolerated option for managing corticosteroid-refractory or life-threatening irAEs. Further randomized studies are warranted to confirm their efficacy and safety in this setting.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".